Block 2

Where does cholesterol come from?

~80% of the cholesterol needed to carry out the physiological functions comes from biosynthesis. The rest comes from the diet. It is recommended that the daily cholesterol consumption should not exceed 200 mg.

Where is cholesterol synthesized and where is it the most abundant?

Cholesterol is synthesized on ER, but it is most abundant in the plasma membrane.

What are some other reactions of molecules in the TCA cycle?

Citrate- Cholesterol, fatty acids Alpha-ketoglutarate- glutamate, other AA, purines Succinyl CoA- Heme, cholorphyll Oxaloacetate- Aspartate, other AA, purines, pyrimidines

What are some sources of ROS

Coenzyme Q (CoQ) Oxidases, oxygenases, Peroxidases Ionizing radiation

What is NAD+ and where does it come from?

Coenzyme that comes from niacin

Where does the pentose phosphate pathway occur?

Cytosol in erythrocytes, liver, mammary gland, testes and the adrenal cortex

Where does omega oxidation occur?

ER of many tissues such as the liver and kidney

What vitamin deficiencies can affect the TCA cycle.

Niacin (vitamin B3) Riboflavin (vitamin B2) Thiamine (vitamin B1) Pantothenate (vitamin B5)

What type of amino acid is alanine and what are its abbreviations?

Non-polar, Ala, A

What type of amino acid is valine and what are its abbreviations?

Nonpolar, Val, V

What type of amino acid is phenylalanine and what are its abbreviations?

Nonpolar/Aromatic, Phe, F (Fenylalanine)

What is the name for vitamin B5 and what does it do?

Pantothenic Acid Combination Pantoic acid + beta-Alanine Precursor in coenzyme A (coA) synthesis

What is alcaptonuria?

"Black bone" or "black urine" disease Disorder: Defect in homogentisate dioxygenase (HGD in Tyr degradation pathway); leads to accumulation of homogentisate in tissues, bone, urine. Homogentisate turns black upon oxidation; urine turns black after exposure to air; dark pigmentation seen in cartilage, bone, sclera. Can lead to arthritis, stones, damage to heart valves (calcification). The accumulating homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves, as well as precipitating as kidney stones and stones in other organs

Describe dense CT

"Dense" CT= Cells/Ground Substance/Fibers-Mostly fibers (collagen) Regular - Fibers arranged in orderly parallel bundles. Tendons, Ligaments, Cornea Transmit force of muscle contraction Attach muscles to bones Protection Tension Irregular - Fibers arranged randomly Skin, GI tract Provide tensile strength Protection

What is the function of the connective tissue?

'Function of CT is reflected in types of cells and fibers present within the CT of structures and the composition of the ground substance in the ECM' Support: Providing Support and Connections e.g. Tendons and Ligaments Defense: The site of inflammatory and immune reactions Physical barrier Nutrition: Reservoir for water and electrolytes Stores energy in the form triglycerides (adipocytes) Support blood vessels Passageway for nutrients and gases

What is the nerst equation?

(-61mV/z)*(log(Cin/Cout)) The Nernst equation follows from the statement of the equality of the electrochemical potential of an ion on both sides of a membrane (It's just a rearrangement of the equation). The Nernst equation is used to calculate the membrane potential where the electrochemical potential of an ion will be the same on both sides of a membrane with the given concentrations. In other words, the voltage where the ion is at equilibrium. The Nernst potential (equilibrium potential) for an ion is called Eion , for example, EK or ENa

What is a genome?

(1) All the genetic information necessary to make another copy of an organism. (2) The total set of different DNA* molecules of an organelle, cell or organism. •i.e.: the human genome consists of 3 x 109 bp divided in 25 distinct DNA molecules including the mitochondrial DNA molecule plus 24 different chromosomal DNA molecules (A cell of a man has 25 distinct DNA molecules while the cell of a woman has 24 different molecules.) *The genome in some viruses is RNA.

What are the definitions of genes?

(1) Classical definition: A factor that controls a phenotype and segregates in pedigrees according to Mendel's laws (cannot fully describe many genes) (2) Genes are segments of chromosomes that encode proteins, tRNAs, rRNAs, or types of small RNAs involved in regulation of gene expression (3) A gene is a unit of genomic sequences encoding a coherent set of overlapping functions (Gerstein et al., 2007 Genome Research 669).

What are the functions and localizations of beta 2 receptors?

**Mainly bronchodilation Vasodilation in some arteries including those in skeletal muscle and in the coronary system **Decrease in peripheral resistance (SVR) drop in diastolic blood pressure Activate lipolysis and fatty acid release Increases gluconeogenisis and insulin release, causes hypokalemia, increases aqueous humor production Uterine & bladder muscle relaxation, ⬇ GI motility ⬇ renin release, ⬇ mast cell histamine release Gs increases cAMP which causes the activation of protein kinase A and RELAXES smooth muscle Arterioles of heart, lung & skeletal muscle, bronchi, uterus, liver & skeletal muscle; pre- and post-synaptic

What are the 3 major phases to a twitch contraction?

- Latent Period This is the period of time from the action potential to the onset of contraction. The time delay is due to the excitation-contraction coupling. - Contraction Phase This is the time that tension is developing due to the cross-bridge cycling. - Relaxation Phase This is the time that the tension is decreasing (i.e., relaxing) and is longer than the contraction phase. This is due to the amount of time it takes to get all the Ca2+ sequestered.

What are the functions of proteoglycans?

-Found in connective tissue and cartilage -Structural properties: have elasticity and resistance to compression -Maintain the shapes of the tissues -Bind cations (e.g. Na+, K+), attract water into extracellular matrix -Act as molecular "sieves" 1.Lubrication 2.Gel formation 3.Cement 4.Ion binding 5.Molecular sieves 6.Shock absorber

Common Drug Endings

-olol = Beta blockers chol = Choline esters "muscarinic agonist" -sin = alpha 1 antagonist -tinib = tyrosine kinase inhibitor -terol = bronchodilator -stigmine= acetylcholinesterase inhibitor thiol = organophosphate

What happens during translation elongation?

1. Binding of aminoacyl-tRNA to the A site (in Eukaryotes) •Incoming aminoacyl-tRNA combines with elongation factor eEF1A bound to GTP. •Aminoacyl-tRNA-eEF1A-GTP binds to A site, GTP is hydrolyzed to GDP, resulting in eEF1A-GDP dissociation. •A second error-checking step in protein synthesis occurs at this stage. •If incorrect, ribosome will not hydrolyze GTP and complex will leave binding site 2. Formation of peptide bond Amino acid on tRNA in A site forms peptide bond with peptide on the tRNA in the P-site (for first round it will be the methonine rather than a peptide) Peptidyltransferase (is not a protein but the rRNA of the large ribosomal subunit) catalyzes formation of the peptide bond. After formation of the peptide bond the tRNA in the A site contains the growing polypeptide chain and the tRNA in the P site is uncharged. 3. Translocation and 4. Ejection of uncharged tRNA •Elongation factor eEF2 complexes with GTP, binds to ribosome, resulting in conformation change that moves the mRNA and paired tRNAs relative to ribosome. •(prokaryotes use elongation factor EF-G) •Uncharged tRNA moves from P to E site, and released from ribosome when charged tRNA enters A site. •Peptidyl-tRNA moved into P site. •GPT hydrolyzed to GDP and released with eEF2 • These elongation steps repeat until stop codon moves into A site. Termination occurs when a stop codon moves into the A site on the ribosome. •No tRNAs with anticodons that can pair with stop codons normally exist in cells •Release factors bind to the ribosome, causing peptidyltransferase to hydrolyze the bond between the peptide chain and the tRNA •Peptide is released from ribosome •Ribosome dissociated into subunits and mRNA is released

How do b-cells and t-cells interact?

1.B cells can bind Ags (BCR receptor) and present the antigenic peptides on their MHC II 2. This MHC II-antigen presentation is then recognized by CD4+ T helper cells 3. The T helper cell then releases cytokines (e.g., various interleukins) which promote division and differentiation of the B cells into plasma cells, as well as memory B cells. Thus, these two cell types activate each other to enhance the immune response.

How is fuel utilized in muscle during starvation?

1.Blood glucose levels decrease, insulin levels decrease and GLUT-4 receptors decrease -significantly decreasing glucose utilization by muscles and spares glucose for the brain and RBCs 2.Fatty acids are the preferred use of fuel 3.Glycolysis and Glycogenesis decreased 4.Ketone bodies can also be utilized

What are the fuel sources to generate ATP?

1.Creatine Phosphate-immediate 2.Glycogen -used to generate glucose for anaerobic glycolysis -pyruvate formed aerobically can be transformed to CO2 and H2O using pyruvate dehydrogenase, Krebs and ETC) 3.Oxidation of fatty acids and ketone bodies 4.Oxidation of specific amino acids -alanine, aspartate, glutamate, valine, leucine and isoleucine

How is fuel utilized in muscles at rest?

1.Dependent on serum levels of glucose, amino acids and fatty acids 2.Balance between glucose and fatty acid oxidation -when energy level adequate, reduction of fatty acid oxidation (increasing malonyl CoA inhibits CPT-1)

How do focal adhesions occur?

1.Dynamic sites of interaction between the ECM and cytoskeleton 2.Regulated by several unique regulatory proteins 3.Bidirectional control of ECM and cytoskeleton; critical for cell migration

What are the three outcomes of an Hfr?

1.F+ The F plasmid excises precisely and nothing happens to the plasmid or chromosome. 2.F' The F plasmid excises and carries of a small piece of chromosomal DNA with it. The F' plasmid is now infectious and the chromosomal fragment basically becomes part of the plasmid. 3.Hfr mating. The pilus and Type IV secretion system are induced and a transfer event is initiated from the integrated plasmid so a large piece of chromosome is introduced into the recipient cells. The plasmid does not recircularize and is lost (NOT infectious) but genes from the donor chromosome can enter the recipient by homologous recombination

What are the functions of the spleen?

1.Filter blood 2.Destroy worn out blood cells 3.Immune responses and antibody production 4.Reservoir of excess blood cells

How do you prepare a tissue for microscopy?

1.Fixation (e.g., Bouins, glutaraldehyde, stabilizing and cross linking reagents), emersion vs perfusion. 2.Dehydration in alcohols 3.Embedding in paraffin 4.Sectioning the tissue: Why section tissue? 5.Removal of paraffin 6.Rehydration 7.Staining (H&E) 8.Mounting sections on glass slide 9.Viewing the tissue (LM)

What are the key steps in migration?

1.For directed migration, chemoattractants drive formation of focal adhesions at the migrating front 2.Cell thins and stretches, creates pressure 3.Focal adhesions at the rear of the cell are disassembled; cell has now moved towards the chemoattractant. 4.In the absence of a trail, cells can also randomly turn "exploring". Process is the same, except that the cells does not actually get anywhere.

What are the types of recombination?

1.Homologous Recombination or general recombination. 2.Site-specific recombination. 3. Illegitimate recombination (transposition).

What are the two assumptions in all studies?

1.Human disease does not occur at random 2.Human disease has causal and preventive factors that can be identified through systematic investigation.

Describe activated growth factor receptors

1.Many growth factor receptors are tyrosine kinases 2.When activated, intracellular (cytoplasmic) domains of receptors act as tyrosine kinases. Will Autophosphorylate 3. Receptor dimerization between two adjacent cytoplasmic tails activates kinase function 4.Phosphorylated tyrosines on the cytoplasmic tail act as binding sites for Intracellular signaling proteins. 5. The intracellular signaling complex orchestrates receptor-specific responses

Describe enzyme-linked receptors

1.Many receptors for growth and differentiation factors are receptor tyrosine kinases. 2.An intracellular domain of tyrosine kinase receptors is activated upon ligand binding to the extracellular domain of the receptor which transfers a phosphate group from ATP to receptor proteins themselves and on specific cellular proteins. 3.ligand binding causes two receptor molecules to come together forming a dimer. Receptor dimerization between the two adjacent cytoplasmic tails activates their kinase function. 4.The auto-phosphorylated tyrosines on the cytoplasmic tail serve as high-affinity binding sites for intracellular signaling proteins "molecular velcro" 5. Tyrosine autophosphorylation serves as a switch to trigger transient assembly of an intracellular signaling complex, which relays the signal into the cell interior. Different receptor tyrosine kinases bind different combinations of these signaling proteins and therefore activate different responses.

What is a uniporter?

1.Only one solute is involved. 2.The carrier protein can expose its binding site to either face of the membrane (cytoplasmic and extracellular). 3.The direction is "downhill". The energy-electrochemical potential across the membrane. 4.Examples: a)Glucose entering fat cells, muscle cells, brain. b)Glucose leaving the basolateral surfaces of kidney proximal tubule cells to enter the blood. 5.As part of the mechanism, the empty carrier can reorient itself from one face of the membrane to the other, i.e., it can "come back empty".

What are synarthroses?

1.Synotosis - bones united by bone tissue allowing for no movement (e.g. cranial sutures) 2.Synchondrosis - bones united by hyaline cartilage with very limited movement (e.g. epiphyseal plates and costal cartilages connecting ribs to the sternum) 3.Syndesmosis - bones joined by dense connective tissue or fibrocartilage with limited movement (e.g. pubic symphysis or intervertebral disk)

How are plasmids transfer via conjugation?

1.The F+ cell is the donor and contains the F plasmid. 2.The F- cell is the recipient cell and does not contain the plasmid. 3.The F+ donor synthesizes a pilus, which is a Type IV secretion system. 4.One strand of the DNA is transferred to recipient. 5.The strands in both cells are replicated so both the donor and recipient now have the plasmid. 6.The recipient has been converted to a donor, so the process is infectious (epidemic) and the plasmid is spread. through the bacterial population.

What is saturability?

1.There are only a finite number of carrier proteins on the cell membrane. When there is a large amount of solute present, all the carriers bind solute and are transporting it. 2.Once the carrier is saturated, changing the concentration gradient by increasing the solute concentration does not increase the transport rate.

What is specificity?

1.There has to be one or more binding sites for the solute on the integral protein. These binding sites give it specificity for the particular solute. 2.How much specificity? a)Some carriers only recognize a specific molecule (absolute specificity) b)Others bind similar molecules and isomers (perhaps similar sugars, e.g., D-glucose and D-galactose) c)Others are fairly nonspecific (e.g., might work with organic acids such as amino acids)

How is the cross bridge cycle initiated in muscles?

1.Tropomyosin is a long molecule covering seven actin molecules. In the resting state, tropomyosin covers the myosin binding sites on actin. 2.Troponin is composed of three proteins: •Troponin C (TnC), which contains binding sites for calcium. •Troponin T (TnT), which binds the troponin complex to tropomyosin and actin. •Troponin I (TnI), which keeps the troponin complex tied to actin and inhibits the interaction between the myosin cross bridge and actin. 3. Calcium initiates the cross bridge cycle when it binds to troponin C. 4. The binding of calcium to troponin C causes troponin I to separate from tropomyosin and actin 5. The movement of TnI allows tropomyosin to move away from the myosin binding sites on actin. 6. Myosin attaches to the exposed binding sites on actin and the cross bridge cycle begins.

What is principle coordinate analysis?

1.organize into OTU (operational taxonomic units; usually species (97% identity or genera 95% identity) 2.do diversity analysis - alpha diversity within a single sample and beta diversity is between specimens 3.Shannon index measure of alpha diversity how many different types of species are present abundant vs rare organisms are weighted 4.Unifrac is a beta diversity metric based on phylogenetic trees 5.Unifrac uses phylogenetic distance as a measure of diversity 6.Unifrac can be weighted taking into account sequence abundance (quantitative) or unweighted (qualitative measure of different sequences) 7.Principle coordinate analysis is a type of ordination technique that summarizes data in one, two or three dimensional scatter plots. Each principle coordinate explains some fraction of the variability. The Shannon index is a weighted alpha diversity measure (scored within the population, the higher the number, the more diverse the population) Principle coordinate analysis is used to determine beta diversity between samples. It can be graphed in 1, 2 or 3 dimensions. It can be weighted or unweighted

What is Turner Syndrome?

1/1500-2500 female live births Only 1 X chromosome Short stature Normal intelligence Ovarian hypofunction or premature ovarian failure/infertility

What is the molecular chronometer for bacterial phylogeny?

16S rRNA It is used because it is: 1. present in all cells. 2. non-transferrable (horizontal gene transfer - from genetics section - would confuse interpretation 3. appropriate level of conservation 4. large enough to have enough base pairs to distinguish thousands of species functional stability

How do platelets function?

1: Plug wounded vessels -Injury to the lining of a blood vessel exposes collagen fibers; platelets adhere and become sticky. -Adhesion activates platelets to release dense and a-granules. 2: Clot formation -By aggregating with each other, platelets facilitate generation of thrombin, which in turn, converts fibrinogen to fibrin, leading to a sealing of the defect in endothelium. -Platelets aggregate and promote coagulation cascade.

What are the two orders of elimination?

1st order- C◦p - initial concentration in plasma = Dose/Vd 1/2 of the C0 = t1/2= ln(2)/t =0.693/t 0 order- A constant amount of drug is eliminated/unit time independent upon concentration Rate of elimination = (Vmax) (C) Km + C C >>>Km ☞ Erate = Vmax

Describe dopamine

2 Dopamine receptors D1 and D2 and it also activates beta-1 and alpha-1 at different dose levels D1=Gs increases cAMP activation of protein kinase A and smooth muscle relaxation, particularly in the renal system. At low doses Increases GFR, renal blood flow and sodium excretion Beta-1 activated at medium does to activate the cardiac system Alpha-1 activated at high doses to increase BP D2=Gi decreases cAMP, found in the CNS **Used in shock and cardiac arrest, and acute renal failure

How are monosaccharides transported into enterocyte in the lumen of the intestine?

2 carrier transport system Na-dependent glucose transporter cotransports either glucose/galactose and 2 Na ions (SGLT1) Na-dependent transport is coupled to a Na/K ATPase; hydrolyzing ATP and pumping Na out of the cell in exchange for K Monosaccharides diffuse out of the cells by facilitated diffusion through GLUT2 down a concentration gradient GLUT5 is a Na-independent facilitated transporter for fructose.

How doe 2,3-bis-phosphoglycerate affect the affinity of Hb for O2?

2,3-bis-phosphoglycerate decreases the affinity of Hb for O2. Right shift the of curve Not with fetal hemoglobin! Because gamma subunits have serines in the BPG binding pocket instead of histidines, so BPG does not bind tightly.

Describe cartilage

3 main types: Fibro (intervetebral) - Type I collagen, less proteoglycan Elastic (inner ear) - Elastin, proteoglycan Hyaline (articular, vocal cord) - Type II collagen, proteoglycan

Describe second messengers

3,5-cyclic AMP (cAMP) 3,5-cyclic GMP (cGMP) 1,2-diacylglycerol (DAG) Inositol 1,4,5-trisphosphate (IP3) Various inositol phospholipids (phosphoinositides) Ca2+. The elevated intracellular concentration of one or more second messengers following ligand binding triggers a rapid amplification in the activity of one or more enzymes or non-enzymatic proteins. Soluble, low molecular weight regulators of signaling proteins. Rapid amplification of signaling

What is the concentration of K+ in the extracellular fluid?

4 mM

Describe the function and regulation of lactate dehydrogenase

5 different LDH isozymes formed as tetramers from subunits encoded by 2 LDH genes, LDHA and LDHB. LDH catalyzes the forward and backward conversion of pyruvate to lactate. The LDH5 M subunit isoform (LDHA) favors formation of lactate and NAD, is expressed in liver/ skeletal muscle. LDHA mutation leads to exercise intolerance. The LDH1 H subunit form (LDHB) favors pyruvate and NADH formation, is expressed in heart/RBC (LDH1). Heart attack leads to high level serum LDH1 Production of lactate regenerates NAD+ allowing glycolytic flux to continue (formation 1,3- bisphosphoglycerate)

What biosynthetic cellular processes are affected by 5-FU? Why is 5-FU effective in killing cancer cells?

5-FU belongs to a class of drugs known as antimetabolites. The process of pyrimidine nucleotide synthesis and DNA replication is disrupted by 5-FU infusion. It acts as an analog of the pyrimidine bases used in DNA replication (i.e. Cytosine, Thiamine), but interferes with the process because the Fluorine atom prevents the hybridization of the analog to the template base. A dividing cell would recognize this as DNA damage event and will undergo p53 mediated apoptosis.

What is EC50

50% of maximal response If 50% of maximal response = 50% of maximal binding then EC50 = Kd As Kd ⬆, the affinity of the drug and receptor ⬇ koff/kon (rates) = Kd If there are spare receptors EC50 < Kd

What enzyme catalyzes bile salt synthesis?

7-α-hydroxylase Cholesterol to 7-α-hydroxycholesterol Inhibited by bile salts Rate limiting enzyme Occurs in the liver Turns NADPH into NADP+

What is alternative splicing?

80-90% of genes encode pre-mRNAs that can be alternatively spliced Major mechanism to increase the diversity of proteins produced Alternative splicing can affect any part of the mRNA molecule.

How is fructose metabolized?

90% of ingested fructose is extracted by first pass in the liver, little enters systemic circulation. Enterocytes can metabolize. Fructose enters enterocytes by GLUT5 and hepatocytes by GLUT2, both Na-independent transporters. Fructokinase (Ketohexokinase) forms F-1-P. The enzyme has a very high affinity (low Km) for fructose and is highly expressed in liver. The enzyme is unregulated. Lack of regulation of Fructokinase/Ketohexokinase can lead to ATP depletion and build-up of F-1-P. Aldolase B (liver-specific) can cleave F-1-P into 2 trioses. Glyceraldehyde is a substrate for triose kinase, yielding Glyceraldehyde-3-P. Ingested fructose has little effect on insulin release. Fate of ingested fructose: glucose lactate glycogen fatty acids Not heavily regulated- Only regulated step pyruvate kinase. Enters glycolysis at glyceraldehyde 3-P Fructose-1-P relieves glucokinase nuclear sequestration by dissociating the GKRP from glucokinase. F-6-P stabilizing the complex between GRP and Glucokinase retaining it in the nucleus. "Normal dietary levels" fructose increase hepatic glucose phosphorylation.

What happens during renal excretion?

: Any soluble substance with a Molecular Weight of less than 5,000 (= inulin) and which is free in the plasma, is filtered in the glomerulus. If nothing else happens to the drug as it progresses through the nephron, the drug (water soluble, ionized) is excreted into the urine. However, there are other processes, which may occur: (1) active tubular secretion - this is a carrier mediated active transport process in the proximal tubule by which organic acids and bases may enter the nephron (there are separate systems for acids and bases). Drugs can compete with each other or endogenous compounds for transport. (2) active tubular reabsorption - this is an active transport process in the proximal tubule by which drugs may be reabsorbed back into the general circulation and (3) passive reabsorption - Process in the proximal and distal tubules in which a drug can re-enter the circulation by passive diffusion. In general, relatively lipid-soluble, non-ionized drugs will be reabsorbed instead of being excreted. By pharmacologically changing the pH of the tubular filtrate, it is possible to alter the excretion of a drug (this is referred to as ion-trapping). The rate at which a drug is filtered by glomerular filtration is related to its free concentration in the plasma. In contrast, excretion by active secretion depends on the total plasma concentration (free and bound) because of the high affinity of drugs for the carrier of the transport system. A change in urine flow and pH of the urine alters the renal excretion of some drugs.

What is a DNA only transposon?

A piece of self perpetuating DNA that makes copies of itself and spreads from host to host (only a small proportion retain the transposing capacity). •Transposons & remnants of transposons comprise ~45% of the DNA in the human genome. (1)cut and paste transposition or (2) replicative transposition mechanisms •Transposition does not require homology between the transposable genetic element and the site on the chromosome •Transposons have short (15-25 base pair) inverted terminal repeat sequences needed for insertion into a target site. •Transposons encode an enzyme called "transposase", which cuts the DNA in the target sequence, inserts the ends of the transposon, and then joins the ends to make a contiguous DNA molecule with the transposon sequence embedded in it, moving the transposon from one genetic site to another. •Transposons can vary considerably in length (800-10,000 base pairs). This is because transposons carry additional genetic information that regulates the frequency of transposition. In bacteria, transposons frequently carry genes for resistance to antibiotics or heavy metals conferring a growth advantage. Medical significance: Bacteria can accumulate multiple transposons either on their chromosomes or on extrachromosomal elements called plasmids. This allows bacteria to become resistant to many different antibiotics at one time.

How are transposons used in bacteria?

A transposon mobile element transposes (moves) from one piece of DNA to another. A transposase (integrase) inserts the transposon into the DNA via binding to the inverted repeats that flank the transposon (insertion sequences; IS). Since the IS and transposase direct the insertion a transposon can insert anywhere in the chromosome and does NOT require RecA or homology = non-homologous recombination Insertion (by integrase) and excision (by excisase) are usually precise, but excision can occasionally cause deletions. Transposons become part of the DNA are not replicons (they are never free like phages or plasmids). Transposons can carry multiple different types of genes including antibiotic resistance determinants and virulence factors The transposons can insert these genes into any location in the chromosome since this is non-homologous recombination mediated the transposase

What are the events that activate the central pathway of cell death?

A wide variety of stimuli can initiate apoptosis. This is in stark contrast to the execution of apoptosis, which appears to be very uniform, both morphologically and biochemically. Initiation and execution Two pathways of apoptotic signaling: 1. Extrinsic or death receptor pathway: Initiated by signaling of cell surface death receptors (TNF or FAS), and via adaptor molecules recruit and activate caspases. 2. Intrinsic pathway: Initiated by withdrawal of growth/survival factors, chemotherapeutic drugs, developmental signals, DNA damage; results in cytochrome c release from mitochondria, activation of Apaf-1 and triggering of a caspase cascade. Most morphological changes observed during apoptosis are caused by caspases- cysteine proteases Caspases are highly conserved through evolution, found from humans down to insects, nematodes and hydra. •All caspases cleave their substrates after specific aspartic acids and are themselves activated by cleavage at specific aspartic acids [these proteases are now referred to as caspases or ASCP (aspartate-specific cysteine proteases)]

What is the underlying genetic cause of AT and why do patients with AT have neurological symptoms?

AT is inherited as an autosomal recessive trait. The disorder is caused by mutations of a gene known as ATM (for "AT mutated") that has been mapped to the long arm (q) of chromosome 11 (11q22.3). The protein is a protein kinase. The ATM gene provides instructions for making a protein that helps control cell division and is involved in DNA repair. This protein plays an important role in the normal development and activity of several body systems, including the nervous system. The ATM protein assists cells in recognizing damaged or broken DNA strands and coordinates DNA repair by activating enzymes that fix the broken strands. In neurons when ATM is affected which participates in non-homologous end joining there is no other ways to fix it

What feature of AZT makes it an effective inhibitor of HIV reverse transcriptase?

AZT is a thymidine analog that has a specificity for reverse transcriptase, as opposed to a DNA polymerase used in human cells. When phosphorylated to its triphosphate form, it mimics dTTP, and reverse transcriptase incorporates it into the cDNA it is producing. The presence of the azido group prevents formation of a phosphodiester bond, resulting in chain termination. Wouldn't work on DNA because DNA polymerase is too specialized and would recognize the incorrect nucleotide. It also lacks exonuclease activity. Mutations of the RT activation site can tighten the binding or mutation that use ATP to hydrolyze AZT and remove it cause resistance Mitochondrial damage could occur- DNA polymerase gamma, responsible for mitochondrial DNA replication, is sensitive to AZT or AZT competitively inhibits thymidine kinase 2 which decreases thymidine phosphorylation. This reduces the TTP pool for mitochondrial dna replication resulting in the mitochondrial side effects exhibited by AZT patients. In either case, inhibition of mtDNA replication reduces the synthesis of proteins required for oxidative phosphorylation and the electron transport chain. This decreases ATP synthesis in susceptible tissues (heart and liver) and increased formation of ROS due to defects in the electron transport chain which further damage tissues.

Describe voltage gated potassium channels

About 40 members, further divided into 12 subfamilies. Main role: repolarizing the cell membrane following action potentials. Assemble as tetramers of highly homologous a subunits to produce a functioning channel. Kv1 channels have cytoplasmic β-subunits that interact with the N-terminal T1 domains. Kv4 channels have two associated proteins; the intracellular protein KChIP, and the single-span membrane protein DPPX.

Describe Choline esters

Acetylcholine (Miochol), Bethanechol (Urecholine), Carbachol (Miostat), Methacholine (Provocholine) Mechanism of Action: Direct activation of cholinergic receptors. Their therapeutic efficacy is due to muscarinic activity. Activation of muscarinic receptors increases potassium flux, accelerates phosphatidyl inositol turnover, thus increasing intracellular calcium (M1, M3, M5), or inhibits adenylyl cyclase activity (M2, M4), based on the subtype which is stimulated. Using acetylcholine as the prototype, effects include: Cardiovascular system vasodilation (via nitric oxide) decrease in heart rate decrease in force of contraction Smooth muscle cells - contraction GI tract - increase in tone and motility Bronchioles - constriction GU system - contraction of ureter and bladder uterine contraction (only slight in humans) Eye - miosis, accommodation for near vision Glands - increase in salivation, lacrimation, sweating, GI secretions, bronchiolar secretions Neuromuscular junction (stimulation of motor end plate); ganglia, adrenal medulla

Describe eosinophils

Acid-ophilic granules FUNCTION - role in allergic reactions (participate in triggering bronchial asthma) and in defense against parasites. Contains specific granules Bilobed nucleus Acid-ophilic granules appear red because basic components bind eosin. Life span in the circulation ~ 18 hours Primary components of eosinophil granules: Eosinophil Peroxidase - Binds microorganisms and facilitates killing by macrophages. Major Basic Protein (MBP) - Major component of Charcot-Leyden crystals in granules. Disrupts parasite membranes. Causes basophils to release histamine. Eosinophil Cationic Protein - Neutralizes heparin and disrupts parasite membranes. Eosinophil-derived Neurotoxin - Secretory protein with ribonuclease and antiviral activity.

Describe the MAP kinase pathway

Activation of a Serine/Threonine Phosphorylation Cascade: Mitogen Activated Protein-Kinase 1.They are serine/threonine kinases MAPK kinases. Activated by RAS 2. The mitogen-activated protein (MAP) kinases (also called extracellular-signal-regulated kinases [ERKs]) are usually at the middle or end of the cascade. 3. Dual phosphorylation. They involve coordination of multiple, interacting cascades of tyrosine phosphorylation coupled to serine/threonine phosphorylation, which is longer-lasting than tyrosine phosphorylation. 4. Dual phosphorylation MAPK kinases are integrators or constriction points of signal transduction signals. 5. MAPK kinases often phosphorylate transcription factors. •An important example is p38, implicated in transduction of inflammatory signals.

How does insulin counteract glucagon signaling?

Activation of a phosphodiesterase (PKB) to reduce cAMP secondary messenger levels Activation of a protein phosphatase (PP1) to reduce PKA-mediated substrate phosphorylation. Type 1 and 2 diabetics with hyperglycemia have elevated glucagon levels.

What happens in hexokinase deficiency?

Activity of hexokinase may limit glycolysis and rbc life span. Some patients have deficient amount (splicing, active site mutation) or stability (mis-sense) of hexokinase. Low activity of HK results in lowered glycolysis, lowered ATP levels (poor ion pumping, lowered synthesis of glutathione), lowered NADH, lowered NADPH (pentose phosphate shunt). Red blood cells become fragile, are easily destroyed.

Describe the zone of polarizing activity

Activity regulates development of the A/P axis Interaction between AER and Mesenchyme Many transplantation and ablation studies suggested that the posterior margin mesoderm was behaving like an "organizing" center that regulated the AP patterning of the limb. It was named the Zone of Polarizing Activity or ZPA. The model from these studies suggested that the ZPA was the source of a diffusible morphogen named Sonic Hedgehog that specified the AP positional identity of cells.

Describe adenylyl cyclase

Adenylyl cyclase is a large transmembrane protein regulated by both G proteins and Ca2+. All receptors that act via cyclic AMP are coupled to a stimulatory G protein (Gs), which activates adenylyl cyclase and thereby increases cyclic AMP concentration. Another G protein, called inhibitory G protein (Gi), inhibits adenylyl cyclase. G Protein generation of cyclic AMP (cAMP). Cyclic AMP (cAMP) is a small intracellular mediator (second messenger) that can change by more than twenty fold in seconds. Cyclic AMP is synthesized from ATP by plasma-membrane-bound enzyme adenylyl cyclase. cAMP modifies gene expression

What is the IgG superfamily?

Adhesion molecules PECAM, ICAM, NCAM, VCAM families are similarly involved in cell-cell adhesion. Important for WBC recruitment and intercellular interaction during development. PECAM - Platelet endothelial Cell Adhesion Molecule ICAM - Inter-Cellular Adhesion Molecule NCAM - Neural Cell Adhesion Molecule VCAM - Vascular Cell Adhesion Molecule

What is the effect of epinephrine on metabolism?

Adipose tissue - Increase in lipolysis Liver - Decrease in glycolysis and glycogenesis - Increase in gluconeogenesis and glycogenolysis - Decrease in fatty acid synthesis Muscle - Increase in glycolysis and glyogenolysis - Decrease in glycogenesis

Where does the conversion of norepinephrine to epinephrine occur?

Adrenal Medulla

Describe Oxymetazoline

Adrenergic agonist Full agonist @ 𝞪1 receptor Partial agonist @ 𝞪2 - ↓ cAMP, ↓NE release Pharmacotherapeutics: **Decongestant conjunctival hyperemia Adverse effects Dependency Tachyphylaxis Rebound congestion

Describe Metaraminol

Adrenergic agonist 𝞪1- selective Predominate action in the vasculature vasoconstriction/pressor **Direct and indirect agonist- Increases NE release **Hypotension due to anesthesia* Activation of Gq ⬆ PLC ⬆ DAG ➠ PKC ⬆ IP3 ➠ Ca2+mobilization Contraindications and precautions: Hypersensitivity Sulfite sensitivity Severe hypertension Ventricular tachycardia Closed-angle glaucoma Adverse effects: Headache Restlessness Excitability Reflex bradycardia Rebound nasal congestion Drug Interactions: Monoamine oxidase inhibitors (MAOIs) Tricyclic antidepressants oxytocics

Describe Phenylephrine

Adrenergic agonist 𝞪1- selective Predominate action in the vasculature vasoconstriction/pressor **Used for nasal congestion because of nasal constriction **Dilates the pupil and causes mydriasis **Increase SVR and therefore increase blood pressure on both the systolic (arteriolar constriction) and diastolic (venous construction) route Used in vascular failure in shock to increase SVR and venous return to maintain cardiac output Reflex bradycardia ** Used in septic shock Activation of Gq ⬆ PLC ⬆ DAG ➠ PKC ⬆ IP3 ➠ Ca2+mobilization Longer duration of action compared to catecholamines Not metabolized by COMT or MAO Contraindications and precautions: Hypersensitivity Sulfite sensitivity Severe hypertension Ventricular tachycardia Closed-angle glaucoma Adverse effects: Headache Restlessness Excitability Reflex bradycardia Rebound nasal congestion Drug Interactions: Monoamine oxidase inhibitors (MAOIs) Tricyclic antidepressants oxytocics

Describe Midodrine

Adrenergic agonist 𝞪1- selective Predominate action in the vasculature vasoconstriction/pressor **Vascular failure in shock **Nasal congestion **Orthostatic hypotension **Cycloplegic/mydriatic Longer duration of action compared to catecholamines Not metabolized by COMT or MAO Prodrug hydrolyzed to desglymidodrine Activation of Gq ⬆ PLC ⬆ DAG ➠ PKC ⬆ IP3 ➠ Ca2+mobilization Contraindications and precautions: Hypersensitivity Sulfite sensitivity Severe hypertension Ventricular tachycardia Closed-angle glaucoma Adverse effects: Headache Restlessness Excitability Reflex bradycardia Rebound nasal congestion Supine hypertension* Drug Interactions: Monoamine oxidase inhibitors (MAOIs) Tricyclic antidepressants oxytocics

Describe Naphazoline

Adrenergic agonist Full agonist @ 𝞪1 receptor Partial agonist @ 𝞪2 - ↓ cAMP, ↓NE release Pharmacotherapeutics: **Decongestant conjunctival hyperemia Adverse effects Dependency Tachyphylaxis Rebound congestion

Examples of GPCRs

Adrenergic receptors Dopamine receptors Opioid receptors Histamine receptors Selective serotonin reuptake inhibitors

Describe Doxazosin

Adrenergic α1-receptor Antagonists Pharmacotherapeutics **Hypertension/Congestive heart failure Pharmacodynamics α1 blockade - dilation of arteries/veins Non-selective for α1A,B,D * > selectivity for α1A&D in prostate ⬇ peripheral resistance and BP ⬇ cardiac preload and afterload ⬇ pulmonary congestion ⬇ LDL & triglycerides ⬆ HDL Adverse effects Light-headedness, dizziness, "first-dose syncope," headache, drowsiness, weakness Retention of salt & water Contraindications/precautions Hypersensitivity Angina - hypotension may worsen Cataract surgery (pupillary constriction ➭flaccid iris

Describe Terazosin

Adrenergic α1-receptor Antagonists Pharmacotherapeutics **Hypertension/Congestive heart failure Pharmacodynamics α1 blockade - dilation of arteries/veins Non-selective for α1A,B,D * > selectivity for α1A&D in prostate ⬇ peripheral resistance and BP ⬇ cardiac preload and afterload ⬇ pulmonary congestion ⬇ LDL & triglycerides ⬆ HDL Adverse effects Light-headedness, dizziness, "first-dose syncope," headache, drowsiness, weakness Retention of salt & water Contraindications/precautions Hypersensitivity Angina - hypotension may worsen Cataract surgery (pupillary constriction ➭flaccid iris)

Describe Prazosin

Adrenergic α1-receptor Antagonists Pharmacotherapeutics **Hypertension/Congestive heart failure Pharmacodynamics α1 blockade - dilation of arteries/veins Non-selective for α1A,B,D ** > selectivity for α1A&D in prostate ⬇ peripheral resistance and BP ⬇ cardiac preload and afterload ⬇ pulmonary congestion ⬇ LDL & triglycerides ⬆ HDL **Used for PTSD Adverse effects Light-headedness, dizziness, "first-dose syncope," headache, drowsiness, weakness Retention of salt & water Contraindications/precautions Hypersensitivity Angina - hypotension may worsen Cataract surgery (pupillary constriction ➭flaccid iris)

Describe Tamsulosin

Adrenergic α1-receptor Antagonists Pharmacotherapeutics **Hypertension/Congestive heart failure **Benign Prostate hypertrophy (BPH)*- Relieves urinary retention Pharmacodynamics α1 blockade - dilation of arteries/veins Non-selective for α1A,B,D ** > selectivity for α1A&D in prostate ⬇ peripheral resistance and BP ⬇ cardiac preload and afterload ⬇ pulmonary congestion ⬇ LDL & triglycerides ⬆ HDL Adverse effects Light-headedness, dizziness, "first-dose syncope," headache, drowsiness, weakness Retention of salt & water Contraindications/precautions Hypersensitivity Angina - hypotension may worsen Cataract surgery (pupillary constriction ➭flaccid iris)

Describe Mirtazapine

Adrenergic α2-receptor antagonists Pharmacotherapeutics Mirtazapine used in depression Pharmacodynamics - sympathomimetics Oppose α2-inhibition of NE release ➠ ⬆ NE and 5-HT release **Increase blood pressure and heart rate Adverse effects CV, restlessness Mirtazapine ⬆ cholesterol Sedation with toxicity

What is oncogene-induced senescence?

Ageing of a person is intimately related to cellular ageing. Progressive time related loss of structural and functional capacity of cells leads to death. Ablation of BRCA1 results in genomic instability and evidence of cellular senescence A continuous process -part of the normal development starting with conception through life span- lead to changes in body structure and function increasing the probability of death. •Normal gradual age related changes. •Change in appearance. •Face, Body contours, posture. •Graying and thing hair, wrinkled skin. •Impaired vision and hearing. •Reduced Ability to adapt to stress. •Decreased resistance to infections. •Slowed movement.

What is the molecular basis of aging?

Aging is characterized by a progressive loss of physiological fitness leading to impaired functionality, which increases the probability of death. Organism aging has cellular basis, and it is at least in part controlled by genetic and biochemical processes. A major contributor is thought to be the accumulation of oxidative damage to macromolecules.

What are the signs of cocaine use?

Agitation, pupillary dilation, hypertension and tachycardia Nasal mucosal atrophy or septal perforation due to vasoconstriction Coronary vasospasm, angina, and myocardial ischemia DO NOT GIVE Beta blocker- extreme hypertension

What are the glucogenic proteins and where do they enter?

Alanine can be made into pyruvate and vice versa Threonine can be made into glycine which along with tryptophan can be converted into Alanine, serine and cysteine which can be converted into pyruvate Arginine, histidine, glutamine and proline can be converted into glutamate which can be convterted into alpha-ketoglutarate Valine, Threonine, Isoleucine and methionine can be converted into propionyl CoA which is converted to methylmalonyl CoA which can then be converted to succinyl CoA Aspartate, Tyrosine, and phenylalanine can be converted to fumarate Aspartate and Aspargine can be converted to OAA Lysine and Leucine are NOT GLUCOGENIC

What are the different plasma proteins?

Albumin- Carrier protein for hormones and drugs, Maintains colloid osmotic pressure Globulins- a-/b-Globulins, include fibronectin, coagulation factors Fibrinogen-Converted to fibrin in clot formation

What are the direct acting selective adrenergic beta 2 agonists?

Albuterol Terbutaline Salmeterol

What are the cytoplasmic enzymes capable of oxidizing ethanol to acetaldehyde?

Alcohol Dehydrogenase (ADH) Microsomal Ethanol Oxidizing System (MEOS) (induced by heavy consumption) Catalase (normally plays minimal contribution)

How is ethanol metabolized?

Alcohol passes from the stomach into the duodenum. Many tissues, including the stomach, have the ability to metabolize ethanol but the liver is the major site for metabolism Alcohol readily partitions in water and circulates unbound in plasma. It enters into cells by passive diffusion through cell membranes. Alcohol distributes into tissues from the blood proportional to their relative content of water The oxidation of ethanol occurs primarily in the liver and most of the ethanol is metabolized by the following steps: Ethanol to Acetaldehyde (ADH) to Acetate (ADLDH) which creates 2NADH

What are the roles of the mitochondria?

All Cells & Tissues Oxidative phosphorylation Apoptosis Cell/Tissue-specific Roles cholesterol metabolism amino & organic acid metabolism fatty acid beta oxidation sex steroid synthesis heme synthesis hepatic ammonia detoxification neurotransmitter metabolism

Why does compartmentalization occur?

Allows specific processes to be controlled without affecting rest of cell (e.g. lysosomal degradation). Provides a way to polarize cells, so that different regions can perform different functions (e.g. absorb nutrients). A specialized example is axons versus dendrites in neuronal cells. Allows different cell types to perform different roles (e.g. cells specialized to secrete specific hormones, absorb nutrients) The flip-side of this added specialization is that if a protein is not in the right place in the cell, often it may as well not be present at all.

What is osteogenesis imperfecta?

Altered collagen I Various defects in collagen I Multiple bone fractures; bone deformities; blue sclera

How does transamination with BCAAs happen in the muscle?

Aminotransferases (AT's) pass amino groups from BCAA's to glutamate. Alanine AT then passes amino group from glutamate to pyruvate to form alanine. Alanine exported to liver: in the liver, alanine AT makes pyruvate (glucose) and glutamate (urea). Sort of like the Cori cycle, but with alanine instead of lactate. Why is this important? bc muscle uses carbon skeletons of BCAA's for energy, so export of NH3 is important. Also achieved by making glutamine, more on this later on...

What is Abetalipoproteinemia?

An autosomal recessive genetic disorder, is caused by mutations in the MTTP gene, which encodes microsomal triglyceride transfer protein (MTTP). Mutations of the MTTP gene lead to low levels of functional MTTP, which hinders the liver and intestines from making and secreting apoB-containing lipoproteins (e.g., VLDL, LDL, and chylomicrons). This, in turn, results in the inability to properly absorb and transport fats and fat soluble vitamins throughout the body. Symptoms: steatorrhea, diarrhea, vomiting, swelling of the abdomen, fat-soluble vitamin deficiency, poor fat absorption, growth retardation, retinitis pigmentosa, acanthocytic red blood cells, neurological complications such as spinocerebellar degeneration Treatment: restriction of long-chain fatty acids and large doses of fat-soluble vitamins (e.g., vitamin E)

What are the three categories of limb development?

Anterior/Posterior: Sonic hedgehog released by zone of polarizing activity (ZPA) Proximal/Distal: Wnt/FGF released by apical epidermal ridge (AER) Dorsal/Ventral: Wnt7A/BMP released by ectoderm on dorsal and ventral sides of developing limb bud Also **-FGF10 initiates limb budding in early stages of embryo development -Finger/toe formation is guided by BMP and cell apoptosis (not necrosis!) -HOX genes, containing homeoboxes, are master regulators of limb development

What do antibodies do?

Antibodies bind to a foreign substance and label the surface so that it is recognized and phagocytosed (opsonization). Antibodies recruit the complement cascade to the membranes of bacteria to cause their lysis. Antibodies recruit effector lymphocytes to attach to the foreign substance and destroy it through cytotoxic immunity.

What types of genetic mutations result in retinoblastoma? What are cytogenetic manifestation of the disease? How are they diagnosed?

As stated before, this cancer results in the mutation of the RB1 gene on chromosome 13. RB1 is a tumor suppressor gene that binds and inactivates transcription factor E2F (genes that code for several transcription factors). This leads to cancer as several cells in the retina will divide uncontrollably. RB1 gene codes for the retinoblastoma protein, a tumor suppressor gene. Its function is to inhibit cell cycle progression until the cell is ready to divide (G1 to S phase). While it represses the targets of E2F, it also binds to 100 other proteins. When inactivated, retinoblasts will divide uncontrollably and this leads to cancer. Phosphorylation of Rb protein via cyclin dependent kinases (CDKs) deactivates them. Rb protein has three different phosphorylation steps. Its unphosphorylated state is during G0, it's mono-phosphorylated during early G1, and hyper phosphorylated when the cell wants to divide. CDKIs will inhibit CDK activity, which in turn will enhance Rb protein activity. If this pathway is inactive, E2F will be able to allow the cell cycle to continue.

Why do medical students need to study G protein signal transduction?

At least 1% of our entire genome encodes G proteins and linked receptors Some of the biological functions of G protein Coupled receptors include taste, perception of light, neurotransmission, control of blood pressure, etc. (There are over 1000 genes concerned with the sense of smell alone) Close to ½ of the drugs on the market target G proteins or G protein receptors

Describe the action potential process

At rest: Most of the voltage dependent Na+ channels and the voltage dependent K+ channels are closed A depolarizing stimulus-before threshold: Causes an inward current, carried by Na+, which increases the probability that m gates will open The membrane potential becomes less negative When the threshold is reached (approximately -55 mV in neurons) a positive feedback event occurs such that there is an explosive opening of all remaining m gates and in turn all remaining Na channels will open Opening of the Na channel, Na+ ions move down their electrical-chemical gradient from the extracellular to the intracellular compartment (Fig 9c) The Na+ ion must move through a water filled channel The Na+ channel has a selectivity filter A short time after the Na channel is activated it inactivates: The h gate closes The Na channel is closed The inward Na current drops to zero The inactivated Na+ channel is closed but not available for activation. Before this channel can be activated again, the membrane potential must return to about -80 mV. When this happens: the "m" gate closes the "h" gate opens When these things have happened, the channel is still closed, but is now available for activation. It is in the same state as it was before the action potential The voltage dependent K+ opens: The voltage dependent K+ channel has only one gate called the n gate, which is the activation gate The "n" gates open when the membrane is depolarized, but they open much more slowly than do the "m" gates of the Na+ channel. Thus, the Na+ channels are open before the K+ channels are. Because the K+ channels don't have any inactivation gates, the K+ channels do not inactivate -- they stay open as long as the membrane is depolarized. When the n gate opens K+ flows out of the cell, restoring the membrane back to its resting potential

What is the function of co-lipase

Attract and anchor the pancreatic lipase to the surface of the emulsion particles In the small intestine, dietary TGs are hydrolyzed to 2-monoacylglycerol (2-MG) and fatty acids (FA).

What happens in pyruvate kinase deficiency?

Autosomal recessive disorder, apparently more common among Amish in SE PA. Chronic hemolysis (shortened rbc lifespan), some splenomegaly. Acute symptoms often precipitated by parvovirus infection

What is the underlying defect of XP?

Autosomal recessive genetic defect in which nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER. Normally, the damage to DNA which occurs in skin cells from exposure to UV light is repaired by nucleotide excision repair. In people with xeroderma pigmentosum, this damage is not repaired. Mutation in the XPA gene causes loss of function for protein that assists with DNA unwinding; Causes neurodegeneration including loss of intellectual functioning, deterioration of neurologic status, impaired hearing, abnormal speech, areflexia, ataxia, peripheral neuropathy, and loss of the ability to walk and talk. The XPV type has clinical overlap with the other forms but does not involve a mutation of the NER system. Instead, XPV is caused by a mutation in DNA polymerase (DDB2 gene), which results in milder photosensitivity and poikiloderma (areas of hypopigmentation, hyperpigmentation, telangiectasias and atrophy); CNS not affected; no neurodegeneration

What are the similarities and differences in DNA replication in Bacteria vs. eukaryotes?

Bacteria and mammalian cells synthesize their DNA using basically the same semiconservative discontinuous mechanism •In mammalian cells primase is part of the DNA polymerase-alpha complex. The primase subunit subunit in the complex generates a short RNA primer de novo and then the DNA polymerase subunit continues to elongate the primer. Then, it dissociates to allow the processive DNA polymerases to continue replication. In bacteria, a separate primase synthesizes primers and DNA pol III synthesizes DNA In mammalian cells, DNA polymerase ε (epsilon) operates on the leading strand (lεading) and DNA polymerase δ (delta) operates on the lagging strand. In bacteria both strands are synthesized by DNA pol III

What are bacteria?

Bacteria are free-living prokaryotes that range in size from 0.1-10 mm.

What are spores?

Bacteria can form spores They appear as phase bright under a microscope because they are dehydrated and high density They contain multiple layers of hard coat proteins, a membrane and then a fully-dehydrated cytoplasm with condensed DNA Spores are dormant and resistant Bleach is one of the few disinfectants that work against them (important in a hospital) Important pathogens form spores - Bacillus anthracis and Clostridium difficile Spore formers grow as vegetative cells Under conditions of poor nutrient availability and high bacterial density (quorum sensing - see next section) the cells will undergo a multi-step programmed developmental program for the formation of spores

What is citrate metabolism?

Bacteria can run the TCA cycle backwards to use citrate as a carbon and energy source

What are bacterial communities?

Bacteria live in multispecies biofilms in the microbiota Pathogenic bacteria tend to form monospecies biofilms on indwelling devices (although some can be multispecies)

How do bacteria respire?

Bacteria that respire transform pyruvate into acetyl-CoA and further break it down to CO2. This provides bacteria with: o NADPH for biosynthesis o additional molecules of NADH+H+ for use in generating a proton motive force FADH+H+ that can also be used for the generation of a proton motive force A proton motive force is produced by passing the electrons from NADH+H+ to a series of electron carriers that use the excess energy to pump protons (H+) outside the cell. Carriers include: o cytochromes o quinones o flavoproteins (Fe-S proteins) The final electron acceptor can be O2 (aerobic respiration, oxidative phosphorylation) or other inorganic compounds (anaerobic respiration). NOTE:both aerobic and anaerobic bacteria can respire. This creates a membrane potential and a pH gradient giving the cell electrical potential energy and chemical potential energ· The potential energy can be used to o produce ATP using F0F1 ATP Synthase o power motility (bacterial swimming) o allow uptake of small molecules In bacteria that ferment the F0F1 pump can be run in "reverse" allowing the bacteria to use ATP to pump protons out of the cell to charge the membrane All respiration occurs at the cellular membrane (inner membrane of Gram-negative bacteria)

Explain random genetic change in bacteria

Bacteria usually have single circular chromosomes (although occasionally bacteria will have linear chromosomes) Bacteria are haploid, so mutations can be expressed in the next generation Single nucleotide polymorphisms Random mutation rate due to uncorrected errors from DNA polymerase during replication 1 in 106 genes/generation o not all mutations will lead to a phenotype Mismatch repair can decrease mutations about about 2 logs 1 in 108 genes/generation Under stress this increases due to error prone polymerases

What are bacterial membranes made up of?

Bacterial membranes are made up of phospholipids Bacterial membranes are made up primarily of phosphotidylethanolamine and phosphotidylglycerol This is part of the reason they lyse when there is no cell wall and L-forms contain different or modified lipids They do not contain sterols with the exception of Mycoplasma that incorporate sterols from their environment into their membranes.

What are bacteriophages?

Bacteriophage (phage) are bacterial viruses (they act much like human viruses that you will be studying) Some phage can switch between the lytic and lysogenic cycle In the lytic cycle the phage replicate and lyse the bacterial cells In the lysogenic cycle the phage integrate into the chromosome of the bacteria (Non-homologous) recombination

When is the microbiota healthy?

Balanced ecology Different bacteria are co-evolved with live and work together (many times they cannot be cultured separately Highly diverse (and different person to person) High numbers of Bacteriodetes and Bifidobacterium Low numbers of Proteobacteria and Clostridia

What binds hemoglobin?

Band 3

What organizes the lattice network?

Band 4.1 and Spectrin

What are some inhibitors of the electron transport chain?

Barbituates (Complex I) Antimycin A (Complex III) H2S, CO, Cyanide (Complex IV) Uncouplers Decrease in ATP synthesis Oligomycin

Describe the basal lamina

Basal lamina is a felt-like extracellular matrix which is in direct contact with the epithelial cell Composed of meshwork of proteins including laminins, collagens, glycoproteins and proteoglycans. Function: Structural attachment of the epithelial cells Compartmentalization of the connective tissue Filtration Tissue scaffolding: In malignancy>breach of BL by epithelial cells could result in the metastasis of tumor to secondary sites Regulation and Signaling

What metabolic changes happen during a fever?

Basal metabolic rate increases Glycogen degradation goes up Glycolysis makes lactate concentration go up Ketone utilization goes up and weight loss occurs Vitamin consumption goes up

How do you design/obtain the DNA to be used as probe and generate a labeled form?

Based on known protein sequence. Usually short oligonucleotides single strand DNA probes that are degenerative in mixture and labeled at the 5' end with a polynucleotide kinase. Based on an already cloned piece of DNA that has been purified.

Describe basophils

Baso-philic granules Contains specific granules FUNCTIONS: Play a role in immediate (bronchial asthma) and type 2 hypersensitivity in response to allergens (allergic skin reaction) and parasitic worms (helminths). Release histamine causing vasodilation and increased vascular permeability. Primary components of basophil granules: Sulfated or Carboxylated Acidic molecules: Heparin and Histamine Similar to mast cells: IgE receptors on basophil surfaces release histamine upon basophil activation by antigen. Unlike mast cells basophils have a short life span ~60 hours. Mast cells survive for weeks to months.

Describe Bcl-2

Bcl2 proteins regulate the intrinsic pathway of apoptosis Oncogene first identified by its involvement in a chromosomal translocation [t(14:18)] linking the immunoglobulin heavy chain locus to a novel gene denoted Bcl-2; found in the majority of non-Hodgkin's lymphomas; reported in 1984; Unlike all previously identified oncogenes, Bcl-2 was shown to promote cellular survival rather than proliferation. Was found to promote or extend survival of many cell types, including factor deprived neurons and hematopoietic cells. Control release of cytochrome C and other intermembrane mitochondrial proteins into the cytosol Pro and anti-apoptotic proteins Bind to each other to form heterodimers to inhibit each others function Balance between pro- and anti-apoptotic proteins determine outcome The three classes of Bcl2 family proteins. Anti-apoptotic : BH1-BH4 (Bcl2)(Guardians) Pro-apoptotic effector effector: BH1-BH3 (Bax, Bak)(Effectors) Proapoptotic; act by perturbing mitochondrial intracellular membranes; need to be "primed" or "activated" Pro-apoptotic BH3-only (Bad, Bim, Puma, Noxa)- mediates the direct interactions between pro-apoptotic and anti-apoptotic family members. (Sensors) Proapoptotic; act by inhibiting guardians; cannot promote kill in absence of effectors [except Bid]; responsive to environmental cues

Describe Acebutolol

Beta 1 selective adrenergic antagonist/partial agonist Pharmacotherapeutics ➯ **Cardiovascular (hypertension, angina, arrhythmia) Pharmacodynamics: Less bradycardia and abnormalities in plasma lipids than other β-antagonists (no dyslipidemia with acebutolol) Overall clinical significance of intrinsic sympathomimetic activity remains uncertain. Local Na+ channel blockade (local anesthetic activity) Interaction with 5-HT signaling, may potentiate the action of traditional antidepressant medications

Bioavailability equation

Bioavailability (F) = AUC oral/AUC IV

How are biofilms formed?

Biofilm · growth of bacteria encased in a matrix material · on a surface (biotic - body surface) (abiotic - pathogenic indwelling devices) Steps in biofilm formation 1. planktonic (free-swimming individual cells) attach to surface 2. matrix secreted o variable species to species o generally composed of polysaccharides, protein, eDNA and amyloid 3. biofilm matures 4. dispersion: planktonic cells released (in some species). Interactions: Abiotic or biotic Electrostatic interactions Hydrophobic interactions Steric hinderance Flow (hydrodynamic interactions)

What is the name for vitamin B7 and what does it do?

Biotin Coenzyme in carboxylation reactions during gluconeogenesis as well as fatty acid and amino acid synthesis. Acetyl carboxylase, Pyruvate carboxylase

What are some examples of basic dyes?

Blue Toluidine blue Methylene blue Hematoxylin

What is the 3rd stage of fracture healing?

Bone Remodeling (months to years): -Conversion of immature (woven bone) into mature (lamellar) bone Haversian systems are reconstituted Biomechanical forces direct relative amounts of bone deposition -More bone is deposited in areas of greater mechanical stress

How is calcium regulated?

Bone serves as a large repository of internal calcium Trabeculae of spongy bone provide a large surface area for rapid deposition and release of calcium PTH Regulation: Ca-sensing receptors on the parathyroid detect changes in serum calcium levels PTH release in response to low circulating calcium levels •Osteoclastic bone resorption •Renal calcium reabsorption •Activated vitamin D which can also stimulate bone resorption

Describe signal transduction and Cholera

Both Gs and Gi are targets for some medically important bacterial toxins. Cholera toxin is an enzyme that catalyzes the transfer of ADP ribose to the a subunit of Gs. This ADP ribosylation alters the a subunit so that it can no longer hydrolyze its bound GTP, causing it to remain in an active state that stimulates adenylyl cyclase indefinitely. The resulting prolonged elevation in cyclic AMP levels within intestinal epithelial cells causes a large efflux of Cl- and water into the gut, thereby causing the severe diarrhea that characterizes cholera.

What is RNA editing?

C to U Editing A to I Editing (I behaves like a G during protein synthesis) The editing of the pre-mRNA occurs after RNA synthesis. mRNA sequence changed but no effect on the DNA sequence of the gene. Can change the protein from say the liver and the intestine

What is the fate of proteins synthesized in the cytosol?

Can remain in cytosol Can enter organelles (mitochondria, nuclei). These proteins contain targeting/signal sequences to facilitate transport to these organelles

What is cardiac hypertrophy?

Cardiac hypertrophy is a thickening of the heart muscle (myocardium). Common causes of cardiac hypertrophy include high blood pressure, heart valve stenosis, pressure or volume overload. Increased protein synthesis. Up- regulation of genes normally expressed during fetal development. An increase in the size of the nucleus and cell width. Possible changes in ECM molecules deposited and cell- cell communication.

What is a major component of the inner mitochondrial membrane?

Cardiolipin (CL)

What lipids can the mitochondria produce?

Cardiolipin (CL), phosphatidylglycerol (PG), in part phosphatidylethanolamine (PE), phosphatidic acid and cytidine-diacylglycerol

What are the therapeutic application for adrenergic antagonists?

Cardiovascular disorders Congestive heart failure Peripheral vascular disease Decrease sympathetic activity Pheochromocytoma Nasal congestion Urinary retention Glaucoma (& miosis) Endocrine disorders Neurologic disorders

How does beta oxidation differ in peroxisomes?

Carnitine is not involved Does not generate ATP Contribute significantly to total b-oxidation in liver and kidney Terminates at octanoyl CoA (C8 CoA) Uses Acyl CoA oxidase enzyme to generate FADH2 and make H2O2 from O2 Peroxisomes are required for normal brain function and the formation of myelin

What is heterozygote advantage?

Carriers have survival advantage over non-carriers and homozygotes Globin mutations prevalent in the malaria belt Cystic fibrosis heterozygotes may be resistant to cholera Tay-Sachs disease carriers may be resistant to tuberculosis infection

What are the non-selective adrenergic antagonists?

Carvedilol Labetalol

What are the descriptive case designs?

Case Report Case Series Ecological Study

How are capsases activated?

Caspases are synthesized as enzymatically inert zymogens. Initiator caspases: begin apoptotic process. Apoptotic signal triggers assembly of large protein platforms that bring multiple initiator caspases together into large complexes. Close proximity (caspase 8) or conformational change (caspase 9) activate initiator caspases. Initiator caspase in intrinsic pathway of apoptosis: •Cytochrome C released from mitochondria into cytosol •Binds to adaptor protein Apaf1 •Causes Apaf1 to oligomerize into wheel-like heptamer called apoptosome •Apaf1 proteins recruit initiator caspase-9 proteins, perhaps activated by proximity in the apoptosome •Each Apaf1 protein contains caspase recruitment domain [CARD]; CARDs bind similar domains in caspase-9 molecules Effector caspases are activated by an upstream caspase. Effector caspase-3, -6, & -7 are considered the workhorses of the caspase family. They are usually the more abundant and active caspases.

How does the activity of caspases disassemble a cell?

Caspases mediate PCD by cleaving selected intracellular proteins including proteins of the nucleus, nuclear lamina, cytoskeleton, endoplasmic reticulum, and cytosol. Cleavage by caspases can result in loss of biological activity. Sometimes cleavage activates biological activity leading to other destructive processes in the cell, and thereby help kill the cell neatly and quickly. Caspases and DNA fragmentation is an example of box 1, d: . Caspase-dependent deoxyribonuclease (CAD), inactive and located in cytosol when bound to the inhibitor ICAD. . Caspase-3 cleaves and inactivates ICAD, releasing CAD. CAD translocates to nucleus and initiates chromosomal degradation.

What are indirect-acting sympathomimetics?

Catecholamine degradation inhibitors inhibit degradation of catecholamines by monoamine oxidase Catecholamine vesicular storage Inhibitors displaces catecholamines in storage vesicles promoting enhanced release Catecholamine transport block reuptake/transporters

How are catecholamines degraded?

Catecholamines in the brain are transported back into neurons following their release ("reuptake") Degradation proceeds by two major reaction types: monoamine oxidase (MAO) and methylation using SAM, and catecholamine-O-methyl transferase (COMT) COMT and MAO can act in any order. Final metabolite is VMA. MAO inhibitors allow signal to persist antidepressants. Certain tumors (pheochromocytoma, tumor of adrenal gland) secrete catecholamines, lead to high levels of VMA

What are the three basic types of muscle fibers?

Categorized by contractile speed, enzymatic velocity and metabolic properties. Identified by histochemical staining. Type I: Slow Oxidative Fibers, dark red: primarily in endurance activities Fast Oxidative Glycolytic Fibers (A) Fast Glycolytic Fibers (B) Contractile speed: determines how fast the fiber can contract and relax. Enzymatic velocity: of the myosin ATPase reaction determines the rate at which the enzyme is capable of breaking down ATP during the contraction cycle. Metabolic profile: capacity for ATP production by oxidative phosphorylation or glycolysis.

What is Niemann-Pick Disease?

Caused by acid sphingomyelinase deficiencies Lysosomal storage disease Buildup of fat in cells and causes cell dysfunction and overtime cell death Symptoms include loss of function of nerves, brain and other organs Example of sphingolipidosis

What happens during spontaneous DNA damage?

Caused by hydrolytic damage Deamination turns cytosine to uracil Deamination of 5-methyl cytosine to Thymine Depurination

What happens in HGPRTase deficiency?

Causes hereditary gouty arthritis, Lesch-Nyhan syndrome Partial deficiency of HGPRTase (X-linked) causes pile-up of uric acid, hereditary gout. Alleviated by allopurinol Complete deficiency causes severe mental retardation, self-mutilation, motor problems (Lesch-Nyhan syndrome; rare disorder!)

What are some functions of microtubules?

Cell division- Segregation of Chromosones, reorganization of cytoplasm Required components: motor proteins, MT dynamics Cilia and Sperm Tails- sperm movement, move phlegm (mucociliary escalator), found in lung epithelium, trachea and fallopian tube Basal Body- A microtubule organizing center for cilia and flagella, the Axoneme: 9+2 microtubule structure of cilia and flagella driven by dynein

What happens during G1?

Cell growth Duplication of organelles Prep for DNA replication *DNA damage

What happens during G2?

Cell growth Duplication of organelles Prep for cell division Homologous recombination

What happens during fatigue of the nervous system?

Central -Changes in the CNS •Altered input from muscle sensory fibers •Reduced excitatory input to motor control centers in brain/spinal cord •Altered excitability of motor neurons •Can be mitigated with conditioning Peripheral: -High-Frequency Fatigue (intense exercise) •High frequency of AP firing •Na/K-ATPase cannot keep up with Na+ entry and K+ exit, normal membrane potential not maintained •RMP becomes more positive (by 10-20 mV) -This depolarization inactivates voltage-gated Na+ channels; harder to fire APs -Also, within t-tubule, impaired ability of L-type Ca2+ channels to activate the SR Ca-release channels •Recovery occurs relatively quickly -Low-Frequency Fatigue (prolonged moderate-intensity exercise) •Less Ca2+ release from SR •Inhibition of SERCA -Decreased stores of Ca2+ •Depression of amplitude of [Ca2+]i transient •Has more effects at lower stimulation frequencies -[Ca2+]I does not remain at continuously high enough levels to saturate TnC, less crossbridges are formed •Recovery takes several hours

What is genetic drift?

Characterized by significant random fluctuations in allele frequency through chance deviation In a large population with random mating, large fluctuations of gene frequency are unlikely In a small population, gene frequency can change dramatically from one generation to the next if only individuals who carry a given allele participate in mating by chance

What are the cell cycle checkpoints?

Checkpoint: Point in the cell cycle where the cell makes sure that an earlier event has been completed properly (fully completed event without damage). Otherwise the cell cycle is arrested to allow task completion and/or repair. G1/S checkpoint: Upon DNA damage (i.e.: by ionizing irradiation). Normal cells arrest in G1 to repair DNA prior to DNA replication. G2/M checkpoint: Entry into mitosis is prevented if DNA replication is not complete or damage is detected. Metaphase checkpoint (spindle): Chromosome segregation is prevented if chromosomes are not properly attached to the mitotic spindle. Checkpoint activation is often associated with inhibition of particular Cyclin/CDKs Loss of checkpoint control leads to genomic instability. Proper cell growth is also often monitored by G1/S and G2/M checkpoints.

What is the effect of cholesterol on membrane fluidity?

Cholesterol has a condensing effect on neighboring phospholipid molecules, therefore, decreasing membrane fluidity. Gauche conformation is abolished by cholesterol; therefore, membrane free volume is reduced by cholesterol.

What are the direct acting cholinergic agonists?

Choline Esters: Acetylcholine Bethanechol Carbachol Methacholine Natural Alkaloids: Muscarine Pilocarpine

Describe Acetylcholine

Cholinergic agonist Choline Ester Miochol No CNS effects **Used for creating miotic eye for eye surgery, lots of effects so often not used often anymore Has muscarinic and nicotinic action Susceptible to ChEs Effects: **Cardiovascular system vasodilation (via nitric oxide) decrease in heart rate decrease in force of contraction Smooth muscle cells - contraction GI tract - increase in tone and motility Bronchioles - constriction GU system - contraction of ureter and bladder uterine contraction (only slight in humans) Eye - miosis, accommodation for near vision Glands - increase in salivation, lacrimation, sweating, GI secretions, bronchiolar secretions Neuromuscular junction (stimulation of motor end plate); ganglia, adrenal medulla

Describe Carbachol

Cholinergic agonist Choline Ester Miostat No CNS effects Act on muscarinic and nicotinic receptors Not susceptible to ChEs **Used for creating miosis of the eye for surgery and glaucoma , reduce intraocular eye pressure

Describe Methacholine

Cholinergic agonist Choline Ester Provocholine No CNS effects Mostly on muscarinic receptors Slightly susceptible to ChEs **Used for diagnosing bronchial hyper-reactivity

Describe Bethanechol

Cholinergic agonist Choline Ester Urecholine No CNS effects Only muscarinic action Not susceptible to ChEs **Used for atony (can't contract) of bladder and paralytic ileum Used mainly in GI and bladder

Describe Edrophonium

Cholinergic agonist Cholinesterase Inhibitor Simple quaternary alcohol Tensilon No CNS effects IV/IM 5-15 minute duration **Used for diagnosis of myasthenia gravis Binds reversibly to AChE, thus preventing access by ACh. Also stimulates nicotinic (Nm) receptors. Short duration of action (5-15 min).

Describe Donepezil

Cholinergic agonist Cholinesterase inhibitor **Used for Alzheimers treatment Penetrate the CNS

Describe Rivastigmine

Cholinergic agonist Cholinesterase inhibitor **Used for Alzheimers treatment Penetrate the CNS

Describe Pyridostigmine

Cholinergic agonist Cholinesterase inhibitor Carbamic acid ester Mestinon No CNS effects Duration 3-6 hours PO, inj administration **Used for chronic treatment of myasthenia gravis Bind to active site of enzyme, thus preventing binding of ACh. Carbamylated enzyme is more resistant to hydrolysis than acetylated enzyme. Pyridostigmine also weak agonist at cholinergic receptors.

Describe Neostigmine

Cholinergic agonist Cholinesterase inhibitor Carbamic acid ester No CNS effect PO, inj administration Duration .5-2 hours **Used in posteroperative paralytic ileus and neurogenic bladder **Used for chronic treatment of myasthenia gravis **Also used for unblocking of NM junctions after anesthesia Bind to active site of enzyme, thus preventing binding of ACh. Carbamylated enzyme is more resistant to hydrolysis than acetylated enzyme. Also weak agonists at cholinergic receptors.

Describe Physostigmine

Cholinergic agonist Cholinesterase inhibitor Carbamic acid ester CNS effect Inj, top administration **Used for antimuscarinic drug intoxication aka atropine overdose from the belladonna plant Duration .5-2 hours Bind to active site of enzyme, thus preventing binding of ACh. Carbamylated enzyme is more resistant to hydrolysis than acetylated enzyme. Lots of side effects: DUMBBELLS (Diarrhea, urination, miosis, bronchospasm, bradycardia, lacrimation, salvation

Describe Sarin

Cholinergic agonist Cholinesterase inhibitor Organophosphate- irreversible Highly lipid soluble and therefore readily cross the blood brain barrier **Toxic nerve gas Duration of action: hundreds of hrs, thus drugs are active until new enzymes are synthesized. Bind to enzyme yielding phosphorylated ChE, which is extremely stable and thus hydrolyzed at very slow rate. Phosphorylated enzyme undergoes AGING- breaking of one of the oxygen-phosphorus bonds of the inhibitor, further strengthening the phosphorylated enzyme.

Describe Malathion/Parathion

Cholinergic agonist Cholinesterase inhibitor Organophosphate- irreversible Highly lipid soluble and therefore readily cross the blood brain barrier. **Found in pesticides Duration of action: hundreds of hrs, thus drugs are active until new enzymes are synthesized. Bind to enzyme yielding phosphorylated ChE, which is extremely stable and thus hydrolyzed at very slow rate. Phosphorylated enzyme undergoes AGING- breaking of one of the oxygen-phosphorus bonds of the inhibitor, further strengthening the phosphorylated enzyme.

Describe Pilocarpine

Cholinergic agonist Natural alkaloid **A muscarinic agonist available for treatment of xerostomia (to induce salivation) and narrow-angle and open-angle glaucoma (to induce outflow of aqueous humor, thus, reducing intraocular pressure). Adverse reactions include difficulty focusing, nausea, abdominal pain, sweating and at high doses, bradycardia and hypotension. Cevimeline (Evoxac) is another muscarinic agonist for treatment of xerostomia

Describe Muscarine

Cholinergic agonist Natural alkaloid Alkaloid present in various species of wild mushrooms (Amanita muscaria, Inocybe, Clitocybe). Exclusively stimulates muscarinic receptors. Not used clinically, but of interest due to accidental intoxication by consumption of muscarine-containing mushrooms. Symptoms due to overstimulation of parasympathetic system. Treatment with atropine (muscarinic antagonist).

Describe Botulinum neurotoxin

Cholinergic antagonist **Botulinum toxin blocks ACh release. Small doses are used for muscle spasticity, wrinkle reduction

Describe Darifenacin

Cholinergic antagonist Antimuscarinic agent **M3 selective antagonists Blockade of muscarinic receptors can cause a decrease in the frequency of micturation and distention of the bladder. Therefore, drugs with antimuscarinic activity can produce urinary hesitancy and retention; this is a particular problem in the elderly male patient. **Antimuscarinics have been used to relieve stress incontinence, and urinary urgency of transient cystitis and bladder spasms due to infection or after urologic surgery

Describe Benztropine

Cholinergic antagonist Antimuscarinic agent **Parkinson's disease (benztropine) to lower the relative excess in cholinergic activity

Describe Ipratropium

Cholinergic antagonist Antimuscarinic agent An atropine analog used by oral inhalation to supplement beta-2 adrenergic agonists. (Tiotropium is longer acting) **Effects include reduction in bronchial secretions and laryngospasm; production of bronchodilation. **May be used as a preanesthetic medication to dry secretions and reduce laryngospasm; as bronchodilator in COPD, bronchial asthma

Describe Dicyclomine

Cholinergic antagonist Antimuscarinic agent Blockade of muscarinic receptors will inhibit gastrointestinal acid secretion and reduce motility. **Anticholinergics have been used to reduce gastrointestinal spasm This occurs at relatively high doses and can lead to constipation, particularly in elderly patients.

Describe Glycopyrrolate

Cholinergic antagonist Antimuscarinic agent Blockade of muscarinic receptors will inhibit gastrointestinal acid secretion and reduce motility. **Anticholinergics have been used to reduce gastrointestinal spasm, treat stomach ulcers This occurs at relatively high doses and can lead to constipation, particularly in elderly patients. **Used for reduction in salivary secretions **Asthma and COPD treatment

Describe Trimethaphan

Cholinergic antagonist Antinicotinic ganglionic blocker All ganglionic blockers are synthetic amines. Hexamethonium (C6), the prototype, is a quaternary ammonium compound which is a ganglionic blocker, but not a blocker at the neuromuscular junction. It is not used clinically. Trimethaphan is a non-depolarizing (competitive) blocker. It binds to the ACh nicotinic receptor site, but has no intrinsic activity. Since ganglionic blockers bind at both parasympathetic and sympathetic ganglia, the organ system effects depend on which division of the autonomic system predominates at each organ system. Central Nervous System - Cause sedation, tremor and mental abberations. Eye - cycloplegia with loss of accommodation and moderate dilation of the pupil. Cardiovascular System - decrease in arteriolar and venomotor tone, thereby causing hypotension, especially marked in upright position (orthostatic hypotension). Moderate tachycardia. GI Tract - reduced secretion and motility GU Tract - urinary hesitancy Sweat Glands - block thermoregulatory sweating **Clinical Application - very limited use for malignant hyperthermia and controlled hypotension. Use in treatment of essential hypertension has been replaced by newer, more effective agents.

Describe Homatropine

Cholinergic antagonist Competitive, reversible antagonists of ACh at muscarinic receptor sites. These agents have marked affinity for muscarinic receptors, but no intrinsic activity. **Can be used for to generate mydriasis of the eye. Last a couple days

Describe Tropicamide

Cholinergic antagonist Competitive, reversible antagonists of ACh at muscarinic receptor sites. These agents have marked affinity for muscarinic receptors, but no intrinsic activity. **Shortest acting mydriasis agent so more likely to be used for eye exams

Describe Atropine

Cholinergic antagonist Competitive, reversible antagonists of ACh at muscarinic receptor sites. These agents have marked affinity for muscarinic receptors, but no intrinsic activity. Atropine is more potent on heart, intestine and bronchial smooth muscle, and has a more prolonged action. Atropine, at therapeutic doses, is a weak CNS stimulant followed by more prolonged sedation. **Used to dilate the pupil, decrease salivary and bronchial secretion, increases heart rate, increases AV conduction, reverse AV block, reduce bronchial secretions, dilate bronchial airways **Used for cholinergic poisoning and myocardial infraction Not much effect on blood vessels at low doses, though atropine will block the effects of cholinomimetic agents. Atropine at higher doses or in cases of poisoning may cause vasodilation, atropine-flush and a reduction in blood pressure. This reaction has partially been explained by induction of histamine release. Atropine blocks muscarinic receptors in eye, causing mydriasis, cycloplegia (paralysis of ciliary muscle), reduced lacrimal secretion, and dry eyes. Muscarinic blockers are used in ophthalmology for eye examination, and to prevent adhesions in uveitis and iritis. **Could cause glaucoma because they are so long acting Blockade of muscarinic receptors will inhibit gastrointestinal acid secretion and reduce motility. This occurs at relatively high doses and can lead to constipation, particularly in elderly patients. **Anticholinergics have been used to reduce gastrointestinal motility (atropine with diphenoxylate-an opioid derivative, as an antidiarrheal) Signs of poisoning include: dry mouth, dry eyes, mydriasis, tachycardia, hot and flushed skin, elevated body temperature, agitation and delirium.

Describe Scopolamine

Cholinergic antagonist Competitive, reversible antagonists of ACh at muscarinic receptor sites. These agents have marked affinity for muscarinic receptors, but no intrinsic activity. Scopolamine has more potent action on the eye. Long acting so it can cause glaucoma When some central depressant effect is desired, scopolamine may be used. **Have been used in treatment of motion sickness Can cross the BBB

Describe Tolterodine

Cholinergic antagonist Detrol Antimuscarinic agent Blockade of muscarinic receptors can cause a decrease in the frequency of micturation and distention of the bladder. Therefore, drugs with antimuscarinic activity can produce urinary hesitancy and retention; this is a particular problem in the elderly male patient. **Antimuscarinics have been used to relieve stress incontinence, and urinary urgency of transient cystitis and bladder spasms due to infection or after urologic surgery

Describe Oxybutynin

Cholinergic antagonist Ditropan Antimuscarinic agent Blockade of muscarinic receptors can cause a decrease in the frequency of micturation and distention of the bladder. Therefore, drugs with antimuscarinic activity can produce urinary hesitancy and retention; this is a particular problem in the elderly male patient. **Antimuscarinics have been used to relieve stress incontinence, and urinary urgency of transient cystitis and bladder spasms due to infection or after urologic surgery

What are the indirect acting cholinergic agonists?

Cholinesterase Inhibitors: Physostigmine Pyridostigmine Neostigmine Edrophonium Organophosphates: Echothiophate Malathion/Parathion Soman/Sarin

What are chondrocytes?

Chondrocytes: cells responsible for synthesis of the cartilage-specific ECM components. Chondrocytes originate from mesenchymal stem cells which can also give rise to osteoblasts (bone), myoblasts (muscle) and adipocytes (fat). The transcription factor, Sox9 is required for the expression of cartilage-specific ECM (collagen type II). Lack of Sox9 expression prevents the chondrogenic differentiate from mesenchymal progenitor cells.

What are the properties of the major lipoprotein classes?

Chylomicron- Mostly triacylglycerol, produced in intestinal epithelial cells from dietary fats, A-1-A3, B-48, C1-C3 VLDL- Mostly triacyglycerol, B-100. C-1-C3, E, produced in the liver mainly from dietary carbohydrates IDL- A good amount of everything, B-100, C1-C-3, E, produced in the blood, endocytosed by the liver or converted to LDL LDL- Mostly cholesterol esters and cholesterol, but also phospholipids and proteins, B-100, produced in the blood, endocytosed by liver and peripheral tissues HDL- Mostly proteins but also cholesterol esters and phospholipids, A1-A-2, C1-C3, D,E, produced in the liver and intestine, returns cholesterol from peripheral tissues to liver, exchanges proteins and lipids with other lipoproteins

What configuration are most naturally occurring double bonds in polyunsaturated fatty acids?

Cis configuartion

What elements regulate the trp operon?

Cis-acting DNA sequences: -10 and -35 (promoter) operator Trans-acting proteins: trp repressor RNA polymerase + Sigma Regulatory Molecule: tryptophan Attenuation in the leader region of the mRNA also occurs at high tryptophan levels Note: 2 Trp codons in the region of the mRNA that encodes the leader peptide

What elements regulate the lac operon?

Cis-acting DNA sequences: -10 and -35 (promoter) operator CAP-binding site Trans-acting proteins: lac repressor CAP RNA polymerase + Sigma Regulatory Molecules: lactose (allolactose) cAMP NOTE: Transcription is never really off completely. Rather extremely low level of transcription.

Describe lymphocytes

Classified as B or T cells. Produced in bone marrow and lymphoid organs (e.g. thymus). RER is abundant, no secretory granules Life span - 20% are short-lived (3-5 days) and 80% are long-lived (from 100 - 200 days to years). FUNCTION: B cells: formation of immunoglobulins T cells: cytotoxic responses Null/NK cells: "Natural killer" cells. LARGE lymphocytes are either activated T/B cells or NK cells. B cells mature to become plasma cells - produce circulating antibodies. T cells (cytotoxic) are produced in bone marrow but mature or "trained" in the thymus. Null/NK cells - lack the specific "markers" that B- and T- cells have; kill certain tumor cells and cells infected with viruses.

What is Cleidocranial Dysplasia (CCD)?

Cleidocranial Dysplasia (cleido = collar bone, cranial = head, dysplasia = abnormal forming) * CCD is an autosomal dominant skeletal dysplasia. * Caused by different mutations in the Runx-2 (cbfa-1) gene (DNA binding domain), on chromosome 6. * Remember that Runx2 (cbfa-1) is the transcription factor that directs mesenchymal stem (progenitor) cells to differentiate along the osteoblast lineage. Characteristics include: •Absence of clavicles •Delayed closure (ossification) of the cranial sutures. •Short stature •Scoliosis of the spine •Teeth abnormalities

How do you generate a pure recombinant protein?

Clone sequences in frame with GST. Transformation and grow-up large quantities of cells. Induce expression. Lyse cells and perform purification based using glutathione beads. Remove tag by protease digestion. Analyze purity by SDS-PAGE. 1=extract 2=supernatant 3=bead purified protein

Describe microvili

Closely packed, finger-like projections of plasma membrane that increase surface area of the cell Number and shape on cell surface correlate with absorptive capacity Can be seen under LM as"brush border"present in kidney and intestine Glycocalyx an amorphous coat of glycoprotein Each microvillus contains a core of actin filaments which are cross-linked by several actin binding proteins Actin filaments extends downward into cytoplasm where they attach to terminal web>> a horizontal network of actin filaments lying below base of microvilli

How do coactivators and corepressors regulate transcription?

Coactivators and corepressors can regulate transcription by making direct contact or indirect contact through mediator with the general transcription factors associated with the core promoter. Binding of Activators and Coactivators can acetylate histone proteins (histone acetyltransferase activity) resulting in loosening of chromatin and activation of transcription. Binding of Repressors and Corepressors can deacetylate histone proteins (histone deacetylase activity) resulting in compaction of chromatin and repression of transcription.

How is budding controlled?

Coat protein complexes control budding 1) Cytosolic adaptor proteins recognize cargo receptors in the donor membrane, which concentrates the receptors and segregates them away from other donor compartment components 2) Coat proteins bind the adaptor proteins. 3) Specific proteins cause the membrane to undergo fission once a 'neck' has formed 4) The vesicle starts its journey to the acceptor membrane. Coat and adaptor proteins are released and recycled. COP = Coat protein. Each coat protein complex can bind multiple Adaptor proteins, which in turn recognize multiple cargoes Clathrin: 'late' steps - from plasma membrane to endosomes, and between TGN and endosomes. COPI: within Golgi, also ER retrieval pathway. COPII: anterograde from ER to Golgi Transport is mediated primarily by microtubules and microtubule motor proteins.

What is the name for vitamin B12 and what does it do?

Cobalamin Required for 2 rxns: Homocysteine-Methionine Methylmalonyl- CoA-Succinyl CoA *Elevated methylmalonate (from MMCoA) is linked to demyelination. *Elevated homocysteine (Met) is linked to increased risk for heart disease **Methionine, Valine and Isoleucine metabolism rely on B12 Major sources of B12: dietary meat, eggs, dairy products Absorption of B12 is critical (pernicious anemia, caused by destruction of parietal cells in stomach, leads to deficiency due to poor absorption of dietary B12)

What does cocaine do?

Cocaine blocks reuptake of DA, NE, E and serotonin, leading to sympathomimetic effects (peripheral and central effects) and euphoria (CNS effects)

What is the function of Acetyl CoA carboxylase?

Converts Acetyl CoA to Malonyl CoA in the cytosol Rate limiting enzyme in fatty acid synthesis Biotin essential and serves as a carrier for CO2

What is the function of Acyl CoA synthetase?

Converts fatty acid to fatty acyl CoA so it can pass through the outer mitochondrial membrane Uses ATP

What happens during a hypercatabolic state?

Cortisol major hormonal mediator Food intake is decreased, so fat mobilized, muscle protein degraded to provide energy, amino acids. Fatty acids are major fuel source for muscle in this state. Immune cells prioritized for amino acid uptake (to synthesize protein, nucleic acids) Characterized by increased fuel utilization and negative nitrogen balance (nitrogen excreted is greater than the amount consumed) Mobilization of protein, lipid and carbohydrate serves to maintain normal tissue function in the presence of limited dietary intake, as well as to support the requirements of the immune response and wound healing Cells of the immune system receive top priority in terms of utilization of amino acids (released from muscle) Glutamine serves as a nitrogen donor for purine synthesis Fatty acids are mobilized from adipose to provide alternative fuels and to spare glucose. Fatty acids major source of fuel for muscle under these conditions Immune cells (macrophages, lymphocytes) receive top priority for amino acids (component of immune response to infection)

What are bacterial plasmids?

Covalently closed, double stranded circular DNA (occasionally linear) Usually not essential for bacterial growth Replicate separately from the chromosome Narrow host range (present in limited number of bacterial species) Broad host range plasmids replicate in many species Conjugative plasmids can transfer

Describe focal adhesions

Create a link between actin cytoskeleton and the ECM proteins via integrins Dynamic structures important for cell migration during wound healing Integrins are the major transmembrane proteins involved in Focal adhesions. Integrins transmit signals (mechanical or biochemical) to the interior of the cell where they affect migration, differentiation and growth. Sites of signal detection and transduction. Detect contractile changes in the ECM and convert then to biochemical signals -mechanosensitivity-allows cells to alter their adhesion-mediated functions in response to external mechanical stimuli. Integrins transmit the signal to the interior of the cell where they affect migration, differentiation and growth.

How is creatinine synthesized?

Creatine phosphokinase (CPK or CK) converts creatine to creatine phosphate using ATP in the muscle and brain Creatine phosphate is then converted to creatinine non-enzymatically which is excreted in the urine Constant rate of irreversible formation, proportional to muscle mass. Creatinine in urine, blood is used to follow kidney function, urine strength, muscle wasting. Because creatinine is made proportional to muscle mass, and freely filtered by kidney (not reabsorbed) its level in blood indicates kidney function (most men, 1 mg/dL is normal; women slightly below 1).

What are the characteristics of skeletal muscle?

Cross-striations are produced by the architectural arrangements of the thick and thin filaments inside a muscle cell (myofiber). Derived from somite under a thin layer of ectoderm Myoblasts-Myocytes-Myotubues MyoD family of trans-activating proteins. The Conserved Basic-Loop-Helix Region in the MyoD Family of Trans-acting Factors. Pax7, MyoD, Myogenin Plasma membrane + basal lamina = sarcolemma

What happens in cyanide poisoning?

Cyanide binds to Fe3+ in complex IV preventing transfer of e- to oxygen so the body cannot generate ATP. It is an irreversible inhibitor of complex IV (cytochrome C oxidase) Cyanide binds to the Fe3+ in the heme of the cytochrome aa3 component of cytochrome c oxidase and prevents electron transport to O2. Mitochondrial respiration and energy production cease, and cell death rapidly occurs.

What are the different cyclins?

Cyclin D (in G1): In response to mitogenic stimuli initiates inactivation of pRB proteins, which otherwise block cell cycle progression. Cyclin E (in G1/S): Cooperate with Cyclin D/CDKs to inactivate pRB proteins and also stimulates the the G1/S transition. Cyclin A (in S phase): Promotes DNA synthesis and blocks re-initiation of DNA synthesis at newly synthesized origins of replication. Cyclin B (in M): Promotes Initiation of Mitosis and many of the critical events associated the generation of the spindle, chromosome condensation, nuclear envelope breakdown, etc

What is the significance of mutations in CDKN2A & B-Raf to the molecular pathology of the melanoma?

Cyclin-dependent kinase inhibitor 2A (CDKN2A) is a tumor suppressor gene that stops a cell going from G1 to S phase by inhibiting CDK4. Without it, CDK4 will phosphorylate Rb protein and that allows the cell to transfer into S phase. B-Raf is an oncogene that codes for the B-Raf protein. This protein takes part in the Ras/MAPK pathway as serine/threonine protein kinase. A mutation of the B-Raf protein will send a constant signal and allow the cell to grow uncontrollably causing cancer.

What is methemoglobinemia?

Cytochrome b5 Reductase Deficiency ? Methemoglobin contains Fe3+ (ferric iron) instead of Fe2+ (ferrous iron). Methemoglobin does NOT bind oxygen. About 1% of hemoglobin is usually in the methemoglobin form. An enzyme, methemoglobin reductase, uses NADH to re-reduce methemoglobin to hemoglobin Patients may either have defect in the enzyme that re-reduces methemoglobin, or defects in the systems that produce NADH (PK deficiency). Patients appear gray or blue.

Where does glycolysis occur?

Cytosol

Where in the cell does ethanol metabolism occur?

Cytosol and mitochondria

What is dorsal ventral patterning?

D-V polarity determined by ectoderm facing it. Wnt7a is expressed in the dorsal but not ventral ectoderm and is needed for dorsal patterning of the limb. Wnt7a-/- embryos have ventral food pads on both surfaces. Wnt7a induces Lmx1 in the dorsal mesenchyme. Mutant Lmx1 in humans results in nail-patella syndrome.

What changes the power when sample size is unchanged?

Decrease in alpha level decreases power Decrease in the detectable difference decreases power

What changes the detectable difference when sample size is unchanged?

Decrease in alpha level increases detectable difference Increase in power increases detectable difference

What is glycine encephalophathy?

Defect in Glycine Cleavage enzyme subunits. Result of toxic accumulation of glycine in blood and tissues (hyperglycinemia); presents in infancy or later, as seizures, breathing difficulties, movement disorders, and intellectual disability. (glycine is an inhibitory neurotransmitter in the CNS, this excess is thought to be responsible for symptoms) Prognosis is poor (death <2yrs).

What can cause megaloblastic anemia and how do you differentiate them?

Deficiencies in vitamin b12 or folate. Homocysteine accumulation suggests that it is not being regenerated back into methionine ( and → SAM → SAH). This process requires both vitamin b12 and folate. Therefore simply knowing that homocysteine is elevated does not inform us whether or not the patient has a deficiency in vitamin b12 or folate. You may wish to measure the amount of FIGLU in the system. FIGLU is an intermediate in the metabolism of dietary histidine which receives a methyl group from folate. In folate deficiency, FIGLU cannot be converted into N5 Formimino-FH4. Alternatively, you would want to measure the amount of methylmalonyl. Vitamin b12 is required in the metabolism of methylmalonylCoA to succinylCoa. A vitamin b12 will lead to a buildup of methylmalonylCoA.

What happens with folate deficiency?

Deficiency of folate results in the accumulation of FIGLU in the urine (FIGLU = formiminoglutamate, product of histidine metabolism); high FIGLU is an indicator of folate deficiency. Importantly, folate is an important single-carbon carrier that is critical in nucleotide biosynthesis; if this is defective, no new DNA! And production of rapidly-dividing cells (like blood cells) will slow down! (macrocytic anemia!) Active form is FH4 Sulfa drugs, the first systemic antibiotics, inhibit growth of bacteria by competitive inhibition of DHPS, bacterial enzyme involved in folate synthesis Carbon atoms from from AA such as Ser, his, gly and trypotphan Creates purines, serine, and SAM

What is zellweger syndrome?

Deficit in trafficking proteins to peroxisomes (most common forms due to mutations in various Peroxins). Peroxisomes are 'empty' - leads to severe abnormalities in brain, liver and kidneys. Survival usually <6 months.

What can initiate an action potential?

Deformation - stretch (touch receptor) Temperature. Light - photoreceptors APs can be initiated in skeletal muscle by neuromuscular transmission (will be discussed later) APs can be initiated in cardiac myocytes via spontaneous generation of APs by the cardiac pacemakers APs can be initiated via gap junctions APs can be initiated in some types of smooth muscle by ligands binding to receptors APs can be initiated when a health care professional or a neurophysiologist applies an electrical stimulus to a membrane

What is variable expressivity?

Degree of gene expression varies among individuals carrying a mutation The gene is always expressed, but some patients have more severe problems than others Neurofibromatosis (NF1) -In some patients, a few light brown skin tone areas known as café au lait spots occur -In others, even within the same family who have the same gene disease variant, hundreds of tumors (neurofibromas) develop that protrude through the skin.

What is Van't Hoff equation?

Delta Pi = nRT(DeltaC) n is the number of particles the solute dissociates into (1 for nonelectrolytes, 2 for NaCl, 3 for MgCl2, etc.); R is the universal gas constant 0.08205 liter · atmosphere/mole · Kelvin; T is the Kelvin temperature ( = 273 + Celsius temperature); ∆C = difference in molar concentration * this assumes that NO solute can Cross the membrane Van't Hoff equation quantitates osmotic pressure across a membrane

What is the difference between type 1 and type 2 diabetes?

Diabetes Type 2: is caused by an insensitivity of insulin receptor rather than a lack of ability to produce insulin as in type 1 Diabetes Type 1: Alterations in β-cell production of insulin → pt eventually becomes insulin dependent & will require endogenous insulin injections, can come from type 2 diabetes, after years of overproducing insulin to compensate for the insensitivity the beta cells will burn out

Describe B-cells

Differentiate in bone marrow (BM) When activated outside BM they differentiate further into Ab-producing cells Respond to cell-free and cell bound Ags Abs neutralize extracellular pathogens Adaptive Immunity

Describe alochol dehydrogenase

Dimeric zinc-dependent enzyme, seven different ADH genes have been described. These can be categorized into 5 different classes. Substrates include: endogenous EtOH from microbiota, EtOH in foods and EtOH from ingestion. Reaction uses NAD+ as cofactor. ADH1 is encoded by 3 genes which code for 3 subunits (A,B.C) that can homo-or heterodimerize. Class I ADH1 isoforms have a low Km for ethanol and are highly expressed in the liver. ADH4 is a homodimer with a high Km (>20 mM) and may be important for metabolizing high levels of EtOH in the upper GI tract.

What does DPPC do?

Dipalmitoylphosphatidylcholine reduces the surface tension with alveoli Provides resistance to compression which helps prevent the sac from collapsing on exhalation

What is the CRISPR-CAS9 system of genetic engineering?

Discovered as prokaryotic "immune system" that confers resistance to foreign genetic elements such as plasmids and phages. Engineered to allow for gene knock-outs/replacement in higher organisms, both in cells in culture and in vivo. Advantages: 1)Efficiency of knock-out/replacement much higher than traditional gene knock-out approaches. 2)Can be done in such a way where there is no permanent residents of exogenous genetic material or vector sequences. 3)Can get complete knock-out of gene (not the case with shRNA) 4)Can me manipulated in many different ways.

What is the capsule composed of?

Discrete layer associated with individual cells Capsule = associated with individual cells Functions of capsule: Mediate adherence Protect from phagocytosis Protect from dying

What is homocystinuria?

Disorder: A defect in cystathionine synthase leads to buildup of homocystine (oxidized homocysteine) in blood and urine. HCU results in a range of symptoms, including risk of cardiovascular disease and thromboembolisms (25% die by age 30). A deformity of the chest sometimes seen (as above), and lens dislocation is frequent (90%). Prevalence: 1/350,000 worldwide, more common in Finland, Denmark (1/20,000). Treatment: Pyridoxine megatherapy works in about half the cases (see next slide). Lower intake of methionine, increase intake of cysteine, take folic acid. Reminder: Metabolism of homocysteine to cystathionine (by cystathionine synthase) requires PLP

What is cystinuria?

Disorder: Failure of renal reuptake (and intestinal uptake) of cystine (oxidized cysteine). Intestinal carrier loss is of little clinical significance (Why?), cystine in urine causes stones (crystals) that damage kidneys, cause pain, death. Drink Water: first-line therapy is large-volume fluid intake (urine output >2.5 L/d), regular urine pH monitoring (urine pH of 7.5 and <8.0), dietary restrictions (low methionine) and urinary alkalization with potassium citrate. Mixed Disulfides: If hydration fails to achieve the urinary cystine concentration of 300 mg/L, then medical therapy with D-penicillamine must be added. Penicillamine combines with cystine to form a soluble disulfide complex (50 times more soluble than cystine), thus preventing stone formation and possibly even dissolving existing cystine stones.

What are thalassemias?

Disorders associated with decreased production of hemoglobin chains Alpha- and beta-thalassemias- Alpha-thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced. The excess β chains form unstable tetramers, leads to abnormal oxygen dissociation curves. Inherited disorder (autosomal recessive). Beta-thalassemias lead to decreased or absent beta-globin Beta-thalassemia major (also called Cooley's anemia), total absence of beta chain, is most severe form. Treatment: bone-marrow transplant! (80-90% success)

What are the disadvantages of exome sequencing?

Disorders due to large repeat expansions (Fragile X, Huntington's Disease) will not be identified* -Need to test for these using adjunct method CNVs, at this time, are still best identified using arrayCGH methods* Not all nucleotides of all genes will be covered Pseudogenes and homologous regions may also be captured. Trios are usually best (proband and both parents). *Also a limitation of Sanger Sequencing

What is the affect of dopamine on the heart?

Dopamine COMPLEX ACTION ⇒ D1 = D2 >β > α Low dose binding to D1/D2 receptors [high] act on β1 myocardial receptors ☛ positive inotropic effect (cardiac dose) [higher] act on α1 receptors resulting in vasoconstriction (vasopressor dose)

How do you determine a dosing rate, loading dose and the maintenance dose?

Dosing ratess = Rate of Eliminationss = CL x TC (or Css) Clearance is important in defining the steady-state to achieve a Target Concentration (TC) The dosing rate can be determined if TC and CL values are known Maintenance dose = dosing rate x dosing interval Mr. W. is a 70kg individual receiving warfarin. The therapeutic concentration of warfarin is 0.75mg/L with clearance and Vd of 0.192L/hr and 8L respectively. Calculate the daily maintenance dose for Mr. W. Dosing ratess = (Cl )(TC) Dosing ratess = (0.192L/hr)( 0.75mg/L) = 0.144mg/hr Maintenance dose = (0.144mg/hr)(24hr) = 3.45mg/day Doseloading= (Css)(Vd) Doseloading= (0.75mg/L)(8L) = 6mg t1/2 =( 0.693)(Vd) Cl = (0.693)(8L)= 28.9 hr 0.192L/hr

Describe tripomyosin

Double helix of two polypeptides, lies in the groove between actin molecules. TnT: Binds the complex of Tropomyosin TnI: Inhibits the binding of myosin to actin TnC: Binds calcium Troponin: three globular subunits

What happens during DNA damage by gamma radiation and x-rays?

Double strand DNA breaks Most lethal Interferes with DNA replication, transcription and causes chromosomal rearrangements

What different types of mutations cause cancer?

Driver mutations confer a growth advantage while passenger mutations do not. These in coding regions affect the activity of oncogenes and tumor suppressor genes. How do you discriminate based on the mutational data? When the number of mutations in a gene is very high, as with p53 or KRAS, it is likely a driver and have been termed mountains. Genes with relatively few mutations (called hills) numerically dominate cancer genome landscapes and it remains unclear which are drivers. Oncogenes are recurrently mutated at the same amino acid position, whereas tumor suppressor genes are mutated through protein-truncations alterations throughout their length.

What happens during biliary excretion?

Drugs from the general circulation may enter the liver and be excreted into the bile. There are at least three different carrier-dependent systems: for organic acids, for organic bases, and for some steroids. Competition can occur within each group. Drugs or their metabolites which have entered the gut via the bile may then be directly excreted in the feces. In some cases, the drug or metabolite undergoes enterohepatic recirculation, thus re-entering the blood stream and prolonging its half-life in the body. The overall transfer from plasma to bile involves three main phases: Active uptake into the hepatocyte. This is a saturable, active transport process. Storage and/or biotransformation in the hepatocyte. Release into the bile. The relationship between drug biotransformation and excretion in the bile varies with different drugs.

What is chronic granulomatous disease (CGD)?

Due to genetic defects in components of the NADPH oxidase and affected individuals cannot produce ROS. These patients suffer from severe and recurrent bacterial and fungal infections.

How are apoptosis and necrosis different?

Dying cells by apoptosis usually undergo a characteristic morphological change, in which the cell and its nucleus shrink and condense and frequently fragment. In contrast, necrosis is when cells die as a result of acute insults such as trauma or lack of blood supply, usually swell and burst, spilling their cytosolic contents into the extracellular space and elicit an inflammatory response. Cells that die by apoptosis are phagocytosed by macrophages, or other neighboring cells, there is no leakage and no inflammatory response. Once inside the macrophage, the apoptotic cell is quickly disassembled and its chemical building blocks reused.

What enzymes are involved in the ubiquitin conjugation process?

E1 (ubiquitin activating enzyme): (E1) loads two ubiquitin molecules (one at its adenylation domain as an adenylate (AMP) and the other linked to a Cys at its active site as a thioester). 2 in human genome E2 (ubiquitin conjugating enzyme): Interacts with E1 and accepts the transfer functions in the transfer of ubiquitin to a Cys residue in its active site. 50 in human genome E3 (ubiquitin ligase): Interacts with substrate and E2 and facilitates the transfer of ubiquitin from the E2 to a lysine residue on substrate or a previously attached ubiquitin. Remains bound to substrate while E2 disassociates. 500

What does it mean that the genetic code is unambiguous?

Each codon specifies only one amino acid

What is anticipation?

Earlier onset with more severe symptoms in subsequent generations -Huntington's disease A type of variable expressivity Occurs primarily with triplet repeat expansions -The larger the repeat, the more severe the disorder, and the earlier the age of onset. -The larger the repeat, the more unstable, and the greater the chance that it will expand further as it is passed from generation to generation.

What happens in sickle cell anemia?

Effect of the Glu6-Val6 (E6V) (negative charged AA to branched AA) change in the beta subunit of HbA is to allow deoxyHbS (only deoxy!) to polymerize as fibers. Result is pleiotropic (affects multiple systems), life-threatening anemia in HbS homozygotes (sickle cell disease). In sickle cell disease, all hemoglobin contains the E6V beta-globin; sickling, hemolysis, hepato- / splenomegaly, pain. HbS can bind and release oxygen but when oxygen is not bound it will form aggregates. The exposed valine will go to an exposed binding pocket on other hemoglobin molecules that is a hydrophobic binding pocket and clump together changing the shape of the blood cell. Also the hemoglobin can no longer bind oxygen in this form

What are the organ effects of antimuscarinic agents?

Effects include reduction in salivary secretions. Can be useful therapeutically, when drying of secretions is preferred or can be an annoying adverse reaction (dry mouth). Effects include reduction in bronchial secretions and laryngospasm; production of bronchodilation. May be used as a preanesthetic medication to dry secretions and reduce laryngospasm; as bronchodilator in COPD, bronchial asthma. Blocks muscarinic receptors in eye, causing mydriasis, cycloplegia (paralysis of ciliary muscle), reduced lacrimal secretion, and dry eyes. Muscarinic blockers are used in ophthalmology for eye examination, and to prevent adhesions in uveitis and iritis Lower doses of atropine may initially cause a transient bradycardia due to central vagal stimulation. Vagal blockade at muscarinic receptors in the heart causes a more prolonged increase in heart rate; atropine may be used to elevate heart rate. Blockade of muscarinic receptors can cause a decrease in the frequency of micturation and distention of the bladder. Therefore, drugs with antimuscarinic activity can produce urinary hesitancy and retention; this is a particular problem in the elderly male patient. Antimuscarinics have been used to relieve stress incontinence, and urinary urgency of transient cystitis and bladder spasms due to infection or after urologic surgery Blockade of muscarinic receptors will inhibit gastrointestinal acid secretion and reduce motility. This occurs at relatively high doses and can lead to constipation, particularly in elderly patients. Anticholinergics have been used to reduce gastrointestinal spasm, reduce gastrointestinal motility and reduce acid secretion in peptic ulceration. Their primary use in peptic ulceration has been overshadowed by histamine-2 receptor blockers, proton pump inhibitors, and antimicrobial therapy. Nonquaternary (uncharged) anticholinergics can cause sedation, have been used in treatment of drug-induced Parkinson's disease to lower the relative excess in cholinergic activity and in prevention and treatment of motion sickness. High doses may produce delirium, mental confusion and memory loss. The antimuscarinic drugs are contraindicated in patients with glaucoma, and in elderly men, especially with prostatic hyperplasia.

What directions do efferent and afferent neurons travel?

Efferent neurons can conduct action potentials down a motor nerve resulting in skeletal muscle contraction Afferent neurons can conduct APs, created when peripheral receptors (touch, vision) convert analog information into digital form, to the central nervous system.

What is the difference between potency and efficacy?

Efficacy is the maximum response that can be achieved, how well the drug can elicit a response Potency is the EC50, the amount of a drug need to elicit a response

How does oxidation of monounsaturated fatty acyl CoA differ?

Enoyl CoA Isomerase to move the double bond Enoyl CoA hydratase to add an OH group to the beta carbon so that beta oxidation can occur

What is the importance of a refractory period

Ensure one direction of AP conduction-we will learn this during next lecture. Ensure enough time for heart relaxation (you will learn this in the future) Separating the first and ensuing action potential, so signal coding is possible. If a neuron has an absolute refractory period of 1.25mS, what is the maximum firing rate? Maximum firing rate = 1 S/ 1.25mS = 1000mS/1.25mS = 800 (Hz)

How is the fidelity of translation ensured?

Ensure tRNA synthetase links the correct amino acid to each tRNA

Describe the p38 MAPK pathway

Environmental stress and/or inflammatory cytokines activate MAPKKKs through a variety of signalling mechanisms. Activated MAPKKKs subsequently activate MAPKKs, which in turn activate MAPKs. Activated MAPKs then phosphorylate several substrates, such as transcription factors. These effector molecules are essential for cellular responses that include cytokine production and transcriptional regulation. In this figure, dotted lines represent indirect effects, and solid lines represent a direct effect.

What is serine hydroxymethyltransferase?

Enzyme is cytoplasmic; major fate of serine in humans is giving C1 to FH4; other product is glycine Single carbon is captured by tetrahydrofolate (THF, FH4) to form "FH4-C1". FH4-C1 can donate single carbons in other reactions (nucleotide and serine synthesis), so this process is really, really important. If nucleotide synthesis is decreased, leads to anemia (seen with folate / B12 deficiency)

What are the cellular defenses against oxygen toxicity?

Enzymes - superoxide dismutase - catalase - glutathione peroxidase and reductase Non-enzymatic - vitamin E - ascorbic acid (vitamin C) - carotenoids - flavonoids - endogenous antioxidants ( uric acid, melatonin)

What are some Diseases Associated with Malfunction ofIntermediate Filament Based Cellular Structures?

Epidermolysis bullosa simplex mutation in keratin genes expressed in basal cell layer of epidermis, result in a skin that is very sensitive to mechanical injury. Progeria 'fast aging disease' associated with a mutation in nuclear lamin protein IFs and disease, cont. 76 distinct diseases have been associated with the intermediate filament gene family (for details see http://www.interfil.org/diseases.php). Keratins - Mutated in greater than 20 diseases. Vimentin - ?? Desmin - Mutated in cardiomyopathies*. Neurofilament proteins - Small subunit mutated in the 1F/2E forms of Charcot-Marie Tooth disease*. Peripherin - Induced after peripheral nerve injury. Glial fibrillary acidic protein - Mutated in Alexander disease (a leukodystrophy, which results in abnormal myelin)*.

What are the direct acting non selective adrenergic agonists?

Epinephrine Norepinephrine Ephedrine Dopamine

How is tRNA synthesized?

Eukaryotic cells contain multiple copies of each tRNA gene. RNA polymerase III transcribes the tRNA genes, recognizing a split promoter within the transcribed region of the gene. The intron in the tRNA precursor is removed leaving a phosphate and OH group that are modified and the loop is closed. CCA sequence is added at 3'-end one at a time by nucleotidyltransferase.

Describe formation of translation initiation complex (in eukaryotes).

Eukaryotic initiation factor 2 (eIF2) releases GDP in exchange for GTP, mediated by the GAP activity of eIF2B. This activates the ability to eIF2 to form a complex with met-tRNA. The eIF2-GTP-met-tRNA complex binds 40S ribosomal subunit, + eIF3. To produce the 43S subunit. Cap at 5'-end of mRNA binds to eIF4 complex (cap-binding complex) (eIF4 comprises eIF4E, eIF4A, and eIF4G) mRNA-cap-binding complex binds to eIFs-met-tRNAiMet -40S ribosome complex (i.e. 43S complex). Complex unwinds a hairpin loop in mRNA and scans mRNA until it locates AUG start codon. GTP is hydrolyzed, eIFs are released and 60S ribosomal subunit binds.

What are the acquired capabilities of cancer?

Evading apoptosis (P53, BCL2) Self-sufficiency in growth signals (H-RAS*, EGFR,ERB) Insensitivity to anti-growth signals (RB loss) Tissue invasion and metastasis (E-cadherin loss) Limitless replicative potential (Telomerase) Sustained angiogenesis (VEGF*)

What is an ecological study?

Evaluation of associations between exposures and outcomes in populations rather than individuals Usually based on existing population data Groups may be any definable population, including schools, cities, nations Information must be available from each group on exposure and disease measures

What happens during fermentation?

Fermentation of pyruvate occurs when bacteria reduce pyruvate to recycle NADH+H+. Enzymes catalyze the reduction of pyruvate using NADH + H+ as the electron donor The end products are acids (short chain fatty acids; scfa), alcohols, diols, and gases Many different species of bacteria produce these endproducts via similar pathways The types of substrates used, the types of endproducts and the regulation of the pathways can vary between the different species of bacteria scfa (acetate, proprionate and butyrate) have influences on the human host Disaccharides and fiber are broken down into hexoses by secreted enzymes Multiple hexoses are taken up through PTS systems by group translocation Hexoses enter glycolysis at fructose 1,6 diP ATP is produced by substrate level phosophorylation Fermentation uses enzymes to reduce pyruvate and recycle NAD resulting in reduced pyruvate endproducts; including SCFA, alcohols and gases Acid production is the hallmark of fermentation

What are some functions of actin?

Fibroblasts stained to reveal F-actin Stress Fibers: myosin, a-actinin, formins Leading Edge Meshworks: Arp2/3, profilin, cofilin, etc. Myosins: F-actin Associated Force Generating Mechanoenzymes with Roles in Contractility and Intracellular Transport, Most myosins move toward the barbed end of filaments Cytokinesis: F-actin amd myosin II at the Contractile Ring During Cell Division Microvilli: actin based epithelial projections-Small intestine: increase surface area for absorption during digestion-Ear cells: detect sound waves using stereocilia Cytoskeleton and Cell Attachment to the Extracellular Matrix (ECM) F-actin serves as scaffold for spectrin web in blood cells

Rate is the rate of elimination?

First order kinetics Rate of elimination is proportional to plasma conc. Plasma half-life or Zero order kinetics (ethanol) Constant AMOUNT eliminated per unit time Doesn't change with plasma concentration

Describe atherosclerosis

First step is the formation of foam cells by oxidized LDL and macrophages Foam cells form fatty streaks Excessive formation of fatty streaks eventually cause further endothelial damages Damaged endothelial cells release TXA2 Platelets and macrophages migrate to the site of injury and release growth factors The growth factors cause proliferation and migration of smooth muscle cells to the intimal layer of the arterial wall Muscle and endothelial cells in the site of injury secret fibrous material such as collagen, which forms a cap. Macrophage cells are trapped by the fibrous cap and die over there making a fibrous plaque Then, calcification occurs on the cap, forming thick and tough deposits. When rupture and hemorrhage of the plaque occurs, a blood clot or a thrombus is formed, which further blocks the blood vessel, causing a myocardial infarction.

How does the heart contract?

First the atria, then the ventricles. Rhythmic contraction of muscle without direct stimulus from the nervous system The SA node, in the upper part of the right atrium of the heart is a specialized bundle of cells known as the sinoatrial node (SA node). The SA node "fires" at regular intervals causing the heart of beat about 60 to 70 beats per minute in a healthy, resting adult. The electrical impulse from the SA node triggers a sequence of electrical events to control orderly muscle contractions that pump the blood out of the heart.

What does Na+/K+ ATPase do?

Found in the plasma membrane (a "P-type" ATPase) Generates the electrochemical gradient for Na+ and K+ ions (keeps cytosolic Na+ low, K+ high) Critical for function of excitable tissues like nerve and muscle; target for digoxin ("cardiac glycoside" used to treat A-fib, heart failure) For most cells, Na+/K+ ATPase uses around 20% of the cellular ATP; for neurons it uses nearly 70%!!! During each transport cycle, moves 3 Na+out, 2 K+ in, 1 ATP consumed.

What is premutation in fragile X syndrome?

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an "adult onset" neurodegenerative disorder, usually affecting males over 50 years of age. Fragile X-associated primary ovarian insufficiency- complete cessation of menstrual periods before the age of 40. Range of symptoms includes irregular cycles, "sub-fertility" or infertility, hot flashes, etc.

What are the different roles of bone?

Framework for the trunk and extremities to withstand mechanical loads Levers for locomotor function Protect vulnerable viscera Skull for the brain Vertebral column for the spinal cord Rib cage for the heart and lungs Site for hematopoiesis (bone marrow) Maintain mineral (calcium) homeostasis

What is the founder effect?

Frequency of a new allele is low in initial population An individual with the new allele founds a new population The frequency of the new allele is markedly higher in the new population than the original, due to its relatively high frequency in the founder's descendants

Describe adipose tissue

Function Depot for triglycerides—main energy stores Insulates body against the heat loss Fat stored as triglycerides High density energy Fills space between tissues Provides cushions certain anatomical parts behaving as shock absorbers (e.g.the soles of feet, around the kidney, in the orbit around the eye). Paracrine and Endocrine Substances Example: Secretes Leptin which acts on hypothalamus to regulate food intake and energy consumption Unilocular (White, common) adipocyte: Structural Features: Contain a large lipid droplet surrounded by a ring of cytoplasm The nucleus is flattened and located on the periphery Richly supplied with blood vessels Secretes reticular fibers that surround the adipocyte Multilocular (Brown) adipocyte: fetal life and first decade after birthL Structural Features: Multiple Lipid droplets Eccentric nucleus Numerous mitochondria Function: Primarily serves to generate heat rather than storage

Describe plasma cells

Function : Produce a single class of antibodies in response to antigen Concentrated in areas with likely penetrationof foreign material, e.g., GI tract. Structural Features: Oval cell, eccentric nucleus Clock face" or "wheel" nucleus; RER >> Basophilic cytoplasm Golgi "ghost" Structural Features : Under EM Typical features of protein secreting cell; Well developed ER and Golgi Apparatus

Describe lymph nodes

Function: Function: Filters lymph Differentiation of B cells Houses T cells Interaction between lymph and blood: allow recognition of antigen presented by APC (dendritic cells) to lymphocytes and generation of T and B cell clones. Three zones in the parenchyma: 1.Cortex (aka Outer Cortex): lymphoid follicles 2.Paracortex (aka Deep Cortex or Inner Cortex): CD4+ T helper cells & venules lined by high endothelial cells. T helper cells interact with B cells to induce their proliferation and differentiation. Medulla

Describe gap junctions

GAP JUNCTIONS (NEXUSES, Gated Channels) Cell-Cell Communication-Uniformity of Function Allows for direct electrical and chemical communication between cells An accumulation of transmembrane channels Generally allows smaller molecules to pass through (ions, regulatory molecules, small metabolites). Large molecules are not allowed to pass. Gap junction ensures that molecules passing through they do not leak into the intercellular space Important where adjacent cell activity must be coordinated. Gap junctions are composed of integral membrane proteins called connexins Six connexins monomers associate to form a connexon Connexon of one cell align with connexon of an adjacent cell to form a intercellular channel Connexons are regulated to open or close by the ionic makeup of the cell. High calcium concentration or low pH results in closing of the channel

How is the cap structure added to hnRNA?

GTP ans SAN react with mRNA precursor

Describe G-Protein signal transduction.

GTP binding proteins Heterotrimeric G proteins All G-protein-linked receptors consist of a single polypeptide chain that threads back and forth across the lipid bilayer seven times. G-protein coupled receptors are coupled to heterotrimeric G proteins. Which consist of three subunits: An alpha subunit, which contains the GTPase domain, can hydrolyze GTP, and activate intracellular targets. A beta subunit, and a gamma subunit, which regulates the activity of the alpha subunit, and can also activate intracellular targets. Step 1. the unstimulated a subunit is GDP bound. When stimulated, the a subunit releases GDP, allowing GTP to bind in its place, causing the trimer to dissociate into two activated components. Step 2. GTP binding causes a conformational change that releases the bg complex, and allows it to interact with its target proteins. Step 3. The bg complex is now available to interact with a second set of target proteins, which relay the signal onward. Step 4. The a subunit is a GTPase, and once it hydrolyzes its bound GTP to GDP, it re-associates with a bg complex to re-form an inactive G protein. The time during which the a subunit and bg complex remain apart and active depends on how quickly the a subunit hydrolyzes its bound GTP. The activity of the Heterotrimeric G protein cycle is directly related to GTP hydrolysis of the alpha subunit

What is an alternative promoter?

Genes may have more than one promoter Each promoter may be regulated very differently Provides diversity in regulation of expression and always effects the sequence of the 5' end of the mRNA

What are the omes?

Genome -~6 gigabytes (6 billion "base pairs") of DNA (diploid genome) -~98% "intergenic" (between genes) Exome -1-2% subset of genome encoding exons of genes Transcriptome -All of the "expressed" RNA "transcripts" of genes

What happens during the fasting state?

Glucagon released and sends signal to the liver to release glucose into the blood by gluconeogenesis and glycogenolysis Fatty acids are released from the adipose tissue to go to the liver for lipolysis Ketone bodies begin to increase for energy Ketone bodies are broken down in the muscle for energy Amino acids are degraded in the muscle and delivered to the liver for gluconeogenesis

What happens during the starving state?

Glucagon released and sends signal to the liver to release glucose into the blood via gluconeogenesis Fatty acids are released from the adipose tissue to go to the liver. Major source of energy for the muscle for lipolysis FFA are metabolized to ketone bodies in the liver and released into the blood. As levels rise oxidized by brain as major energy source (still uses glucose). Glycerol released by lipolysis is a gluconeogenic substrate. Muscles are no longer utilizing ketone bodies as energy fuels The Cori cycle: the release of lactate and pyruvate from glucose-dependent tissues (ex. RBC) are gluconeogenic substrates. Proteolysis of muscle decreases as glucose use by the brain is reduced due to rising ketone levels. Protein sparing, optimizing survival. Gluconeogenesis continues in liver, kidney and small intestine. Renal gluconeogenesis ramps up Substrates are lactate, aa and glycerol.

How is glycogenolysis regulated?

Glucagon: Phosphorylase kinase is activated (phosphorylated) by PKA whereas Glycogen synthase is inactivated by PKA phosphorylation and GSK3 phosphorylation (no insulin) Phosphorylase kinase activates (phosphorylates) glycogen phosphorylase Glycogen phosphorylase exists in two interconvertible forms: a which is catalytically active and b catalytically inactive Glycogen phosphorylase is dephosphorylated and thereby inactivated by insulin G-6-p inhibits Glucose inhibits glycogen phosphorylase in the liver ATP inhibits glycogen phosophorylase in the liver and muscle Ca activates phosphorylase kinase in muscle activating glycogen phosphorylase AMP activates glycogen phosphorylase in the muscle

What happens in Gaucher's disease?

Glucocerebrosidase (aka glucosyl-𝞫-glucosidase) is the enzyme that catalyzes the breakdown glucocerebroside (aka glucosylceramide) turned on by SAP-C protein. Specifically, this enzyme catalyzes the hydrolysis reaction that breaks the glycosidic linkage in glucocerebroside, resulting in a ceramide and a sugar (glucose) molecule. Reduced activity of glucocerebrosidase results in accumulation of glucocerebroside. Gaucher's Disease is the associated sphingolipidosis.

What ligand act on the steroid hormone receptor family?

Glucocoticoids (cortisol), the mineralocorticoid aldosterone Sex hormones: estrogens, progesterone and testosterone Thyroid hormone, T3 Calcitriol, the active form of vitamin D Vitamin A and retinoic acid

How is glucokinase regulated?

Glucokinase transciption is induced by insulin Glucokinase is inhibited by binding to glucokinase regulatory protein (GKRP) leading to its nuclear sequestration. GKRP has multiple allosteric binding sites and is present at greater levels than GK. F-6-P binding tightens GKRP binding to GK leading to nuclear sequestration and inhibition. High glucose binding to GKRP releases Glucokinase allowing cytoplasmic translocation and glucose phosphorylation F-1-P binding to GKRP releases Glucokinase allowing cytoplasmic translocation and glucose phosphorylation.

How is insulin secreted from the beta pancreatic cells?

Glucose enters b pancreatic cells via Glut2 and is phosphorylated by Glucokinase G-6-P is metabolized increasing ATP levels ATP binds to and closes an ATP-gated K channel on the cell membrane Depolarization of the cell membrane opens a voltage gated Ca channel Ca increases exocytosis of pre-formed insulin and C-peptide containing granules Insulin is released in two waves; an immediate exocytosis and a second ~60 min later The amount of insulin secreted correlates with the concentration of blood glucose Insulin mRNA expression is stimulated by the elevated Ca levels

How is lactose synthesized?

Glucose enters mammary epithelial cell (MEC) via GLUT1. Glucose-1-P is converted UDP-galactose by GALT UDP-galactose and glucose enter into the Golgi by 2 transporters. Glucose and UDP-galactose linked by β-1,4-galactosyltransferase (β4Galt) associated with α-lactalbumin (LALBA). α-Lactalbumin is a MEC-specific protein that lowers the Km of β4Galt for glucose binding 10000fold. A Specifier In the absence of α-Lactalbumin β4Galt synthesizes Gal-β-1-4-GlcNAc-disaccharide. Lactose is only formed in MECs expressing α-Lactalbumin (tight regulation)

What are the pathway steps in glycogenesis?

Glucose phosphorylation G-6-P conversion to G-1-P by Phosphoglucomutase Activation of G-1-P to the sugar nucleotide UDP-G. Presence of a primer (pre-existing glycogen or Glycogenin). Transfer glucose to linear glycogen by a1-4 linkage by Glycogen Synthase. Transfer alpha1-4 linked sugars to a alpha1-6 branch by Branching enzyme

What is a marker for the ER?

Glucose-6-phosphatase, a membrane-bound enzyme

What happens in a G6PD deficiency?

Glucose-6-phosphate dehydrogenase is used in the pentose phosphate metabolic pathway to reduce NADP+ to NADPH. NADPH is needed to reduce oxidized glutathione to glutathione which combats oxidative stress from reactive oxygen species generated in red blood cells. Stressors require a higher number of such enzymes to be present to counteract the stress. Older RBCs, where there are lower amounts of total G6PD are more subject to stressors and as a result patients become symptomatic. Body has other defences to get rid of ROS (there are other antioxidants), but under stress more ROS are being made and these other systems are overwhelmed,so we need the glutathione to reduce the ROS If G6PD is deficient, a buildup of ROS/radicals will cause damage to the cell → cell death. Glutathione cannot be reduced as a result of lack of NADPH, so cell is subjected to this stress.

What is formed through glutamate semialdehyde?

Glutamate is interconverted to proline Glutamate can also be converted to ornithine

What are the major excitatory and inhibitory neurotransmitters?

Glutamate is the major excitatory neurotransmitter in the CNS. Activation of its glutamatergic synapses makes a neuron more likely to fire a signal. GABA is the major inhibitory neurotransmitter in the CNS. Activation of its GABAergic synapses makes a neuron less likely to fire a signal.

What amino acids is glutamate a precursor of?

Glutamine, Proline, Histidine, Arginine All glucogenic Histidine is essential, Arginine essential in children

What molecules does glycine contribute to?

Glycine - Heme Glycine - Glutathione Glycine - Purines Glycine - Creatine Glycine - Glycochenodeoxycholate

How is creatine synthesized?

Glycine and Arginine form ornithine and guanidinoacetate in the kidney Guanidinoacetate in the liver is converted to Creatine using SAM Creatine is a rapidly-mobilized "energy buffer" in muscle and brain Creatine is used by athletes to enhance muscle formation

What is the rate limiting enzyme in glycogen synthesis?

Glycogen Synthase

What is the rate limiting enzyme in glycogen degradation?

Glycogen phosphorylase

How are glycogen branches formed?

Glycogen synthase catalyzes the synthesis of the linear unbranched molecule with alpha-1,4 glycosidic linkage Branching enzyme (glycosyl a4,6 transferase) transfers a small fragment of 5 to 8 glucose residues from the non-reducing end of a glycogen chain to a glucose residue where it is linked by alpha-1,6 bond The glycogen polymer is further elongated and branched

How is glycogen phosphorylase activated during exercise?

Glycogenolysis in skeletal muscle is initiated by muscle contraction, neural impulses, and epinephrine AMP produced from the degradation of ATP during muscle contraction allosterically activates Glycogen phosphorylase The neural impulses that initiate contraction release Ca2+ from the sarcoplasmic reticulum. The Ca2+ binds to calmodulin, a modifier protein that binds to and activates Phosphorylase kinase Epinephrine activates Protein kinase A (PKA) which phosphorylates Phosphorylase kinase that in turn activates Glycogen phosphorylase

What happens to carbohydrate metabolism in a hypercatabolic state?

Glycolysis - energy, pyruvate, lactate Gluconeogenesis - net synthesis of glucose - maintain blood glucose levels. Enhanced in hypercatabolism. Uses amino acids Glycogenesis - synthesis of glycogen, UDP-glucose. Lessened in hypercatabolism Glycogenolysis- breakdown, glucose-1-P, glucose, liver vs muscle. Allows liver to provide glucose in hypercatabolism. Pentose Phosphate Pathway - NADPH, ribose-5-phosphate for nucleotide synthesis

What are membrane structures found in gram negative bacteria?

Gram negative membrane structure: Both leaflets of the cytoplasmic (inner membrane) are made of a mix of phosphotidylglycerol and phosphotidylethanolamine Inner leaflet of the outer membrane made of predominantly phosphotidylethanolamine Outer leaflet of the outer membrane is composed of LPS (lipopolysaccharide)

What are the structural differences between gram positive and gram negative cells?

Gram-positive bacteria have a thick peptidoglycan layer and an inner (cytoplasmic) membrane Gram-negative have a outer membrane, thin peptidoglycan layer and an inner (cytoplasmic) membrane

What are the different types of leukocytes?

Granulocytes: Neutrophils Eosinophils Basophils Agranulocytes: Lymphocytes Monocytes

Describe Norepinephrine

Greater effect on alpha than beta-1 receptors Vasoconstriction, increased SVR and blood pressure on both the systolic (arteriolar constriction) and diastolic (venous construction) Reflex bradychardia Increase stroke volume and cardiac contractility Increase in pulse pressure Neurotransmitter in CNS Similar, not as prominent as EPI in peripherySkeletal muscle vessel dilation (β2)Smooth muscle, relax &/or contract (β2/α)Urinary retention (mixed α/β)Metabolic⬆ plasma glucose (α2)⬆ glycogenolysis (β)⬇ insulin secretion (α2); ⬆ (β2) **Used in septic shock, to increase blood pressure

What is the 1st stage of fracture healing?

Hematoma Formation Hematoma Formation and Inflammation (within hours): -Pain, warmth, tenderness and instability -Recruitment and proliferation of MSC progenitor populations (periosteum) Children have thicker and better vascularized periosteum facilitating faster healing. Low pO2 at the fracture site promotes: -MSC differentiation into chondrocytes, which will produce cartilage. -Angiogenesis

Describe the catalase enzyme

Heme containing enzyme, Fe is co-factor. Present in the liver peroxisomes. Normally an important antioxidant, eliminates H2O2. Capable of metabolizing EtOH as shown below: CH3CH2OH + H2O2 - 2H20 + CH3CHO Metabolism does not require NAD or NADP but does require H2O2. Low rate of H2O2 production suggests insignificant role in liver oxidation of EtOH in normal conditions. ADH in brain has very low activity, HOWEVER brain expresses catalase that plays a role in local production of acetaldehyde from EtOH.

How is bilirubin processed?

Heme oxygenase converts heme to biliverdin Biliverdin reductase turns biliverdin into bilirubin Some of the bilirubin in the intestine is processed by bacteria to urobilinogen and stercobilinogen. Urobilinogen can be reabsorbed, processed further to urobilin, and secreted by the kidney, giving yellow color to the urine

What is a complete blood count?

Hemoglobin (HGB) Hematocrit (HCT) Total red blood cell count (RBC) Mean corpuscular volume (MCV) Red blood cell distribution width (RDW) Total white blood cell (leukocyte) count (WBC) -A white blood cell count differential may also be ordered •Platelet Count (PLT)

Why is HA1c tested?

Hemoglobin A1c (A1c or glycohemoglobin) -measures what percentage of hemoglobin is non-enzymatically glycated -correlates with average glucose level in the blood over lifespan of RBCs analyzed (2-3 months) -non-fasting sample adequate

What are some diseases Associated with Malfunction ofActin Based Cellular Structures

Hereditary spherocytosis deforms red blood cells to fragile spherocytes because of weakened binding affinity of spectrin to Band 4.1 Hereditary elliptocytosis deforms red cells to fragile elliptocytes because of incomplete formation of spectrin Breast cancer in some forms the actin associated protein Tensin, which links integrin receptors to the actin cytoskeleton, is disrupted promoting metastatic migration of cancerous cells Mutations/alterations in actin underlie diseases. Familial hypertrophic cardiomyopathy- mutations in a specific cardiac actin. Mutations in skeletal muscle actin are associated with congenital myopathies characterized by structural abnormalities of the muscle and variable degrees of muscle weakness. Mutations/alterations in myosin underlie diseases. Myosin VI mutations cause deafness. Myosin VII mutations associated with deafness, neurological disorder, and blindness (Usher syndrome Type 1) Pathogens usurp the endogenous actin machinery to translocate within cells

Mutations in which genes can cause spherocytosis? Why is this an autosomal dominant disorder?

Hereditary spherocytosis is caused by a variety of molecular defects in the genes that code for the red blood cell proteins spectrin (alpha and beta), ankyrin, band 3 protein, protein 4.2, and other red blood cell membrane proteins. The ANK1 gene mutation shows up in about half of the cases. It codes for ankyrin-1. Other genes are EPB42 (protein 4.2), SLC4A1 (Band 3) , SPTA1, and SPTB (these two are spectrin). This disorder only requires one copy of the mutant gene. This means there's a 50% chance a parent with the mutant gene can pass it along

What are the color euchromatin and heterochromatin in a TEM?

Heterochromatin is dark and euchromatin is light

How ate G-proteins regulated?

Heterotrimeric G proteins can require Regulators of G protein signaling (RGS) Step 1: Guanine nucleotide exchange factor (GEF) facilitates dissociation of GDP from G protein. Step 2: GTP then binds spontaneously, and GEF dissociates yielding the active G protein -GTP form. Accelerates the exchange of GDP with GTP Steps 3 and 4: Hydrolysis of the bound GTP to regenerate the inactive G protein-GDP form is accelerated a hundredfold by GTPase-activating protein (GAP). The efficiency of hydrolysis is regulated by Regulators of G protein signaling (RGS).

What are HEVs?

High endothelial venules Lymphocytes enter nodes mainly through HEVs. In lymph nodes and Peyer's patches, high endothelial venules (HEVs) especially adapted for lymphocyte trafficking control entry into lymphoid tissues. HEVs express vascular addressins (ligands to the homing receptors of lymphocytes) that regulate lymphocyte entry into lymphoid organs and are critical to the function of lymphoid organs.

How is histamine synthesized and degraded?

Histamine is made and released by mast cells and gastric mucosa, invokes inflammation. Requires PLP for synthesis Degraded to N-methylhistamine at synapses of the brain. Uses SAM Blockers of Type I and Type II receptors are important medicines: H1: Diphenhydramine (Benadryl), Loratidine (Claritin), Fexofenadine (Allegra) H2: Ranitidine (Zantac), Cimetidine (Tagamet) IMPROPER STORAGE of raw fish can result in high levels of histamine, as bacteria and proteases degrade protein to amino acids, and histidine is degraded to histamine by those bacteria. This can lead to scombroid poisoning. Symptoms of histamine toxicity include face flush, sweating, rapid heart rate, excitement, dizziness (as well as itching, hives, etc.). Death is rare; can be treated with epi-pen or benadryl.

What happens in Glucose 6-phosphate Dehydrogenase Deficiency?

Historically, a condition known as favism X-linked disorder, but heterozygotic women can have hemolytic attacks. The most common clinical feature is a lack of symptoms. Disease is marked by episodic hemolysis, linked to exposure to precipitating agents or stress Note the clear Heinz bodies in these erythrocytes. Symptomatic of G6PDH deficiencies. Their removal in spleen leads to "bite marks" in rbc Avoid oxidant drugs such as the antimalarial drugs primaquine Affected cells provide a poorer environment for Plasmodium growth. AKA help against malaria Fava beans contain compounds that further oxidatively stress erythrocytes, making the environment even more inhospitable to Plasmodium. This may explain continued use of Fava beans

What are the ways in which double stranded breaks are repaired?

Homologous recombination Single strand annealing Non-homologous end joining

What is Familial Dyslipidemias Type I?

Hyperchylomicronemia- VLDL and chylomicron lipid abnormalities Caused by familial lipoprotein lipase (LPL) or apoprotein CII deficiency, resulting in increased chylomicrons, VLDL, TGs, and cholesterol in the blood Symptoms: hepatosplenomegaly, acute pancreatitis and eruptive xanthomas Treatment: restriction of dietary fat

How do DNA methylation patterns affect gene expression?

Hypermethylation of tumor suppressor genes leads to repression Hypomethylation leads to activation and chromosome instability

Firmicutes are the major AI-2 producers in the GI tract. How does this information, together with the information from Fig. 1, help to explain the results why depleting AI-2 did not make a difference?

I mice with high levels of Al-2 there was a significant decrease in relative levels of bacteroidetes and a significant increase in relative levels of Firmicutes when compared to normal and low levels of AI-2. Therefore there was a significant impact on the heterogeneity of the microbiota. However this heterogeneity appears to be only marginally better than normal/low AI-2 when compared to the heterogeneity before streptomycin treatment. At normal levels the Al-2 does not appear to have reached the threshold for proliferation of the Firmicutes. Therefore, by further depleting its levels below this threshold one would not expect to have any impact on Firmicute proliferation. Only once that threshold has been met (i.e. high Al-2 group) will the cells enter into the SOS response.

What genetic test(s) would you order for fragile X syndrome?

I would order a DNA blood test for the FMR1 gene. The blood test can be done with either a southern blot or PCR analysis, but PCR testing can give a more precise amount regarding the number of repeats. The Southern blot analysis test determines if the gene has a full mutation, its approximate size, whether the gene has been "methylated," and if there is mosaicism of the gene (a mixture of different cell types). The polymerase chain reaction (PCR) analysis can determine the actual number of CGG repeats (a pattern of DNA) that are present in the Fragile X gene. For various technical reasons, PCR has not been the test of choice to diagnose a full mutation, but is quite accurate in determining premutation and normal gene repeat numbers. However, PCR is less expensive and quicker than Southern blot, and recent advances in technology have increased its ability to identify Fragile X full mutations. PCR may thus be the only test used in the near future.

What is the difference between inactivation and deactivation

I.Inactivation and deactivation are not the same. Don't use the words interchangeably. A.Inactivation: the time-dependent process by which a Na+ channel closes because its inactivation gates (h gates) close. B.Deactivation: (You don't need to know this) means the voltage-dependent closing of a channel. C.K+ channels do not inactivate. They stay open as long as the membrane is depolarized. They close (deactivate) as the membrane returns to a normal resting potential. D.Because of inactivation of Na channels, an action potential has a refractory period.

How do graded potential contribute to AP initiation?

If a depolarizing graded potential is of sufficient strength and duration the membrane will reach threshold and an action potential will be generated Graded potentials occur in all tissues that spontaneously generate or conduct APs because they are the stimuli which is required to generate an AP: »In cell bodies and dendrites of neurons »In cells (e.g. cardiac myocytes) electrically connected by gap junctions »Post-synaptic membranes

What is a normal distribution?

If a variable has a normal distribution, about - 68% of observations will be within ± 1 SD of mean - 95% will be within ± 2 SD - 99.7% will be within ± 3 SD

What is the glyoxylate shunt?

If bacteria are using three carbon sugars as a source of carbon, they can use the glyoxylate shunt to generate o NADH + H+ for energy generation by ETS chain/proton motive force/ATP synthase o oxaloacetate for biosynthesis of NAD and amino acids WITHOUT the loss of the carbons as CO2 o the bacteria are cannot make alpha-ketoglutarate so need to scavenge amino from amino acids

What are reticulocytes?

Immature Red Blood Cells Higher than normal reticulocyte counts in blood=loss or destruction of RBCs Have polyribosomes

Diseases Associated with Malfunction of Microtubule Based Cellular Structures

Immotile cilia syndrome - a body-wide defect in axonemal structure that result in obstructive lung disease and sterile males. Kartagener's syndrome - a combination of Situs inversus (reversal of normal body asymmetry) and Immotile cilia syndrome Cancer: target for therapeutics, e.g. disruption of MT dynamics to block cell division (e.g., Taxol) Mutations/alterations in microtubule proteins underlie diseases. Lissencephaly -- mutations in the microtubule proteins LIS1 and doublecortin. Charcot-Marie-Tooth -- mutation in specific kinesin has been reporteddisease type 2A in one case (other families have mutations in mitofusion2, a protein of mitochondria). Neurodegenerative -- abnormalities/mutations in tau, dynein, kinesin,disorders spastin Neurotopic viruses exploit the neuron's microtubule based transport system to reach cell bodies

What activates an immune response?

Immunogen=Foreign structure that causes immune response (Activates) Antigen=Target of the resposne Epitope=Region of antigen that react with the antibody

What is the odds ration?

In a case control study, we use the ODDS RATIO to estimate the association between the exposure and the disease. OR = Odds of case exposed Odds of control exposed =AD/BC A=Cases with disease who were expose B=Cases without disease who were exposed C=Cases with disease who were not expose D=Cases without disease who were not exposed If Risk = 1 •Risk in exposed equal to risk in unexposed (no association) If Risk > 1 •Risk in exposed greater than risk in unexposed (positive association) If Risk < 1 Risk in exposed less than risk in unexposed (negative association; possibly protective Disadvantages: Cannot address causality Cases may reflect survival benefit Only investigates 1 disease outcome Can only approximate relative risk of disease in exposed vs. unexposed persons High, HIGH likelihood of bias

Why are spontaneous mutants to antibiotic resistance more likely to occur inside the biofilm than on the biofilm surface? Is this occurring in this patient? Why or why not?

In deep layers of a biofilm, there is oxidative stress because there is no oxygen present. This can cause the already error-prone DNA polymerases being used for cell division in the inside of the biofilm to be even more error-prone because of the SOS response, creating mutations that can lead to antibiotic resistance. It is likely that this was occuring in this patient because he did have multiple rounds of septicemia caused by the same bacteria S. aureus. This recurrence of the same infection likely shows that at least some of the bacterial cells were experiencing mutations that gave them antibiotic resistance. But in the long term they did not have resistance to antibiotics, so their mutations may have no given them resistance to the antibiotics that he was being given for the long period of time.

What is the microbiome?

Includes bacteria, viruses and eukaryotes Used to be called "normal flora" Vast numbers on body sites exposed to the environment -Not usually inside tissue -One gram of feces = 109 ->100x more genetic material in microbes than in the human genome -Thousands of species (only about 100 are pathogens) Acquired at immediately after birth & persists through life On the body surface (not in blood or deep tissue) Mainly in the gastrointestinal tract (colon) Different flora are found in different physical locations - depends on the environment Numbers of gastrointestinal flora increase as you progress down the digestive system

What are the functions and localizations of beta 1 receptors?

Increases contractility and accelerates the heart with increased SA node activity Found on cardiomyocytes including the SA and AV nodes ***Overall leads to increased cardiac output Also found on glomerular cells where they increase renin release which contributes contributes to maintaining blood pressure Gs increases cAMP causes increased calcium Heart and kidney; post-synaptic

What happens when you increase the afterload?

Increases the latency between activation of the muscle and shortening. Increases the force produced by the muscle during shortening. Decreases the velocity of shortening. Decreases the amount of shortening.

What happens during osteoporosis?

Increasing the RANKL/OPG ratio Uncoupling of Bone Formation and Resorption * Factors: Aging, Post-menopausal, Disuse, Inflammation and Diabetes. Response to mechanical forces strengthens bone by increasing deposition of minerals and production of collagen fibers (exercise may slow down the bone loss in some forms of osteoporosis).

How is endochondrial ossification regulated?

Indian hedgehog (Ihh) protein is produced by pre-hypertrophic and early hypertrophic chondrocytes; stimulates the synthesis and secretion of parathryroid hormone related protein (PTH-RP) and regulates formation of the periosteal bone collar. PTH-RP produced by chondrocytes and perichondrial cells at the ends of long bones stimulates chondrocyte proliferation and prevents them from differentiating into hypertrophic chondrocytes. Hypertrophic chondrocytes secrete type X collagen, a marker of terminal differentiation and vascular endothelial growth factor (VEGF), an inducer of vascular invasion.

What is bacterial genomic flexibility?

Individual bacteria within the population can vary on the genomic level •SNP single nucleotide polymorphisms - mutations •Genetic content due to mobile genetic elements Minor changes in the bacteria - e.g. antibiotic resistance Major changes in the bacteria - e.g. commensals (microbiota) vs. pathogens (cause disease) even though they are the same species

What is methotrexate?

Inhibitor of Folic Acid Metabolism Methotrexate acts against leukemia by inhibiting DNA synthesis by blocking the formation of functionally active folate (FH4). Methotrexate is a competitive inhibitor of the dihydrofolate reductase enzyme. By blocking DNA synthesis, methotrexate preferentially kills cells that are quickly dividing. This is a hallmark of many cancer cells and is therefore used as a chemotherapeutic agent. Anti-cancer drug; Competitive inhibitor of dihydrofolate reductase Blocks formation of FH4 (functionally-active folate) Thus inhibits nucleotide/DNA synthesis, important in rapidly-dividing cells (like cancer cells, but also epithelial cells, hair follicle cells, blood cells)

How is apoptosis regulated?

Inhibitory Proteins to Restrain Extrinsic [death receptor] Pathway Some cells produce FLIP, which dimerizes with caspase- 8 in the DISC; prevents caspase-8 activation thereby blocking apoptosis DISC [death inducing signaling complex]: multiprotein complex of members of the death receptor, ligand and adaptor proteins. Regulation of intrinsic cell death- Bcl-2

What does palmitoyl COA inhibit?

Inhibits G-6-P dehydrogenase in the PPP phosphate stopping production of NADPH Inhibits acetyl CoA carboxylase stopping the production of malonyl CoA Inhibits translocation of citrate out of the mitochondria so it cannot be converted to acetyl CoA in the cytosol Inhibits pyruvate dehydrogenase which converts pyruvate to acetyl CoA in the mitochondria

What does Disulfiram (Antabuse) do?

Inhibits acetaldehyde dehydrogenase so acetaldehyde accumulates Leads to hangover symptoms prescribed to help recovering alcoholics to avoid drinking.

What does Fomepizole do?

Inhibits alcohol dehydrogenase, antidote for suspected ethylene glycol or methanol poisoning. EtOH can also be given to prevent MeOH metabolism by acting as a competitive inhibitor for the enzyme. MeOH is metabolized to formaldehyde and formate each highly toxic.

What happens during lead poisoning?

Inhibits porphobilinogen synthase (ALA dehydratase), causing buildup of ALA, which is neurotoxic. Ferrochelatase inhibition, causes replacement of Fe2+ with Zn2+ (Zn-protoporphyrin). Binds to sulfhydryl groups The major metabolic pathway affected is the production of heme. Anemia results from a lack of hemoglobin, and energy production decreases because of the lack of cytochromes for the electron-transport chain. Lead directly affects the hematopoietic system through restraining the synthesis of hemoglobin by inhibiting various key enzymes involved in the heme synthesis pathway. It also reduces the life span of circulating erythrocytes by increasing the fragility of cell membranes. Increase in ROS decreases the lifespan of the blood cells. This is because glutathione system is affected because it also binds sulfhydryl groups as well as lead. The combined aftermath of these two processes leads to anemia

What post-translational modifications happen to proteins?

Initial methionine can be removed by specific proteases; methionine is not N-terminal amino acid of all mature proteins Other cleavages can occur to convert proteins to more active forms, e.g., proinsulin to insulin. Amino acid residues can be modified enzymatically; can activate/inactivate a protein, stabilize/destabilize a protein, direct it to subcellular compartment, or prepare it for secretion. Addition of various types of functional groups: 1.N-terminal amino acid can be acetylated; alters charge on protein 2.Methyl group(s) can be added to lysine residues; alters charge on protein 3.Proline and lysine can be hydroxylated. In collagen, hydroxylation stabilizes protein. 4.Carboxylation -important for blood coagulation. Formation of g-carboxylglutamate allows proteins to chelate Ca2+, a step in clot formation 5.Addition of fatty acids or other hydrophobic groups (eg, prenyl groups) anchor proteins in membranes 6.ADP-ribose can be transferred from NAD+ to some proteins. 7.Addition/removal of phosphate groups (on serine, threonine, or tyrosine) activate/inactivate many proteins (eg, enzymes of glycogen degradation; regulators of gene transcription) 8.Glycosylation (addition of carbohydrate group) occurs on proteins destined to be secreted, incorporated into lysosomes or cellular membranes

What are the steps of the urea cycle?

Initial steps occur in mitochondrial matrix (CPS-1, citrulline) Citrulline pumped out of mitochondria, combines w/aspartate, makes arginine. Urea (+ ornithine) generated from metabolism of arginine. Ornithine pumped back into mitochondria (exchange for citrulline). Only five reactions; if defective, can lead to hyperammonemia (big problems); more in this later. HCO3-+NH4++2ATP-carbamoyl phosphate Carbamoyl phsophate+ornithine-citrulline Exported out of the mitochondria into cytosol Citrulline+Aspartate+ATP-Arginosuccinate Arginosuccinate-Fumarate+Arginine Arginine+H2O-Urea+Ornithine Arginine

What happens during initiation of translation in eukaryotes?

Initiation complex: composed of methionyl-tRNAiMet, (met-tRNAiMet), mRNA and a ribosome 1.met-tRNAiMet forms complex with protein eukaryotic initiation factor 2 (eIF2), which binds GTP. 2.Complex then binds 40S ribosomal subunit, + eIF3. (eIF3 also involved in preventing premature association of the 60S ribosomal subunit with the pre-initiation complex) 3.Cap at 5'-end of mRNA binds to eIF4 complex (cap-binding complex) (eIF4 comprises eIF4E, eIF4A, and eIF4G) 4.mRNA-cap-binding complex binds to eIFs-met-tRNAiMet -40S ribosome complex 5.Complex unwinds a hairpin loop in mRNA and scans mRNA until it locates AUG start codon (requires hydrolysis of ATP because of helicase activity of one of the eIF subunits) 6.GTP is hydrolyzed, eIFs are released and 60S ribosomal subunit binds. During initiation, met-tRNAiMet binds to ribosome at the P site, located at start codon for translation. Three binding sites for tRNA, P (peptidyl), A (aminoacyl) and E (ejection) sites. FOR EXAM DO NOT NEED TO KNOW FACTORS AND WHERE/WHEN GTP IS BOUND

Describe dobutamine

Inotropic adrenergic agent and shock Direct interaction with α and β receptors (racemic mixture β1 > β2, α1) **Mostly a beta-1 agonist **Increase cardiac output by increased HR and contractility and positive inotrope (β1 & α1 stimulation) **Used in cardiogenic shock, myocardial infraction, cardiac surgery, refractory congestive heart failure Little effect on peripheral resistance (due to opposing actions of β2 and α1 ) Increases pulse pressure Increases systolic pressure (B1) and decreases diastolic pressure (B2)

Describe the resting state

Inside of the cell is more negative than the outside of the cell 1.Most of the voltage dependent Na+ channels and the voltage dependent K+ channels are closed (there are always some random opening and closing of channels) 2.The inward Na+ current and the outward K+ currents are equal to each other so the membrane potential remains constant 3.Please remember, resting membrane potential is set by leaky Na+ and K+ channels, which are NOT voltage-gated channels.

Describe graded potentials

Inside still negative A.A depolarizing stimulus is applied to the membrane (Fig 9-2) 1.The depolarizing stimulus causes an inward current, carried by Na+, which increases the probability that m gates will open to allow the voltage sensitive Na channels to open 2.As more and more Na channels open the membrane potential will become more depolarized, the membrane potential becomes less negative 3.When the threshold is reached (approximately -55 mV in neurons) a positive feedback event occurs such that there is an explosive opening of all remaining m gates and in turn all remaining Na channels will open

What is the mechanism of insulin action?

Insulin binding activates the intrinsic tyrosine kinase activity of the cell surface insulin receptors This initiates a phosphorylation signal cascade of intracellular proteins. This results in substrate changes in activity localization ect. Details: Initiates P13K and Akt activation Akt is a Ser kinase responsible for the transcription factor FoxO phosphorylation which induces nuclear exclusion and loss of its ability to activate the expression of target genes Reduced insulin signaling prevents FoxO1 phosphorylation, Akt kinase is inactive. Unphosphorylated FoxO translocated into the nucleus, binds promoter DNA sequences and activates the transcription of target genes Genes involved in gluconeogenesis and G-6-Pase are regulated in this manner, insulin resistance fails to repress haptic glucose production

How does potassium homeostasis and insulin work?

Insulin causes a rapid uptake of plasma K into the liver and skeletal muscle via the cell surface Na/K ATPase exchanging 2 Na for 2K Administration of insulin can result in a sudden drop in plasma K, hypokalemia Elevated K can stimulate the secretion of insulin

How is insulin synthesized?

Insulin is translated to preproinsulin Preproinsulin is post-translationally converted into proinsulin Proinsulin is packaged into vesicles with processing enzymes to produce active insulin. This step cleaves of the C-peptide between the a and b chains. The mature active insulin hormone is composed of the a and b chains. These are held together by disulfide bridges. The biologically active insulin and the inert C-peptide are co-released into the blood.

What happens during the fed state?

Insulin released sending signals to the skeletal muscle and liver to take up dietary glucose and make glycogen Insulin stimulates body cells to take up glucose Insulin sends signals to the adipose tissue to take in dietary lipids Insulin therefore inhibits lipolysis and increases lipogenesis Glucose metabolism is shifted toward energy storage favoring synthesis of glycogen and triglycerides Malonyl CoA is synthesized inhibiting CPT-1 preventing fatty acid oxidation AND is substrate for fatty acid synthesis (blocks potential futile cycle) Insulin increases SREBP1c activity thereby increasing expression of genes involved in fatty acid synthesis. Cells uptake amino acids and store them or make them into proteins

What are some examples of tyrosine kinases?

Insulin, Insulin-like growth factors (IGF), Nerve growth factors (NGF), Epidermal growth factor (EGF), other growth factors ect. Gleevac a drug for this *inib drugs

Describe hemidesmosomes

Integrin's extracellular domains enters the BL and interacts with collagen IV and laminin 5. Hemidesmosomes are adhesive junction anchoring the basal domain of epithelial cell to the basal lamina mostly found in epithelium of skin Intracellular attachment plaque attaches to the intermediate filament Outer plate interacts with the BL via integrins

What is gene therapy?

Involves the direct genetic modification of cells of the patient to achieve a therapeutic goal. Germ-line gene therapy would produce a permanent transmissible modification and could be achieved by the modification of gamete, zygote or early embryo. It is widely banned for ethical issues. Somatic gene therapy seeks to modify specific cells or tissues of a patient. In somatic cell gene therapy, the cells are targeted are often those directly involved in the pathogenic process, but in some cancer gene therapies, the object is to modify normal immune system cells genetically in the patient so as to provoke a powerful immune response against the tumor. Gene augmentation: The aim is to supply a functioning gene copy that will supplement a defective gene. Involves the direct genetic modification of cells of the patient to achieve a therapeutic goal. Elimination of pathogenic mutation: The object is to restore/replace the function of the mutated gene. Targeted inhibition of gene expression: Block expression of disease causing proteins. Viral proteins that cause disease, oncogenes in cancer, dominant acting mutations in various hereditary diseases. Targeted killing of specific cells: In cancer, introduce toxic gene into cancer cells or augment immune system to eliminate tumors. Genes can be transferred to a patient's cells either in culture or within the patients body Transduction: Using replication deficient recombinant viruses Transfection: Non-viral methods Generation of replication deficient recombinant viruses carrying therapeutic gene-Retroviral as an example... co-transfect packaging cells with retroviral genes on different plasmids. One containing gag, pol, and env, but lacking Psi packing signal and one containing Psi packaging signal and therapeutic gene.

What happens during site specific recombination?

Is a mechanism used by some bacterial viruses to insert their genomes into a specific site in the bacterial genome. There are also bacterial and yeast recombinases that can catalyze this type of recombination at specific sites in the genome. The DNA segment that is transferred carries short recombination sites Medical significance: Widely used as tools in experimental genetics, e.g. the Cre and Flp recombinases are used to delete genes in eukaryotic organisms (inducibly or in a tissue specific manner) Site specific recombination involves exchanges that occur at very specific sequences on DNA molecules

Describe the golgi complex

Isolated Golgi cisterna (saccules) General Structure Flattened Membrane Enclosed Compartments = Cisternae Tubular Connections between Cisternae Located Near Cell Nucleus GOLGI COMPLEX: ALL CISTERNAE ARE NOT IDENTICAL! TWO DISTINCT FACES. PROTEINS AND LIPIDS ENTER THE CIS AND EXIT THE TRANS GOLGI NETWORK. Enzymes are not precisely localized, but highly enriched on cisternae Cis Golgi - Osmium Reduction TGN (trans) - -Acid Phosphatase Proteins produced by rough ER and those that are properly folded move, via small vesicles, to the Golgi Complex. While in transit through the Golgi complex the proteins undergo many post- translational modifications, including glycosylation, sulfation, etc. The Golgi complex is comprised of functionally distinct compartments. FUNCTIONS OF THE GOLGI COMPLEX: Post-translational modification of proteins. Processing of carbohydrates Addition of sugar, sulfate or phosphate residues Condensation and packaging of proteins into membrane-bound granules Synthesis of lipoproteins Processing of acid hydrolases Formation of the acrosome in sperm Sorting of proteins GLYCOSYLATION IN THE GOLGI: assembly of the carbohydrate component of glycoproteins and glycolipids Constitutive secretory pathway: Continual, unregulated discharge of material from the cellregulated secretory pathway: The discharge of products stored in cytoplasmic granules, in response to appropriate stimuli

What are the direct acting non selective beta adrenergic agonists?

Isoproterenol Dobutamine

What is Mucolipidosis II (ML II), also known as I cell disease?

It is a genetic, metabolic, and lysosomal storage disorder caused by defect in N-acetylglucosaminyl-1-phosphotransferase. Patients are not able to add phosphate to mannose to make mannose-6-phosphate on glycoproteins in the Golgi. The glycoproteins are secreted extracellularly, rather than delivered to lysosomes. As a result, the patients are not able to break down mucolipids (a sphingolipid which contains neuraminic acid, or called sialic acid). Symptoms: coarse facial features, restricted joint movements, hand deformities, developmental delay, heart valve abnormalities, weak muscle tone, abnormality of nervous system morphology, often fatal in childhood

What is homologous recombination?

It is an essential cellular process* that: 1.1 provides mechanisms to restart collapsed DNA replication forks. 1.2 allows cells to retrieve sequences lost as result of DNA damage in newly replicated DNA by using an homologous DNA molecule. 1.3 mediates genetic variation: •In eukaryotes, distribution of genetic information from parents to the offspring (during meiosis for generation of gametes). •Genetic exchange in bacteria (between the bacterial chromosome and DNA entering the cell (viral transduction or bacterial conjugation). Defects in homologous recombination are associated with cancer, i.e.: BRCA1/2 mutations (proteins that play a major function in HR). Limited recombination of homologous chromosomes in mitotic cells can lead to loss-of-heterozigosity of a mutation in a tumor suppressor gene. Homologous recombination has been routinely used for the generation of gene-knockout and transgenic mouse models to study gene function and disease.

What is saltory conduction?

It is easy for the current to flow down the center of the axon but hard to flow out across the membrane The nerve axon the axial resistance (Rax) is much less than the membrane resistance (Rm) Thus, axoplasmic current transfer faster and farther in myelinated axons Myelinated axons have faster conduction velocities than unmyelinated axons of equal diameter. Myelination allows us to have fast-conducting axons that are also slender.

1. Knowing the important role S. pneumoniae played in the discovery of DNA, what is the most likely mechanism that a virulent strain picked up the DNA? 2. What is the hallmark of this kind of transfer that could be tested for in a laboratory experiment? 3.What molecular mechanism allowed for integration of the new capsule gene into the chromosome? 4. Under what conditions could this mechanism be used to transfer a new capsule gene to the chromosome of a species that does not contain capsule?

It is likely that they picked it up via transformation, aka they picked up naked DNA from outside of the cell from another cell that had lysed, brought it in, and incorporated it into their own genome. It is DNase sensitive, so if a DNase being present with the bacteria prevents them from taking up the DNA and getting the gene, we know that the DNase was able to digest the DNA that was outside of the cell that apparently held the gene for the capsule. It is integrated by homologous recombination. The bacterium taking up the naked DNA needs to be competent. If it is gram-positive, it can take up any naked DNA. Gram-negative bacteria are only able to take up their own species DNA. If DNase is present, there would be trouble for the bacteria to take up the gene, but it may still happen if it happens quick enough and if there is not too much DNase. You also need flanking regions, you require recA, negative for restriction enzymes and no CRISPR cas system

What are the components of a "quad screen"?

It measures the levels of 4 substances in a pregnant woman's blood during the second trimester. Alpha-fetoprotein (AFP), a protein made by the developing baby - HIGH Human chorionic gonadotropin (HCG), a hormone made by the placenta - HIGH Estriol, a hormone made by the placenta and the baby's liver - LOW Inhibin A, another hormone made by the placenta - HIGH Those values would be indicative of Down Syndrome

What is fibronectin and what does it do?

It's essentially the protein scaffold that comes together after injury, binds and stabilizes fibrin and cells together. Attracts fibroblasts and macrophages to help. Monomer with different formations such as stacked B-sheets, anti-parallel B-sheets

What is mutant specific medication?

Ivacaftor (Kalydeco) -FDA approved 2/2012 -Activates the CFTR channel that is already present at the plasma membrane Only for G551D mutation (gating defect) -Improvement in pulmonary function, weight gain, sweat chloride, decreased pulmonary exacerbation rate Kalydeco combined with lumacaftor FDA approved 7/2015 Targets deltaF508 most common CF mutation -targets a folding deficiency that otherwise targets mutant CFTR for intracellular destruction allowing trafficking to the plasma membrane. -deltaF508 mutation also causes a secondary gating defect such that channels that do reach the plasma membrane do not open like wild-type channels.

What happens during base excision repair (BER)?

Just removes the nitrogenous base by cleaving the glycosidic bond Major enzymes: Glycosylase, AP(apurinic/apyrimindic) endonuclease, DNA polymerase delta and epsilon, ligase Types of lesions repaired: Uracil, OxoG, O6-methyl-G The glycosylase cuts the bond between the damaged nitrogenous base and carbon 1' of the deoxyribose sugar An apurinic/apyrimidinic (AP) site is created An AP endonuclease cleaves the phosphodiester backbones near the AP site DNA polymerase I initiates repair synthesis from the free 3' OH at the nick, removing a portion of the managed strand (with its 5'-3' exonuclease activity) and replacing it with undamaged DNA Nick remaining is sealed by ligase There is a separate glycosylase for each type of DNA damage ( 8 identified, i.e. OxoG glycosylase 1).

What is kcat and km?

Kcat is the rate the enzyme-substrate complex converts to free enzyme and product Km is the dissociation constant for the enzyme-substrate complex.

What is Kp and what does it mean?

Kp is the partition coefficient Kp = solubility in oil / solubility in water This expression shows that: If Kp is > 1 it means the solute prefers to be in the oil. If Kp is < 1 it means the solute prefers to be in the water. If Kp is = 1 it means the solute has no preference. Fick's Law of Diffusion (with Partitioning) J = Kp • D •∆C / ∆x J = P(Cin - Cout) Positive values mean there is a net outward flux of a solute from a cell.

Describe osteclasts

Large, multinucleated cells that are responsible for bone resorption or the degradation of mineralized bone. Actively resorbing cells sit within Howship's (resorption) lacunae. Osteoclasts are derived from hematopoietic stem cells and share a common progenitor with the monocyte/macrophage lineage. Large size, multinucleated (polykaryon) Polarized Cell Clear zone (sealing zone) and Ruffled border

What is the function of primase?

Leading strand- Synthesizes a short RNA primer (20nt) and then DNA replication occurs continuously moving on the direction of replication fork Lagging strand- synthesizes a short RNA primer. Then, the primer's 3'OH allows DNA polymerase to synthesize new DNA in a 5'è 3' direction while moving opposite to the direction of replication fork progression. Replication is semi-discontinuous Primase activity increases dramatically when associated with DNA helicases, which functions to unwind DNA at the replication fork generating the single strand DNA needed by primase, ensuring that primase only works where is supposed to do so.

What is the optimal level of LDL cholesterol?

Less than 100 mg/dL

What is the desirable level of cholesterol in the blood?

Less than 200 mg/dL

What happens when urea fails to excrete?

Liver failure: No urea made. hyperammonemia ("flapping tremor", slurred speech, somnolence, vomiting, blurred vision) leads to cerebral edema, coma, death. Tx: Liver transplant? Kidney failure: urea builds up (increased blood urea nitrogen ("BUN")) later ammonia, death. Tx: Dialysis, limited protein diet, transplant. Inherited disorders of urea cycle (these are somewhat rare). The most common is ornithine transcarbamylase deficiency ("OTC" deficiency). X-linked, incidence is ~1:60,000 What is ornithine transcarbamylase? ornithine + carbamoyl phosphate - citrulline Leads to hyperammonemia (brain damage results from first incidence, often in infancy but later onset can occur, fatal 50% of time). Treatment includes liver transplant, low-protein diet + use of nitrogen scavengers like benzoate and phenylacetate, shown in next slide (cannot correct neurological damage).

What is Conjugated hematobilirubinemia?

Liver is functioning. conjugated bilirubin is elevated (can't leave liver)(can't be eliminated by the bile due to obstruction so it goes back to the circulation), SGOT (measures liver function) is elevated (liver damage). Obstruction of bile duct leads to increased bilirubin in circulation - increased bilirubin in urine.

What is the main gluconeogenic organ?

Liver is the principal gluconeogenic organ (but not the only including kidney and small intestine)

How is heme regulated?

Liver: Repression of mRNA synthesis Post-transcriptional inhibition Inhibition of enzyme transfer Erythrocyte: Induction of mRNA synthesis by erythropoetin Stimulation of transciption by Fe3+ Inhibition of enzyme transfer by heme Inhibited by Heme

What is located in white pulp

Lymphocytes surrounding central arteries. Lymph follicle-like. Produces B cell clones in the presence of T cells

Describe the different types of leukocytes

Lymphocytes: Nucleus occupies most of the cell reducing the cytoplasm to a thin basophilic rim Surface markers: classify them as T, B or NK lymphocytes. Eosinophil: Nucleus is typically bilobed Cytoplasm contains bright red granules Functions in allergic reactions and parasitic infections Neutrophil: Nucleus is usually segmented into 3-5 indented lobes Cytoplasm contains primary granules

What two amino acids only form ketone bodies?

Lysine and leucine

What are the essential amino acids?

Lysine, isoleucine, leucine, threonine, valine, tryptophan , phenylalanine, methionine, histidine, arginine (required for kids)

How are catecholamines metabolized?

MAO and COMT Ex: Epinephrine, Norepinephrine, Dopamine

Describe monoamine oxidases

MAO: monoamine oxidases MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine and trace amines like tyramine MAO-B preferentially deaminates phenethylamine and certain other trace amines Dopamine is equally deaminated by both types. MAO inhibitors (MAOI): the third-line drugs for depression (after selective serotonin inhibitors, SNRI, and tricyclic antidepressants). Dietary restrictions when taking MAOI: avoid foods rich in tyramine (which causes release of NE), such as liver and fermented substances (e.g. alcoholic beverages and aged cheeses)

What are the differences between MHC1 and MHC2?

MHC I: Expressed on ALL nucleated cells 2 polypeptide chains, α chain with 3 domains encoded by MHC locus and β chain (microglobin) not encoded by MHC locus Ags presented to CD 8, cytotoxic T cells (CTL cells) MHC II Expressed on Ag-presenting cells, thymic epithelial cells and endothelial cells 2 poly peptide chains α and β, both encoded by MHC locus Ags presented to CD 4, Helper T cells

What is SCCmec?

MRSA SCCmec is a large chromosomal cassette containing the methicillin resistance genes and can contain many other resistance and virulence factors. This is a novel type of transposon-like mobile element whose mechanism of movement is unknown. The different cassettes are variable in genetic content. The MRSA SCCmec are often flanked by insertion sequences, transposons and integrated plasmids in them.

How are osteclasts and osteoblasts maintained?

Macrophage colony stimulating factor (M-CSF): stimulates early commitment to osteoclast lineage. Receptor activator of NF-κB (RANK) and its ligand (RANK-L): induces osteoclast formation and activation. Osteoprotegerin (OPG): produced by osteoblasts it acts as a RANK-L decoy receptor. The ratio of RANK-L/OPG is directly proportional to number/activity of osteoclasts.

How is heme made?

Made From Glycine and Succinyl CoA (BCAA) Uses the enzyme ALA Synthase which is the rate limiting enzyme It is negatively regulated by heme Occurs in the mitochondria and cytosol Heme synthesis occurs in liver (to make cytochrome, other hemes), and in marrow (for hemoglobin)

How are chromosomal bands named?

Main cytogenetic bands labeled p1, p2, p3, q1, q2, q3, etc., -counting from the centromere out toward the telomeres. Sub-bands also numbered from the centromere out toward the telomere. 7q31.2= chromosome 7, q arm, band 3, sub-band 1, and sub-sub-band 2. -CFTR gene Ends of the chromosomes labeled ptel and qtel. -7qtel refers to the end of the long arm of chromosome 7.

How are amino acids metabolized in the gut epithelial cells?

Mainly glutamine, glutamate, aspartate used as fuel after a protein-containing meal (N released as alanine, NH4+, citrulline, ornithine, directed mainly to liver; urea also can be made) Glutamine (from blood) used as primary fuel during fasting Urea cycle enzymes are present in gut (but capacity is limited); citrulline, ornithine synthesized in the gut and released; urea can be released from arginine

How are amino acids metabolized in the brain?

Major function of amino acids in neural tissue is neurotransmitter synthesis Large neutral amino acids cross the blood-brain barrier: Phe, Tyr, Trp, His: used in neurotransmitter synthesis Met also used in synthesis (as SAM) BCAA's (Val, Leu, Ile) used in some energy production Brain is a net glutamine producer (produced from bcaa's / TCA cycle intermediates and NH3); carries N away. Glutamate and GABA (neurotransmitters) released at synapses; taken up by glia, converted to glutamine; glutamine released and taken up by neurons ("glutamate-glutamine cycle").

Describe microglia

Major immune cell in the CNS. Cell body physically smaller than other glial cells. An embryonically-derived, self-renewing tissue macrophage. Activation by physical injury, local inflammation / infection changes microglial morphology from ramified to amoeboid (cell body expands, processes/branches become less defined). Microglial have both beneficial and harmful effects in disease (e.g. they aid clearance of damaged tissue, but also secrete cytokines that can exacerbate inflammation).

How are purines degraded?

Major product is uric acid*, formed either guanine or hypoxanthine through xanthine, by xanthine oxidase (XO). Insolubility of Na-urate causes precipitation in joints, immune response in some people causes gout (sometimes iatrogenic; from diuretics).

Why is albumin tested?

Major protein within the extracellular portion of the blood Maintains colloid osmotic pressure -Also transport function •bilirubin, calcium, long-chain fatty acids, toxic heavy metal ions, and numerous drugs Synthesized in the liver and therefore is a measure of hepatic function

Where does drug metabolism occur?

Major site is the LIVER First Pass metabolism Oral to sm. intestine to liver to circulation Some drugs may also be partially metabolized in the intestine. First-pass metabolism may greatly limit the oral bioavailability of a drug, thereby limiting its effectiveness by the oral route.

How are amino acids metabolized in the liver?

Major site of amino acid metabolism Major site for urea synthesis Conjugation of xenobiotic compounds with glycine, glutathione Synthesis of heme, nucleotides, glutathione Major site of synthesis of nonessential amino acids Amino acids (alanine, etc.) transported to liver Glucagon activates amino acid degradation (deamination), gluconeogenesis Glucagon facilitates glucose release NH4+ generated, drives urea cycle

What is X-linked transmission?

Males have only one X chromosome Only one allele for every gene Any X-linked allele in a male is expressed as if it were a dominant allele (called hemizygosity) X-linked recessive alleles have dominant expression in males and recessive expression in females X-linked Dominant Rare Females express the disorder in the heterozygous state Males more profoundly affected than heterozygous females Affected father transmits the disorder to all of his daughters (affected) and to none of his sons Affected woman transmits to 50% of both male and female offspring

What happens in the Microsomal Mixed Function Oxidase System?

Many drug-metabolizing enzymes are located in the lipophilic membranes of the smooth endoplasmic reticulum. When these membranes are homogenized and fractionated, they re-form into vesicles called microsomes. The metabolic enzymes which remain associated with this fraction are known as the mixed function oxidases. The activity of these enzymes requires a reducing agent (NADPH) and molecular oxygen. In a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in water. Two microsomal enzymes play a key role: NADPH-cytochrome P450 reductase and cytochrome P450, which serves as the terminal oxidase. Multiple forms of cytochrome P450 exist with differing substrate specificity. Drug oxidations can occur which are not mediated through cytochrome P450. These include xanthine oxidase and alcohol dehydrogenase.

How does tissue remodeling occur by MMP?

Matrix Metalloproteins are a major family of proteases responsible for removing ECM At least 25 different members. Why so many? These proteases function outside of cells - control of activation, specificity in targeting and limiting mobility are major mechanisms limiting their function Minimal MMPs have no domains limiting their mobility and targeting, but retain their pro-domain; this domain can bind the catalytic domain via SH-Zn interactions and block its activity. MMPs with a furin site lack the pro-domain when they are released from cells and are active Hemopexin-like domains, fibronectin repeats and collagen-like domains interact with other proteins providing a mechanism for control over trafficking Transmembrane and GPI domains anchor to the surface of cells, giving those cells the ability to move freely through ECM barriers - characteristics common to immune cells, fibroblasts and cancer cells

What is the mean corpuscular volume?

Measure of the average volume of the RBCs Mean of the red blood cell volume distribution Reference range is typically 80 - 100 fL - (fL= femtoliter = 10-15 L ) The MCV is important in classifying anemias -Normal MCV = normocytic anemia -Decreased MCV = microcytic anemia -Increased MCV = macrocytic anemia

What is a northern blot?

Measurement of abundance of a specific RNA Isolation of RNA. Gel electrophoresis. Transfer to nitrocellulose. Generation of a gene specific probe and hybridization. Washing, and exposure to film.

Describe Anti-transport (counter transport/exchanger)

Mechanisms: 1.Both solutes have to be present 2.Transport is reversible. The direction is determined by the electrochemical gradients for each of the solutes. 3.Can be electrogenic or electroneutral

What are the mediators of inflammation?

Mediators of Inflammation: Histamine: increase permeability of blood vessels (edema/itching), increases mucus production (anti-histamines). Heparin: Sulfated GAG that is an anticoagulant used to treat thrombosis and involved in signal transduction. Serine proteases: e.g. Chymase involved in synthesis of angiotensin II and vascular repair. ECF and NCF: attract eosinophils and neutrophils to the site of inflammation. TNF-alpha: Cytokine regulates many processes both positively and negatively

What do cholestyramines do?

Medication A resin that binds some of the bile salts causing, down-regulation of intracellular cholesterol, up-regulation of LDL receptors, and then down-regulation of serum cholesterol

What is the fluid mosaic model?

Membrane lipids form a bilayer in structure and contribute to the membrane its basic barrier properties. In the bilayer, lipids undergo a variety of motions such as vibration, rotation, and translation. Proteins are immersed to varying degrees in the lipid bilayer. Because the bilayer is fluid, proteins are able to move in both rotational and translational modes. The dynamic nature of the protein components give rise to time-dependent patterns in the compositional mosaic. Lipids do not just serve as the structure components in the membrane bilayer. Membrane proteins can be regulated by lipids through lipid-protein interactions. Membrane fluidity Lipid microdomains Membrane fluidity and lipid microdomains are inter-related and both are affected by membrane lipid composition, temperature, pressure, membrane curvature and foreign molecules such as metal ions and drugs.

What is dysbiosis?

Microbial inbalance Caused by: Antibiotics, Lifestyle, Diet, Hygiene, Ect.

What is the difference between microbiota and microbiome?

Microbiota are the bacteria present Microbiome is the ecology as a whole * terms are now used interchangeably

What happens during increased misfolding of proteins in the ER

Misfolded proteins that accumulate in the ER bind to BiP, which causes it to be released from the UPR sensors and triggers their signalling pathways. ATF6α is trafficked to the Golgi apparatus for processing by the enzymes S1P and S2P, to release a soluble cytosolic fragment that enters the nucleus to induce the expression of target genes. IRE1α and PERK homodimerize or oligomerize and trans-autophosphorylate to activate their downstream pathways and promote cell survival. B. The maladaptive UPR is induced by sustained activation of the PERK pathway, which is the result of prolonged severe ER stress and leads to apoptosis (solid red lines). The role of IRE1α-induced JNK and RIDD in ER-stress-induced apoptosis remains unclea

How do molecules leave the nucleus?

Molecules larger than 9nm are transported by an active process mediated by receptors and utilize energy. Macromolecules transport across NPCs through a large aqueous pore than through protein transporters spanning lipid bilayers, as in other membranes (unfolded). Nuclear localization signal on proteins is recognized by nuclear import receptor. NIR binds to NLS and to fibrils of the NPC. The receptor-cargo moves through the pore by binding, dissociating, binding again to proteins that line the nuclear pore. Inside the nucleus the NIR dissociates from the cargo and returns to the cytosol.

How is most protein imported into the ER?

Most Protein Import into the ER is Co-translational Signal sequence on growing polypeptide chain recognizes the signal recognition particle and they bind together Binding of SRP to signal peptide causes a pause in translation The SRP binds to the SRP receptor in the ER membrane and the signal sequence attaches to the protein translocator. Translation continues and translocation begins Signal sequence is clipped and the protein is released in the ER During the process of translocating a protein, a stop transfer sequence can occur which creates a transmembrane protein If the start transfer sequence is not located at the N terminal end of the protein then a multi-pass transmembrane protein can be created

Can bacteria form stable wall-defective cells?

Most bacteria will lyse without a cell wall Some bacteria will undergo a programmed change in their cell membranes to allow them to survive without a cell wall CWD (cell wall defective forms) = partial loss of the wall L-forms = complete loss of the cell wall

In what phase of the cell cycle are most of the cells in our bodies?

Most cells in our bodies are not in the cell cycle. In the absence of mitogenic stimulation, they exit the cell cycle into G0 (quiescent state). Reversibly (stem cells, hepatocytes, etc.) Irreversibly in most cases that leads to terminal differentiation (e.g.: red blood cells) Genetic and epigenetic alterations in the genes that control these processes lead to cancer.

Describe fibroblasts

Most common cell type in connective tissue and spend all their life in CT Synthesize precursors of Ground substance, Collagen & Elastic fibers Rarely divide, but capable in response to injury and inflammation Contractile ability Specialized fibroblast: Myofibroblast Structural Features: Spindle shaped cells with elliptic nucleus Cytoplasm thin; Not resolved by light microscopy Function: Synthesis and secretion of Collagen and Elastin precursors, Proteoglycans, Glycoproteins

Where are most proteases released from?

Most digestive proteases are released from the pancreas

Where is glycogen found?

Most livers can can form and store glycogen but the larget stores are found in the muscle and liver

How does anesthesia work?

Most local anesthetics block Na+ conductance and therefore prevent action potential.

What is located in the lysosome?

Most of the lysosomal membrane proteins are highly glycosylated, which protects them from attack by the hydrolytic enzymes inside the lysosome. Acid Hydrolases: Nucleases, proteases, glycosidases, lipases, phosphatases, sulfatases, phospholipases It would be dangerous for the cell if these enzymes were delivered to the wrong compartment. Signal for targeting lysosomal hydrolases to the correct destination is mannose 6-phosphate (M6P). 1. Lysosomal enzymes are synthesized & carbohydrate (mannose) is added 2. Mannose groups on lyso-somal enzymes are phosphoryl-ated, generating signal (M6P). 3. M6P binds to M6P-receptor in membrane, leading to aggregation of lysosomal hydrolases & their packaging into transport vesicles 4. At low pH (≈6) in late endosomes, the hydrolase dissociates from M6P-receptor & the receptor is recycled back to Golgi Clathrin coat proteins concentrate M6P receptors and their lysosomal hydrolase cargoes in specific transport vesicles

Where is glycogen made and stored?

Most tissues can make glycogen, these are just the two major sites for glycogen synthesis and storage Glycogen has distinct functions in liver and muscle Liver: prevention of hypoglycemia Muscle: energy for contraction

What are stem cells?

Most tissues contain stem cells, which are determined to generate specific types of differentiated cells. These stem cells are responsible for cell renewal in many tissues that exhibit fast-to-slow cell turnover. However, in other tissues stem cells exhibit limited capacity for tissue renewal. Stem cells are required to produce new cells to replace differentiated cells which are unable to divide and exhibit a limited life span. Stem cells often seat in protected areas within the tissue they reside on. The basal layer contains stem cells and transit amplifying cells. Stem cells divide slowly and contain a membrane protein that interacts with the basal lamina (integrin). Transit cells contain lower levels of this protein, divide faster, but only for a few times and subsequently differentiate. Properties of stem cells • A stem cell is not terminally differentiated • It can divide without limit (animal life time) • When it divides, one daughter cell can remain as a stem cell, while the other, typically following a limited number of cell divisions, differentiates. (In certain situations symmetrical cell division leads to two stem cells to repopulate the stem cell pool.) Two mechanisms: Asymmetric division or independent choice (Determined stochastially or by environment)

Why is total protein level tested?

Mostly Albumin and immune globulins (antibodies) Reflects nutritional status, liver disease, and kidney function -Need amino acids to synthesize protein -Liver synthesizes albumin -Minimal protein excreted by kidney Prolonged application of tourniquet during blood collection can result in a falsely elevated total protein

Describe cilia

Motile Cilia Monocilia/Primary Motile cilia-Movement of fluid over an epithelial surface Motile Cilia are capable of actively propelling particles along cell surface Beat in a synchronous pattern Arranged into orderly rows (respiratory tract) By LM, cilia appear as hair-like structures at the apical surface Basal bodies appear as a thin, dark-staining band at base the base of a cilium Microtubules arranged in a 9+2 pattern Each microtubule doublet contains a pair of dynein arms Radial spokes extend from the outer doublets to the center Basal body has a core of 9 microtubule triplets, assembly of cilia is initiated by the basal body Multiple motile cilia work to coordinate fluid flow on the surface of an epithelium Kartagener's syndrome is caused by a structural abnormality that results in the absence of dynein arms > results in dysfunctional cilia > results in respiratory diseases such as bronchitis Non-Motile Primary Cilia (Monocilia) Chemosensors, osmosensors, mechanosensors (e.g. in kidney fluid flow cause them to bend which initiates Ca influx into cell, i.e. provides the cell with information about the external environment) Essential for normal tissue morphogenesis during embryogenesis. Located at the primitive node Essential to the process of gastrulation-develop left/right asymmetry Important during aortic valve delvelopment

Describe cholinergic receptors

Muscarinic (m1, m2, m3, m4, m5), all GPCRs: Produce parasympathetic nerve effects in the heart, smooth muscles, and glands. GPCR- can excite or inhibit, Gi&Gq The M2 receptor is the predominant subtype in the cholinergic control of the heart, The M3 receptor is the predominant subtype in the cholinergic control of smooth muscle, secretory glands, and the eye. The M1 receptor has an important role in the modulation of nicotinic cholinergic transmission in ganglia. Nicotinic (ganglionic, neuronal and neuromuscular), ligand gated ion channels, pentamers: Postsynaptic membrane of all autonomic ganglia, all neuromuscular junction, some CNS pathways, eccitation

What role do the following human enzymes: Mut Y homologue (hMYH) and Mut T homologue (hMTH) play in the BER pathway, specifically with the removal of oxo-G from DNA?

MutY homologue is a DNA glycosylase that is used in BER to remove the A that has paired with oxo-G. It cleaves the glycosidic bond between the adenine and the sugar it is attached to, creating an AP site. (OGG removes oxo-G when it is base paired with C) MutY is the second line of defense (after OGG) MutY is not part of base excision repair. It is part of nucleotide excision repair MUT Y is in the nucleus and mitochondria. MutT homologue is a phosphatase that converts 8-oxodGTP to 8-oxodGMP after it has been removed from the DNA so that it cannot be incorporated into DNA by DNA polymerases during replication. Can do this before it has even been incorporated into the DNA in the first place to prevent the mutation in the first place MUT T is In the cytoplasm

How can disease arise from alternative 3' end cleavage/polyadenylation disease?

Mutation of the normal polyadenylation site results in the utilization of a cryptic polyadenylation site - this can change the 3' UTR or both the 3' UTR and 3' end of the coding region.

How can disease arise from alternative splicing mutation?

Mutations in 5' GU or 3' AG generally inactivate that splice site Mutations in other regulatory sequences can reduce the efficiency of splicing When a mutation inactivates or alters the efficiency of a splice site often other DNA sequences nearby (called cryptic splice site) that are not normally used become active splice site with different efficiencies

What genes are most often mutated in PCD, and what is the role of their cognate protein in cilia? What is the inheritance pattern? What are odds for future siblings?

Mutations in the DNAI1 and DNAH5 genes account for up to 30 percent of all cases of primary ciliary dyskinesia. Mutations in the other genes associated with this condition are found in only a small percentage of cases. Over 30 have been identified that have involvement in this condition DNAI1 encodes the intermediate chain dynein which helps mediate attachment and may also participate in regulating dynein activity and DNAH5 encodes the heavy chain dynein that does the cilia "power stroke". It's an autosomal recessive disorder. If both parents are carriers of the trait, then the child has a 25% chance of getting the disorder.

Describe how AlgT mutations lead to increased alginate in P. aeruginosa biofilms.

Mutations that leave AlgT non-functional relieve the inhibition of AlgU on the transcription of algR. Without, this inhibitory effect of AlgT, AlgU is free to constitutively promote the expression of algR, which codes for the positive alginate biosynthesis regulatory protein. This protein acts as a master regulatory transcription factor to increase genes associated with alginate biosynthesis (such as AlgX, GDP-mannose 6-dehydrogenase, Mannuronan synthase, and Alginate production protein AlgE).

How does myelination change an axon?

Myelin increases the membrane resistance greatly Myelin decreases the membrane capacitance greatly No current can flow out of the membrane to the extracellular fluid because of the presence of myelin The myelin sheath is not continuous. The gaps are called nodes of Ranvier where the axonal membrane is exposed. Current traveling down the center of the axon can only escape through the membrane at the nodes of Ranvier. Only Na channels at the node of Ranvier need to be activated, which saves time and increases the speed of propagation •

What is the purpose of myelination?

Myelination makes action potential conduction faster The insulating myelin increases membrane resistance, so the length constant increases i.e. membrane depolarization can propagate further along the axon without needing the time-consuming process of action potential generation. Myelination also makes action potential propagation more efficient because...i) The increased membrane resistance also minimizes leak of local current across the membrane (fewer local circuit paths)ii) the energy-dependent process of action potential generation is only needed at nodes This is known as saltatory conduction (from Latin saltare - to hop or leap).

Describe cardiac muscle cells

Myocytes in the heart wall are organized into fascicles. Centrally located nuclei Connected by gap junctions Can synthesize collagen, elastin, PGs and ECM

What is the UDP-Glucuronate pathway?

NAD+ requiring reaction that oxidizes UDP-Glucose to UDP-Glucuronate and forms NADH. Functions: Conjugation of glucuronic acid to various molecules enhances solubility and excretion. - Bilirubin - Steroids - Drugs Synthesis of glucosaminoglycans present in extracellular matrix Hyaluronic acid Chondroitin sulfate Synthesis of L-Ascorbate But not in humans. We need vit C

What are the products of the pentose phosphate pathway?

NADPH, ribose 5-phosphate, CO2, fructose-6-phosphate and glyceraldehyde-3-phosphate DOES NOT generate ATP

How do amino acids control the urea cycle?

NAG, produced in mitochondria, is an essential allosteric stimulator of CPS-I Glutamate+Acetyl CoA- N-Acetyl-glutamate (NAG) High Arginine: signals that NH4+ is in excess, drives production of NAG

What are tetramer ionotropic glutamate receptors?

NMDA receptors, AMPA receptors, Kainate receptors The major excitatory neurotransmitter receptors in the CNS Play critical roles in synaptic plasticity, thus learning and memory Long term potentiation

What is the difference between NRTI and non-nucleoside RT inhibitors (NNRTIs)? Why is it likely or unlikely that viral progeny will emerge resistant to both drug types? Explain the "common" mechanism of action of non-nucleoside RT inhibitors?

NNRTIs are allosteric inhibitors Non-nucleoside RT inhibitors target the hydrophobic pocket in the 'palm' of the reverse transcriptase protein.

Can ethanol be converted into glucose?

NO

Some patients with asthma have an exacerbation of their symptoms when they take NSAIDS. Why?

NSAIDS inhibit only cyclo-oxygenase activity Thus arachidonic acid builds up and creates a lot of leukotrienes through lipoxygenase which is also a bronchoconstrictor increasing the asthma

Describe upstroke

Na+ channel opening at upstroke 1.The movement of the Na+ channel m gate requires a very tiny current to flow called the gating current which opens the M gate: moves sensor rapidly. 2.The inward Na+ current is determined by the driving force on Na+ (Em - ENa) and the sodium conductance gNa 3.The inward Na+ current eventually drives the membrane potential to about +30 mV, this forms the overshoot of the action potential

What is the polyol pathway?

Named for first step in pathway in which sugars are reduced to a sugar alcohol by the enzyme Aldose reductase and NADPH is oxidized. Pathway synthesizes fructose from glucose. Aldolase reductase is expressed in vasculature, eye, heart, kidney and neurons Also important during spermatogenesis and formation of seminal fluid. Under hyperglycemic conditions, glucose is shunted to polyol pathway resulting in a buildup of the sorbitol In the eye lens, nerve, heart, and kidney of diabetics sorbitol and low NADPH contribute to tissue damage.

What is the synthesis and fate of HDL?

Nascent HDL is synthesized in liver and intestinal cells. It exchanges proteins with chylomicrons and VLDL. HDL picks up cholesterol (C) from cell membranes. This cholesterol is converted to cholesterol ester (CE) by the LCAT reaction. HDL transfers CE to VLDL in exchange for triacylglycerol (TG). The cholesterol ester transfer protein (CETP) mediates this exchange. An HDL of 60 mg/dL and above is considered protective against heart disease.

What are the adrenergic beta 1 antagonists?

Nebivolol Metoprolol Atenolol Betaxolol

What is regulated necrosis?

Necroptosis: execute necrosis is a programmed fashion Necrosis appears to be favored under certain circumstances Viral defense mechanism Response to other diseases Component of inflammatory diseases such as Crohn's, pancreatitis and myocardial infarction

Describe nicotinic agonists

Nicotine (Nicorette) Binds to α - subunits of nicotinic receptors yielding an increase in sodium influx. Prolonged activation leads to blockade of effector response (depolarizing block). Actions: Central Nervous System Respiration - small doses increase the rate and depth of respiration. Toxic doses lead to stimulation of respiratory center followed by depression. Tremors - finger tremors at low-moderate doses. Convulsions at toxic doses. Others include: irritability, nausea and vomiting, antidiuretic, increase in alertness and memory Cardiovascular - Effects due to stimulation at sympathetic and parasympathetic ganglia and adrenal medulla. Net effects at low doses include increase in heart rate, cardiac output, total peripheral resistance and increase in blood pressure. Nicotine can exaccerbate hypertension, heart disease, angina and peripheral vascular disease. Gastrointestinal tract - Increase in secretions and motility; exacerbate peptic ulceration. Pharmacokinetics: Nicotine is highly lipid soluble, and therefore well absorbed from all routes of administration. Inhalation yields brain levels in 8-10 secs. Inactivated in the liver. Acute intoxication: Respiratory failure, cardiovascular collapse, nausea, vomiting, headache, dizziness, palpitations and convulsions Chronic toxicity: Tolerance develops very rapidly; Physical dependence; Association with respiratory and cardiovascular disease; and cancer. Other drugs used for smoking cessation: Bupropion, an antidepressant, is also used as an aid in smoking cessation. Varenicline is a direct acting nicotinic partial agonist, approved for smoking cessation. It reduces symptoms of withdrawal. It may produce nausea, headache and sleep disturbances.

What are some examples of ligand-gated ion channel receptors

Nicotinic Acetylcholine (cation selective) Glutamate Glycine (Cl-) Adenosine Triphosphate GABA (Cl-) 5-HT3 serotonin receptor (cation selective)

How is erectile dysfunction treatment work?

Nitric oxide (NO) is the endothelium-derived relaxation factor for vascular smooth muscles NO acts by activating soluble guanylate cyclase, which converts GTP to cGMP. cGMP causes vasodilation cGMP à GMP by phosphodiesterase (PDEs) PDE5 is present most prominently in the corpus cavernosum and the retina. Sildenafil (Viagra), Vardenafil (Levitra), Tadalafil (Cialis): potent selective inhibitors of phosphodiesterase 5 (PDE5) Inhibit PDE5, increase cGMP, cause vasodilation

Does fatty acid oxidation happen in the brain?

No or little fatty acid is detected except for in astrocytes Likely because the brain has a low enzymatic capacity for the beta-oxidation pathway. AKA low percentage of beta-oxidation enzymes Probably not caused by BBB Maybe due to low translocation rate of long-chain fatty acyl CoA across the inner mitochondrial membrane

What are the characteristics of smooth muscle cells, comparison with skeletal muscle cells?

No visible sarcomeres, but operates by a sliding filament mechanism Relaxed cells 20-500 µm long, 5-10 µm wide No t-tubules. SR is close to the plasma membrane and is associated with invaginations of the plasma membrane. Dense bodies (contain a variety of plaque proteins) to which thin filaments are attached. No troponin. Cells have caldesmon and calponin (actin-binding proteins), and calmodulin (calcium binding protein) Interconnected by gap junctions Produce an external lamina (Type III and IV collagen)

Are plasmid transfers specific?

No, broad host range plasmids can mediate horizontal gene transfer through numerous genera and species

Is DNA synthesized de novo?

No, the annealed primer provides an exposed 3'OH end required for addition of a new nucleotide. Only the primer is chemically modified (no de novo synthesis).

What are the different types of variables?

Nominal Variable: a characteristic measured as unordered categories •EX: Blood type (A, B, AB, O) •EX: Type of cancer (lung, colon, breast, etc.) Binary (or dichotomous) Variable: only two possible values •Special type of nominal variable •EX: Yes/no; present/absent; alive/dead; male/female Ordinal Variable: characteristic measured as ordered categories •EX: Stage of cancer (I, II, III, IV) •EX: Response to treatment (complete, partial, stable, progression) •EX: Opinions on questionnaires (strongly agree, somewhat agree, etc.) Interval: equal distance between values but zero point is arbitrary EX: 1Q, Quality of Life . Ratio: possible values limited only by precision of measurement, zero has real meaning, negative values are invalid. EX: height, weight, cholesterol, blood pressure Values have units

Describe scaffold molecules

Non-catalytic proteins Function to put other proteins into reactive proximity SH2 and SH3 domains. (for Src Homology regions 2 and 3). These domains recognize phosphorylated tyrosines and enable proteins that contain them to bind to other intracellular signaling proteins that have been transiently phosphorylated on tyrosines PTB domains. These also bind to phosphorylated tyrosines in a particular peptide sequence PDZ domains, WD domains, each of which binds to a specific motif on a receptor or signaling protein. Protein-protein interactions are facilitated by a multitude of other types of domains.

Describe Pindolol

Non-selective Beta adrenergic antagonist/partial agonist Pharmacotherapeutics ➯ **Cardiovascular (hypertension, angina, arrhythmia) Pharmacodynamics: Less bradycardia and abnormalities in plasma lipids than other β-antagonists (no dyslipidemia with acebutolol) Overall clinical significance of intrinsic sympathomimetic activity remains uncertain. Local Na+ channel blockade (local anesthetic activity) Interaction with 5-HT signaling, may potentiate the action of traditional antidepressant medications

Describe Dobutamine

Non-selective Beta-adrenergic agonist Beta 1 preferring Pharmacotherapeutics: Bronchodilation Bradycardia (stimulate heart rate in heart block) Ventricular arrhythmia (Torsades de pointes) Relaxes smooth muscle, ie., bronchial and GI Decreases vascular resistance Increases cardiac output Positive inotropy and chronotropy **Used for cardiogenic shock and acute heart failure Adverse Effects ➯ Palpitations, Tachycardia, Flushed skin

Describe Isoproterenol

Non-selective Beta-adrenergic agonist Pharmacotherapeutics: Bronchodilation Bradycardia (stimulate heart rate in heart block) Ventricular arrhythmia (Torsades de pointes) Relaxes smooth muscle, ie., bronchial and GI Decreases vascular resistance Increases cardiac output by increasing HR and contractility (B1) Vasodilation decreases SVR and diastolic pressure (B2) Increases pulse pressure which makes systolic pressure unchanged **Used for bronchospasm during anesthesia, AV block, cardiac arrest, bronchial asthma Adverse Effects ➯ Palpitations, Tachycardia, Flushed skin

Describe Carvedilol

Non-selective adrenergic antagonist α1 blocker (both isomers are equal) Greater potency at β receptors **Used for chroic heart failure Inhibits vascular smooth muscle mitogenesis independent of adrenoceptor blockade.

Describe Phenoxybenzamine

Non-selective alpha antagonist Irreversible Phentolamine Pharmacodynamics: Competitive blockade of α1 and α2 receptors ⬇ peripheral resistance & blood pressure (α1, and possibly α2 on vascular smooth muscle) Cardiac stimulation due to blockade of presynaptic α2 Minor effects at other receptors; 5-HT antagonist, Ach & H-agonist effects Pharmacodynamics: Noncompetitive blockade ≫ α1 than α2 receptors Inhibits reuptake of NE Some blockade of Ach, 5-HT, H-receptors Pharmacotherapeutics: **Pheochromocytoma **Attenuation of catecholamine-induced vasoconstriction ⬇ BP only in high sympathetic tone Adverse effects Tachycardia, orthostatic hypotension ⇒ α2 blockade Nasal congestion Inhibition of ejaculation

Describe Phentolamine

Non-selective alpha antagonist Reversible Phentolamine Pharmacodynamics: Competitive blockade of α1 and α2 receptors ⬇ peripheral resistance & blood pressure (α1, and possibly α2 on vascular smooth muscle) **Causes vasodilation Cardiac stimulation due to blockade of presynaptic α2 Minor effects at other receptors; 5-HT antagonist, Ach & H-agonist effects Pharmacotherapeutics: **Pheochromocytoma hypertensive crisis **Local anesthetic reversal agent in soft tissue (dental applications) Adverse effects: Tachycardia due to α2 blockade Stimulation of gastric acid and pepsin Contraindications Angina (due to reflex tachycardia from α2 blockade) Gastric and duodenal ulcers

Describe Propranolol

Non-selective beta adrenergic antagonist Pharmacodynamics - Non-selective blockade of β1 /β2 receptors ⬇ HR, myocardial contractility & CO ⇒ ⬇ BPêPR ⬇ AV conduction **Bronchoconstriction **Used for hypotension Inhibits sympathetic stimulated lipolysis, glycogenolysis Local Na+ channel blockade (propranolol) Adverse effects Bradycardia, AV block Sedation Erectile dysfunction Dyslipidemia with chronic use General Contraindications/Precautions Pulmonary edema & diseases Bradycardia or heart block Abrupt withdrawal may precipitate angina or hypertension

Describe Nadolol

Non-selective beta adrenergic antagonist Pharmacodynamics - Non-selective blockade of β1 /β2 receptors ⬇ HR, myocardial contractility & CO ⇒ ⬇ BPêPR ⬇ AV conduction **Bronchoconstriction Inhibits sympathetic stimulated lipolysis, glycogenolysis Adverse effects Bradycardia, AV block Sedation Erectile dysfunction Dyslipidemia with chronic use General Contraindications/Precautions Pulmonary edema & diseases Bradycardia or heart block Abrupt withdrawal may precipitate angina or hypertension

Describe Timolol

Non-selective beta adrenergic antagonist Pharmacodynamics - Non-selective blockade of β1 /β2 receptors ⬇ HR, myocardial contractility & CO ⇒ ⬇ BPêPR ⬇ AV conduction **Bronchoconstriction Inhibits sympathetic stimulated lipolysis, glycogenolysis Adverse effects Bradycardia, AV block Sedation Erectile dysfunction Dyslipidemia with chronic use General Contraindications/Precautions Pulmonary edema & diseases Bradycardia or heart block Abrupt withdrawal may precipitate angina or hypertension

What type of amino acid isoleucine and what are its abbreviations?

Nonpolar, Ile, I

What type of amino acid is leucine and what are its abbreviations?

Nonpolar, Leu, L

What type of amino acid is proline and what are its abbreviations?

Nonpolar, Pro, P

What drugs are used in shock?

Norepinephrine, dopamine, dobutamine

Marfan syndrome is an autosomal dominant genetic disorder caused by a mutation to the gene FBN1, encoding the Fibrillin-1 protein. What is the function of the Fibrillin-1 protein?

Normally, fibrillin is located in the extracellular matrix between cells. It binds to other fibrillin molecules as well as other extracellular matrix proteins resulting in the formation of microfibrils, which are threadlike filaments. These provide strength and flexibility to connective tissue Additionally, fibrillin binds/stores many growth factors including TGFB. When TGFB is bound to fibrillin, it is inactive and when unbound to fibrillin it is active. With a mutation in fibrillin and hence storage of TGFB, there is an increased in the amount of active TGFB. Increased TGFB leads to decreased elasticity of tissues, overgrowth and instability of tissues. Fibrillin is important for the assembly of elastin into elastic fibers. Mutations in the fibrillin-1 gene are closely associated with Marfan syndrome.

Describe monocytes

Nucleus often eccentric, indented and pale-staining Life span 12 to 100 hours in blood. FUNCTION: Monocyte exits a blood vessel, enters connective tissue and becomes a macrophage. The monocyte is the transport form of the tissue macrophage

What is incidence rate and how is it calculated?

Number of study participants who experience the outcome (for the first time) per unit time (e.g., per 100,000 person-years) (Number of new cases of disease)/(Person-time of observation in population at risk) This measure is a true rate because it directly integrates time into the denominator Incidence rates do not make assumptions of complete follow-up

What types of specimens can be taken for bacterial analysis?

Numerous types of samples can be used to characterize the microbiome and microbiota. Tissues can be obtained in animal models, surgical biopsies, resections or early post=mortem specimens Swabs can be used to sample microbiota on mucosal surfaces Fecal samples can be used to study gastrointestinal microbiota o fecal specimens will have bacteria shed from the surface o usually growing bacterial populations or sheared pieces of biofilms o may or may not be fully representative of the entire microbiota

How does microbiota benefit us?

Nutritional benefits -Vitamin K, B12 -Steroid metabolism (breaks down bile acids) -Organic acid production -Food breakdown Pathogen antagonism Promotes angiogenesis Promotes enteric nerve function Enhance host immune defenses -Presence of microbiota is required for the development of a normal immune system.

How are the non-essential amino acids made?

OAA uses transaminase to make aspartate that combines with glutamine to make asparagine Phosphoglycerate from glucose forms serine that is converted into glycine or joins with methionine to make cysteine Pyruvate transaminates with Alanine Phenylalanine makes tyrosine Glutamate uses transaminase or glutamate dehydrogenase to make glutamate that can be converted into glutamine, proline or arginine

What DNA repair pathway is defective if the OGG1 gene is mutated and why heavy smokers would be at higher risk of developing laryngeal cancer?

OGG1 is an enzyme involved in the base excision repair pathway, so this pathway would be defective with this mutation. Specifically, this enzyme is needed to repair 8-oxo-G mutations, which are caused by oxidative stress and are a common mutation found in cancers. Heavy smokers are exposing their tissues to a lot of oxidative stress, which can lead to these 8-oxo-G mutations. If they cannot use the BER pathway, these mutations can build up and increase the smoker risk of cancer. OGG1 is the first enzyme used in the BER pathway. It is needed to cut the damaged base from the sugar it is attached to so it can be removed and create an AP site. If the damaged base is never removed, the rest of the BER pathway will not be able to continue and the mutation will never be repaired. Has dual activity: glycosylation and endonuclease activity, so it takes care of the first two steps of the BER pathway by itself

What are polycistronic messages?

Operons Polycistronic messages contain genes for more than one protein Each structural gene has its own initiation and termination signal Overlap between the termination signal and the initiation signal for each gene can be an additional level of regulation of translation in an operon

What are the therapeutic effects of antimuscarinics?

Ophthalmologic examinations - when mydriasis and cycloplegia are needed. Also used in uveitis and iritis To dry salivary secretions As preanesthetic medications Parkinsonism (adjunct to L-dopa; drug-induced symptoms) Motion sickness - Scopolamine Peptic ulceration - secondary to H2-blockers, PPIs Diarrhea and gastrointestinal spasm Bladder spasm COPD and bronchial asthma - adjuncts to beta-2 adrenergic agonists Bradycardia/ acute myocardial infarction in patients with excessive vagal activity Poisoning with cholinomimetics

What are the different routes of administration?

Oral - most common, relatively safe, Gastrointestinal irritation, not good for emergency, first pass metabolism Sublingual - under the tongue, eliminates first pass biotransformation Rectal - 50% bypasses the liver Respiratory - inhalation for local or systemic effect Subcutaneous - under the skin Intramuscular - can be used for depot effect Intravenous - directly into bloodstream, rapid onset, excellent in emergency, can be dangerous Skin - topical, transdermal

What is the difference between osmolarity and tonicity?

Osmolarity is a physiochemical property of a solution The osmolarity of a 0.15 M NaCl solution would be nC where n = 2, and C = 0.15, or about 0.3 osmolar. The osmolarity is the concentration of ideal particles that would produce the same effect. If two solutions have the same osmolarity they are said to be isosmotic, iso-osmotic, isosmolar, or iso-osmolar. A solution with a greater osmolarity is hyperosmolar A solution with a lesser osmolarity is hypo-osmolar. Tonicity is defined as the concentration of particles in a solution outside the cell that cannot cross the membrane: If a cell is placed in an isotonic solution it will maintain its volume. If a cell is placed in a hypertonic solution, it will shrink. If a cell is placed in a hypotonic medium it will swell. The tonicity of a solution refers to the long-term steady state volume of the cell, and depends on the concentration of impermeable solutes

Describe the osteoblast lineage

Osteoblasts originate from mesenchymal stem cells (progenitors) which can also give rise to chondrocytes (cartilage), myoblasts (muscle) and adipocytes (fat). The transcription factor, Runx2, is required for the expression of bone-specific ECM (collagen type I, osteocalcin and other non-collagenous proteins).

What helps the support the nucleus and aids in maintaining its shape?

Outer membrane - bears ribosomes Lamins (intermediate filaments, 10-12nm) "coat" the inner surface of the nuclear membrane, the nuclear lamina: -stability to the nucleus -chromosomes attach

How do miRNAs regulate mRNA translation and stability?

Over 1000 miRNAs and they are estimated to regulate at least 1/3 of protein-coding genes. 3'-5' One miRNA can affect many different mRNA miRNAs are synthesized as a larger precursor molecules. Ultimately a short single-stranded molecule of ~22 bases is retained as part of the RISC complex. The miRNA guides the RISC complex to the target mRNA molecule based on base pairing. If the RNA-RNA match is extensive, the target mRNA is cleaved and rapidly degraded. If the RNA-RNA match is limited (no more than 7-nucleotides near the 5' end of the miRNA), translation is inhibited, mRNA destabilized and the mRNA is transferred to P-bodies where it is degraded.

Why is oxalate poisonous?

Oxalate is poisonous to humans solely because Ca-oxalate is insoluble Ca-oxalate formation in kidney causes stones, or kidney failure. Ca-oxalate in gut is excreted in feces Rhubarb pie is safe, but rhubarb leaves contain lots of oxalate (do not eat!) Formed from ethylene glycol Ethylene glycol is common antifreeze; sometimes ingested accidently Ethylene glycol is converted in liver (alcohol dehydrogenase) to oxalate. Ca-oxalate precipitates, forms crystals in blood: brain, heart, lungs affected, kidney stones form rapidly and kidney failure ensues rapidly. Therapy is alcohol, to inhibit alcohol dehydrogenase (whiskey, vodka). Fomepizole (4-methyl pyrazole) is a potent ADH inhibitor, much more expensive

How is asparagine synthesized and degraded?

Oxaloacetate transaminated to Aspartate using PLP Aspartate interconverted with asparagine Aspartate converted to asparagine using ATP and the nitrogen group from glutamine creating glutamate via the asparagine synthetase Asparagine is converted back to aspartate via asparaginase using H2O and releasing NH4+

What are some other ways to create TCA intermediates?

Oxaloacetate- Pyruvate, aspartate Malate- Glucogenic AA Fumarate- Pyruvate Succinyl CoA- Valine, isoleucine, methionine, threonine, propionyl CoA, odd chain fatty acids Alpha-ketoglutarate- Glutamate

What are the direct acting non selective alpha adrenergic agonists?

Oxymetazolin Naphazoline

What does p53 do?

P53 is by DNA danage upstream of CDKs. Activated by phosphorylation Upon activation, p53 induces cell cycle arrest by inhibiting CDKs. Induces cell cycle by causing the transcription of the p21 CDK inhibitor protein which prevents cell cycle progression. The p53 gatekeeper tumor suppressor, halts the cell cycle in response to DNA damage to allow DNA repair (p53 can also trigger apoptosis)

How do you stain for glycoproteins/carbohydrates?

PAS Periodic Acid Schiff Goblet stains will show up in PAS and not Hematoxylin

What is the mechanism of glutathione?

PPP supplies NADPH to maintain the tripeptide Glutathione in the reduced state for protection against oxygen radicals. Glutathione Peroxidase, a selenocysteine enzyme, reduces peroxides by oxidizing GSH to GSSG. NADPH is required for Glutathione Reductase to reduce Oxidized Glutathione (GSSG) to its reduced form (GSH). This rxn requires also riboflavin (B2) At steady state, 99.8% of glutathione in the RBC is present as reduced Glutathione due to the activity of Glutathione Reductase and the supply of NADPH from the PPP GSH is a tripeptide composed of γ-glutamate, cysteine and glycine.

Describe the pathway that synthesized PTH follows to be released from the cell.

PTH is formed as a larger prepro-PTH. This precursor undergoes two successive proteolytic cleavages to yield PTH. The signal peptide is cleaved first during cotranslational translocation, releasing the pro-PTH into the lumen of the rough endoplasmic reticulum (RER). Pro-PTH is processed later in the Golgi apparatus to produce the mature PTH.

What is the wobble hypothesis? ***?

Pairing between 3'-base of codon and 5'-base of the anticodon does not always follow base-pairing rules (i.e., A pairs with U, G pairs with C). At the third base of the codon, the base pairs can wobble, i.e., G can pair with U; and A, C or U can pair with the unusual base hypoxanthine (I) found in tRNA. Thus, three of four codons for alanine can pair with a single tRNA. Due to this phenomenon, fewer than 61 tRNAs are required to translate the genetic code.

Can the body synthesize fatty acids with the chain length longer than 16 Cs?

Palmitate is the end product of the fatty acid synthase complex. However, the acyl chain can be further elongated in the endoplasmic reticulum using reactions similar but not identical to those that occurred on the fatty acid synthase complex. In the process of further elongation, the fatty acyl chain is attached to CoA rather than to the phosphopantetheinyl residue of an ACP. The last two carbons in the resulting fatty acid originate from acetyl CoA, and the remaining carbons in the acyl chain are contributed from malonyl CoA. In this case, acetyl CoA is called the "primer".

What is the difference between a parameter and a statistic?

Parameters (Population) -Fixed characteristics of a given population Statistics (Sample) -estimates of parameters derived from samples

What is the function of peroxidase?

Part of the cyclo-oxygenase enzyme that converts PGG2 to PGH2 with 2GSH-GSSG PGH2 can then go on to make thromboxane TXA2 through TXA synthase and PGI2 through PGI synthase such as other

What are the different structures of a bone?

Parts of long bone: Epiphysis (ends) Metaphysis (beneath growth plate) Diaphysis (shaft) Medullary (marrow) cavity Endosteum - contains osteoprogenitor cells Periosteum - membrane around the bone • fibrous layer • osteogenic layer Articular cartilage - hyaline cartilage covers the articulating surfaces of bones

What is trisomy 13?

Patau syndrome 1/10,000 to 16,000 births Severe developmental and functional abnormalities Stillbirths and early neonatal deaths are common Of those who are born alive, more than 90% die within the first year of life

What are pathogens?

Pathogens, which cause disease in healthy individuals, can be carried asymptomatically as part of the microbiota. Opportunistic pathogens are normal flora (microbiota species) that can cause disease in immunocompromised patients or if they are introduced into sterile sites (e.g. blood).

How is serine made de novo and what does it make?

Pathway takes 3-phosphoglycerate to serine. Excess serine inhibits 3-PGA-dehydrogenase, phosphoserine phosphatase Abundant serine normally in diet, or made from glycine. Makes glycine by the enzyme that transfers the methyl group from Ser to FH4 is serine hydroxymethyltransferase

What is cachexia?

Patients with tumors frequently develop a condition known as cachexia in which weight loss and muscle wasting occurs, accompanied by anorexia. Surprisingly, our understanding of cachexia is still quite weak. It is known that the presence and severity of cachexia is an indicator of a poor prognosis. Cachexia seems simple at first: give patient more protein and glucose equivalents to feed the tumor. But it has proven far more complex. Nutritional supplements and IV feeding are not as successful as one might wish.

Describe Brimonidine

Pharmacodynamics ➱ sympatholytic α2 -selective **Used for Open-angle glaucoma by decreasing aqueous humor production Also: Hypertension Adjunct for ADHD ⇣ CNS sympathetic outflow via inhibition of presynaptic NE release Possible ⇣ NE release at peripheral presynaptic α2 Lower efficacy at peripheral postsynaptic α2 sites Adverse effects: Dry mouth, sedation, constipation Hypertensive crisis (sudden withdrawal)

What is PKU?

Phenylketonuria Phenylalanine hydroxylase is defective; Tyr cannot be made and is now essential. Phe is converted to other products such as phenylpyruvate and phenylacetate. This rare disorder requires supplementation of diet with Tyr, dopa, and a serotonin precursor. Very hard to treat successfully. Newborns with PKU from a complete lack of the enzyme suffer progressive intellectual disability, pigmentation deficit (blond, blue eyes, pale skin). Screening test of newborns for PKU is routinely performed. Treatment: Diet must restrict levels of Phe, usually by low protein. Tyrosine is an essential amino acid in these patients. Aspartame (Nutrasweet) contains phenylalanine equivalents. Partial deficiencies also exist, may show up in later childhood. If BH4 synthesis or its recycling are defective, individuals fail to make Tyr from Phe, dopamine/epinephrine/norepinephrine from Tyr, and serotonin from Trp ("malignant PKU" ).

Where does phosphatidic acid come from and what does it create?

Phosphatidic acid can be synthesized from fatty acyl CoA and glycerol-3-phosphate Creates glycerophospholipids such as cardiolipin, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phostphatidylinositol and phosphatidylglycerol

What is the primary component of lung surfactant?

Phosphatidylcholine aka dipalmitoylphosphatidylcholine

What types of lipids are cell membranes composed of?

Phosphoglycerides, sphingolipids, and cholesterol.

Which enzyme converts a phospholipid to a lysophospholipid?

Phospholipase A2

What is phospholipid scavenging?

Phospholipid lipids can be broken down by phospholipases This yields glycerol-3-P that can be converted to o PEP o pyruvate o acetyl CoA and the fatty acids can be converted to acetyl-CoA by beta-oxidation The 3-carbon sugars can be converted to 6 carbon sugars by gluconeogenesis (see next slide) in order to make membranes, cell wall, and capsule/matrix components of the bacterial cell Gluconeogenesis can be used to convert 3-C sugars to hexoses need for biosynthesis · these reactions require ATP

What happens during DNA damage by UV light?

Photochemical fusion of two adjacent pyrimidine T-T C-T Defective base pairing stops replication and transcription

What is functional stability and selection?

Phylogeny is dependent on the accumulation of random mutations in the DNA Whether those random mutations are kept depends on the selection for the mutation An important protein will have fewer mutations than a non-important protein This is the concept of selection So the protein has to have the same level of selection in all bacteria meaning in has the same functional stability The 16S rRNA is part of the ribosome and has the exact same function - making proteins - that is equally important to all bacteria

What determines the initial distribution of a drug?

Physicochemical properties of the drug - Ability of the drug to pass biological membranes. This will be determined by the drug's lipid solubility, pKa, molecular weight and presence of appropriate carrier systems in the membrane. Cardiac output Regional blood flow to various tissues & size of organs Degree of plasma protein binding - Binding may facilitate absorption into the blood. However, it will reduce the ability of the drug to enter other tissues since only free molecules readily leave the capillaries. Note that drugs may displace each other from binding sites, on occasion causing adverse reactions. Degree of binding to tissue proteins Drugs with sufficient lipid solubility will first distribute to those areas with high regional blood flow (liver, heart, CNS). The drugs will accumulate less rapidly in skeletal muscle and even more slowly into adipose tissue. Entrance to the CNS is restricted due to the anatomical arrangement comprising the Blood Brain Barrier. Drugs may cross the placental barrier, thus affecting the fetus, and cross into maternal milk, thus affecting nursing infants. Drugs highly bound to plasma proteins have a slower rate of distribution. Only unbound (free) drug can reach its site of action.

How are bacterial populations compared?

Populations are compared by: Relative abundance of different bacteria Diversity of the population

Describe epinephrine

Potent alpha and beta agonist Greater beta activity As does increase Vasoconstrictor and cardiac stimulant by increasing HR and cardiac contractility Bronchodilation Vasodilation that drops diastolic pressure at low doses and thus decreases SVR Used for cardiac arrest and shock At higher doses alpha effects predominate such as vasoconstriction, increase SVR, increase BP Increases pulse pressure Skeletal muscle vessel dilation (β2)Smooth muscle, relax &/or contract (β2/α)Urinary retention (mixed α/β)Metabolic⬆ plasma glucose (α2)⬆ glycogenolysis (β)⬇ insulin secretion (α2); ⬆ (β2) ***Anaphylactic shock, elevate blood pressure, restore cardiac function

What causes up to 75% of laboratory error?

Pre-analytical variables Encompasses the time from when the test is ordered by the physician until the sample is ready for analysis Time of collection -Diurnal variation, e.g., cortisol Effects of eating -Some specimens are increased or decreased after eating (i.e., glucose, triglycerides) -Specimens for these tests are usually collected in a fasting state Tourniquet Application and Time -Prolonged tourniquet time blocks the flow of blood eventually leading to a sieving effect. Small molecules, water and ions are forced out blood vessels and larger molecules are concentrated Proper Venipuncture Technique -hemolysis Proper tube mixing Correct specimen volume

What is the mechanism of homologous recombination during double strand break repair?

Preferred method for repair of double strand breaks* that arise after DNA has been replicated and sister chromatids are held together. (Synthesis Dependent Strand Anneling: SDSA) Since after DNA replication and prior to mitosis, sister chromatids are held together, these double strands breaks can be repaired by homologous recombination. The steps and many of the proteins implicated are the same as in the the repair of damaged DNA replication forks. An exonuclease degrades the 5' end to generate a 3'end that pairs with the complementary strand of the other sister chromatid. DNA synthesis and branch migration mediate synthesis of the missing sequence and re-ligation with the original strand. Branch migration also allows pairing with the original complementary strand and synthesis from the other 3'end. Initiation of strand exchange is mediated by an enzyme called a recombinase (strand invasion): RAD51 Recombinase molecules attach to one end of the DNA strand broken during step 1 and then invade a duplex DNA molecule (the recipient). Many molecules of the recombinase bind forming a nucleoprotein filament. The recombinase requires ATP to bind and digests a phosphate bond as it releases. Once bound to both single and double stranded DNA the recombinase searches for homology between the base sequences in the invading (donor) strand and the recipient strands. If homology is found, strand exchange takes place. The recombinase catalyzes formation of a three-stranded DNA structure called a D-loop. This is made up of two strands from the recipient duplex and one strand from the nicked donor which is essentially homologous with the duplex being invaded. One strand of the recipient duplex is displaced and replaced by hydrogen bond base pairing with the single strand of DNA from the donor.

What is a western blot?

Preparation of protein extract. SDS-polyacrylamide gel electrophoresis. Trasfer to nitrocellulose. Incubation with monoclonal antibody that recognizes a specific protein and washing. Incubation with secondary antibody that recognizes the primary and also contains an enzyme that when exposed to substrate, emits a signal. Washing, expose to chemical that activates enzyme on secondary and reading of this signal.

What is the Philadelphia chromosome?

Present in 95% of CML cases: derived from a translocation between chromosomes 9 and 22 The oncogenic properties of the BCR-Abl fusion were revealed by studies of the Ableson murine leukemia virus and identification of the v-abl oncogene When they mapped the chromosome location of this gene, found it to be on chromosome 22 and very close to the breakpoint region in CML. Homologous to c-Src and has SH3, SH2 and SH1 domains. SH1 is a tyrosine kinase domain..The BCR fusion suppresses auto-inhibition and leads to constitutive activation of the kinase . Engineering of a recombinant virus harboring a mutation in the tyrosine kinase domain revealed that it tyrosine kinase activity was required for its leukemia inducing function.

What is the relation between prevalence and incidence rate?

Prevalence depends on the incidence rate and duration of disease (duration lasts from onset of disease to its termination) Prevalence = Incidence rate x Duration P = IR x D assumes steady state, that is: lIncidence rates and duration are stable over time Factors that cause prevalence to increase: Increase in incidence Longer duration of the case In-migration of cases Prolongation of life of patients without a cure Factors that cause prevalence to decrease: Decrease in incidence Shorter duration of disease In-migration of healthy people Improved cure rate of disease

What are the functions and localizations of alpha 2 receptors?

Prevent release of NE, vasoconstriction Decrease the effect of sympathetics ***Decrease in blood pressure Inhibits neurotransmitter release Decreases insulin release, decreased lipolysis, decreased fatty acid release **Active in ciliary bodies in the eye and can decrease aqueous humor production used for glaucoma Gi pathway that causes a decrease in cAMP levels Presynaptic nerve terminals, autonomic ganglia, brain, blood vessels, platelets, pancreas, liver, kidney; post-synaptic

How are amino acids metabolized in the kidney?

Primary role is to provide NH3 for H+ titration: Ammonia carried by blood glutamine Two NH3 released from glutamine, through actions of glutaminase and glutamate dehydrogenase (GDH) Produces alpha-ketoglutarate, converted to glucose for use by renal medulla Also, CO2 produced by metabolism of alpha-ketoglutarate, released as bicarbonate ion (buffers pH in blood) The kidneys increase production of NH4+ to relieve acidosis Kidney increases glutamine metabolism during acidosis Note: some gluconeogenesis occurs in the kidney, kidney makes glucose mainly for its own use

What is the cause of Infant respiratory distress syndrome (IRDS) and adult respiratory distress syndrorne (ARDS)?

Problems with lung surfactant production or secretion

What is cell differentiation?

Process by which a cell undergoes physiologic change(s) to become more specialized. Differentiated cells are the functional cells that form tissues. The functional cells of most tissues are terminally differentiated, which means that they have permanently exited the cell cycle. Differentiation is associated with changes in gene expression triggered by the environment. Totipotent: fertilized egg, cells from the morula Þ any cell type Pluripotent: cells from the blastula Þ ectoderm, mesoderm and endoderm Multipotent: Fibroblasts Progenitor hematopoietic cells Unipotent: dividing cells that give rise to a particular cell type

How are collagens synthesized?

Process occurs as collagen proceeds through the secretory pathway 1.Pre-pro-α chains are synthesized in rough ER, where signal peptide is cleaved 2. Prolines and lysines in pro-α chains are hydroxylated 3. Glycosylation of pro-α chains occurs in the smooth ER 4. Triple helix-containing procollagen forms inside the Golgi 5. Cleavage of extension peptides occurs outside the cell, as does assembly of tropocollagen units into collagen fibers Collagens fibers assemble to form fibrillar collagens which contain overlapping regions and lacunar regions

At what stage of mitosis are karyograms done?

Prometaphase

What does insulin do?

Promotes glucose uptake - Rapid Promotes potassium uptake - Rapid Promotes storage of glucose as glycogen (liver and muscle) Promotes triglyceride synthesis and storage in adipose and liver Promotes glycolysis Promotes protein synthesis, cell growth and AA uptake Suppresses lipolysis in adipose Suppresses glucose output from the liver Suppresses protein degradation Suppresses appetite by increasing satiety

What are the types of regulatory DNA sequences?

Properties of Enhancer/Silencer DNA sequences (cis-acting DNA sequences): Short DNA sequences (~8 to ~16 bp in length) that function as a double strand Position independent - can function long distances upstream and downstream of start site of transcription •Orientation independent - sequences are often palindromic and can function in both 5' to 3' direction and 3' to 5' direction

What are the different stages of mitosis?

Prophase, metaphase, anaphase, telophase

How is propionyl CoA converted to succinyl CoA?

Propionyl CoA is carboxylated to make methylmalonyl CoA (requires biotin). Methylmalonyl CoA is rearranged to succinyl CoA (requires B12). Succinyl CoA drives TCA cycle to form new malate, glucose. Propionyl CoA is also generated from metabolism of odd-chain fatty acids Why is this important? bc even-chain fatty acids produce only acetyl-CoA, which yields CO2; propionyl-CoA is metabolized to succinyl-CoA, which can eventually yield new glucose (see slide 14).

What is penetrance in dominant disorders?

Proportion of people who express the condition versus all who possess the allele High Penetrance -Huntington's Disease approaches 100% -gender differences and other factors influence the age of disease expression and the rate of neurologic deterioration. "Reduced" penetrance Women who carry dominant acting mutations in the breast and ovarian cancer gene BRCA1 -This gene has a penetrance rate of about 80%, which means that of 100 individuals who actually have the gene, only about 80% will develop breast or ovarian cancer.

What are the non-selective beta adrenergic antagonists?

Propranolol Timolol Nadolol

What are the ubiquitin mediated degradation pathways?

Proteasome: •properly folded soluble proteins or terminally misfolded soluble proteins. •specified by lysine 48 linked ubiquitin chains. Lysosome: •cell surface proteins. •specified by lysine 63 linked ubiquitin chains or mono-ubiquitination. Autophagy: •protein aggregates. •specified by lysine 63 linked ubiquitin chains.

What is protein degradation?

Protein degradation is a necessary component of terminating biological processes and destroying mis-folded proteins that are constantly being produced. Intracellular protein degradation is rapid, complete, and selective. For soluble proteins (properly folded and misfolded), relies on the proteasome. For membrane proteins on the cell surface, relies on endocytosis and lysosomal mediated degradation For protein aggregates, relies on the autophagy pathway. Ubiquitin modification of proteins plays an essential role in targeting many proteins to these destinations for destruction.

How are proteins in the ER degraded?

Protein folding in the ER is facilitated by the many resident chaperones, such as PDI, ERp57 and ERO1, as well as peptidylprolyl isomerases (PPIases). Peptide-binding proteins, such as BiP, GRP94 and GRP170, prevent aggregation. The addition and trimming of N-linked core oligosaccharides, together with re-glucosylation by UDP-glucose glycoprotein glucosyltransferase 1 (UGGT1), facilitate the interaction of proteins with the chaperones calnexin (CNX) and calreticulin (CRT), which assess the quality of folding and direct transport and degradation of proteins. Correctly folded proteins move to the Golgi apparatus in cargo-trafficking complexes. Unfolded, misfolded or aggregated proteins are retrotranslocated to the cytosol for ubiquitination and degradation by the 26S proteasome through ER-associated protein degradation (ERAD), for which the structure of the N-linked glycan seems to be important.

What are the common themes in sorting and targeting?

Proteins contain targeting (sorting) signals that identify their destination. (Usually linear segments but sometimes a 'signal patch' arising from 3D structure of the protein) Machinery (usually other proteins) identifies these targeting signals and direct the proteins to the correct destination.

What are sigma factors?

Proteins that bind specific promoter sequences and instruct RNA polymerase where to begin transcribing Each sigma ·factor preferentially binds a consensus sequence present in the promoter of multiple genes

What are proteoglycans?

Proteoglycans are a special type of glycoprotein Glycoproteins Proteins carrying carbohydrate Proteoglycans Glycoproteins with 1-100s of long, unbranched, polyanionic, repeating disaccharide chains, called glycosaminoglycans (GAGs) Typically < 12 - 15 sugars/attachment site Sugar structure may be branched Several different sugars/structure Sugars are N-linked (to Asn) or O-linked (to Ser or Thr) Glycosylated enzymes may or may not require the sugars for correct folding or for activity. Sugar structures are often recognized by other proteins. Sugars are usually on proteins that are secreted, or on the extracellular portion of membrane proteins (not on completely intracellular proteins). The glycosylation pattern of the same protein may vary from tissue to tissue, depending on the presence of sugars and glycosyl transferases.

How are glycosaminoglycans attached to proteins?

Proteoglycans are always O-linked Sugars are added 1 at a time. Sugars are donated from nucleotides Nucleosides are recycled

What are PROTACS?

Proteolysis Targeting Chimera-New class of drugs using the ubiquitin system

What is a cross sectional study?

Provide "snapshots" of the health of a specified population at one moment in time. Usually descriptive in nature Often used to determine 'prevalence' of a condition or correlation between 2 variables Temporality cannot be determined → 'chicken or egg problem' Low cost and no loss to follow-up

What does cortisol do?

Provides for changing requirements over the long term; stimulates amino acid mobilization from muscle protein; stimulates gluconeogenesis; stimulates fatty acid release from adipose tissue

What is PLP and what is it used for?

Pyridoxal phosphate, PLP, is a cofactor for many enzymes interacting with amino acid substrates Transamination- Aspartate to OAA; alpha-ketoglutarate to glutamate Decarboxylation (see GABA, histamine, serotonin) PLP is derived from vitamin B6 B6 found in meat, whole grains and vegetables (also added to processed foods) PLP is the active (co-factor) form. Deficiencies in alcoholics (increased degradation of PLP), sometimes dialysis patients (filtered out). PLP reacts with isoniazid (anti-tuberculosis drug), leading to deficiency.

What is the name for vitamin B6 and what does it do?

Pyridoxine Active form is pyridoxal phosphate (PLP). Required for synthesis, catabolism and interconversion of amino acids. Including aminotransferases and decarboxylases Required for the synthesis of sphingolipids, conversion of tryptophan to niacin, and hemoglobin synthesis. Required for the synthesis of various neurotransmitters, such as serotonin and norepinephrine.Component of glycogen phosphorylase (role in glycogenolysis).

What is serum protein electrophoresis?

Qualitative separation of protein fractions in serum using cellulose acetate or agarose gel electrophoresis •Proteins are separated according to electrical charges Protein stain (e.g., Ponceau S) intensity related to protein concentration Test for presence of abnormal proteins, primarily monoclonal immune proteins

What is the mortality rate and how is it calculated?

Quantifies number of deaths that occur during a specific period of time in a population at risk for dying; Most often calculated as 'overall' or for death due to a specific disease. Number of study participants who die from the outcome per unit time (e.g., per 100,000 person-years) (Number of deaths from disease)/(Person-time of observation in population at risk) This measure is a true rate because it directly integrates time into the denominator

What is prevalence and how is it calculated?

Quantifies number of existing cases of disease in a population at one point in time or during a period of time Number (proportion) of existing cases of disease in a population at one point or during a period of time (Number of cases of disease present in the population at a specified time)/(Number of persons in the population at the specified time) Point prevalence: Prevalence of disease at one point in time Period prevalence: Number of people who have had disease at any time during the specified time interval.

What is incidence and how is it calculated?

Quantifies number of new cases of disease that occur during a specific period of time in a population at risk for developing the disease Proportion of study participants who experience the disease/outcome (for the first time) in a specified period: (Number of new cases of disease)/(Number of persons in population at risk over specified period of time) "at risk" = theoretically at risk of disease but no known disease (yet) Assumes that everyone is followed for the entire period of time ("complete follow-up")

What is the case-fatality rate and how is it calculated?

Quantifies the proportion of people diagnosed as having a certain disease who died during a specific period of time after diagnosis Proportion of people, among those who develop a disease, who die from the disease during a specified period of time (Number of individuals dying during a specified time period after disease diagnosis)/(Number of persons with the specified disease) Sometimes all deaths among patients, rather than just deaths from the disease, are counted in the numerator Difficulty distinguishing death from specific disease and deaths from other causes Case-fatality rate is a measure of disease severity

Describe the RER

RER is continuous with the nuclear envelope and the SER ENDOPLASMIC RETICULUM (ER) : an anastamosing network of interconnecting channels and sacs formed by a continuous membrane which encloses a space. Rough ER - ribosomes -connect with perinuclear cisternae Rough ER is abundant in protein-secreting cells. Stain intensely with basophilic dyes. FUNCTIONS OF THE ROUGH ER: Protein synthesis: albumin, hormones, milk proteins, receptors, antibodies, collagen, enzymes, lipoproteins, some secreted, some retained within the cell, etc. Proteins synthesized here (1) remain in the cell, (2) are incorporated into membranes, (3) enter the nucleus and/or are (4) secreted/exported from the cell.

Which polymerases transcribe each of the different RNAs?

RNA Polymerase I - transcribes large rRNAs RNA Polymerase II - transcribes mRNA RNA Polymerase III -transcribes small RNAs (tRNA and 5S rRNA) They recognize different types of promoters

Which strand of DNA does RNA nearly copy (Except T become U)?

RNA is nearly a copy of the DNA coding strand. RNA uses the template strand to make the transcript

Why is phosphorylation an ideal mechanism for transmission of intracellular signals

Rapid, reversible, linked into cascade

What factors effect drug metabolism?

Rate of blood flow to liver Rate of entry into the liver Enzyme induction/inhibition Drug-drug interactions Genetic factors (polymorphisms) Diet, exercise, environmental factors Tissue pathology Age & gender

What are the NADPH dependent reaction?

Reduction of oxidized gluthathione Cytochrome P450-mediated metabolism of drugs and xenobiotics Fatty acid and cholesterol synthesis Fatty acid chain elongation Catecholamine synthesis Nucleotide synthesis Steroid hormone synthesis Superoxide synthesis

What happens during direct DNA repair?

Refers to mechanisms that remove damage directly, without cutting or rearranging segments of DNA Major Enzymes: •DNA Photolyases: Photoreactivated: uses visible light to cleave pyrimidine dimers-ALSO NER •Methyl transferases Adaptive response,Transfers methyl group from O6 -guanine to a cysteine residue within the protein

What are joints?

Regions where bones are joined together Type of joint determines movement: 1.Diarthroses - permit free bone movement -Joints that generally unite long bones and allow plenty of movement (e.g. elbow, knee, etc.) 2.Synarthroses - permit limited or no movement

How is Glucose-6-Phosphatase regulated?

Regulated by dephosphorylation The dephosphorylation of glucose-6-P occurs in the ER lumen Most cell express the G-6-P translocase (Transporter) but liver, intestines and kidney also express glucose-6-phosphatase In the presence of insulin, G-6-Pase gene expression is inhibited (nuclear exclusion of FoxO) (prevent futile cycle with glucokinase) Loss of insulin signaling and glucagon-induced stimulation of PKA increases the expression of G-6-Pase mRNA

How is initiation of translation regulated?

Regulated by initiation factos that can be active of inactive Ex: When cells are stressed (ie, starvation), eIF2 is phosphorylated to inhibit protein synthesis Reticulocytes synthesize O2-carrying hemoglobin from globin and Fe-binding heme. When cells lack heme, globin synthesis decreases. Heme activates eIF2 by inhibiting its phosphorylation, allowing protein synthesis to initiate.

How is cell cycle specific gene expression regulated?

Regulation of cell cycle specific gene expression is mediated by CDK inactivation of pRB-family members and reversed by protein phosphatases at mitotic exit Mitogenic stimuli control the expression and/or activation of G1 and G1/S cyclins, respectively. In response to mitogenic stimuli Cyclin D (in G1) and Cyclin E (in G1/S) cooperate to hyperphosphorylate and inactivate pRB proteins, which otherwise block cell cycle progression in G1 (or block cell cycle entry from G0), by repressing a family of E2F transcription factors. E2F binds elements in the promoter regions of numerous genes involved in DNA replication and cell cycle control. Inactivation of pRB proteins and the consequent activation of of E2F-dependent transcription leads to a wave of cell cycle specific gene expression that commits cells to a round of DNA replication and mitosis. It is sais that cells pass the restriction point (RP). Cyclin A (in S phase): Promotes DNA synthesis and blocks re-initiation of DNA synthesis at newly synthesized origins of replication. Also maintains pRB proteins inactive. Cyclin B (in M): Promotes Initiation of Mitosis and many of the critical events associated the generation of the spindle, chromosome condensation, nuclear envelope breakdown, etc. Also maintains pRB proteins inactive. The pRB/E2F cycle is reset back to repressor complexes as cells exit mitosis.

What happens during nucleotide excision repair (NER)?

Responds to Bulky Lesions in DNA (pyrimidine dimers induced by UV) One set of enzymes responds to any and all types of bulky DNA damage Steps: Pair of coordinated incisions on either side of the DNA strand carrying the lesion. Helicase removes the single stranded segment with the lesion DNA polymerase fills in gap Ligase seals In eukaryotes the components of the protein complex that makes the initial incision in damaged DNA get their names from the genetic disease Xeroderma pigmentosum (XP) XPC : scans for distortion in DNA backbone ="damage" XPB & XPD: helicase XPA: Binds DNA and confirms DNA lesion XPE, DNA binding XPF: 5' nuclease XPG: 3' nuclease XPV: translesion DNA polymerase (Pol η) Nucleotide excision repair (NER) is coupled to RNA transcription -Transcribed genes are repaired first. -Stalled RNA polymerases trigger action by the incision complex.

What is the function of reverse transcriptase?

Retroviruses have single strand RNA genomes that are replicated through one step that copies their RNA into cDNA using a reverse transcriptase (RT) The double strand DNA generated by RT integrates into the genome, where it is transcribed to generate full length genomes and transcripts for viral protein synthesis •Synthesizes DNA from an RNA template but also uses DNA templates (RNA and DNA directed DNA polymerase). •Synthesizes 5'è 3' •Requires a primer (RNA) •Uses dNTPs as substrate •Lacks proofreading exonuclease has RNaseH activity

What are the structures of ribosomal RNA and ribosomes?

Ribosomes are subcellular compartment where protein synthesis occurs. Prokaryotic ribosomes contain three types of rRNA molecules •The 50S and 30S subunits form the 70S ribosomes that participates in protein synthesis. Cytoplasmic ribosomes from eukaryotic cells contain 4 types of rRNA molecules. •The 40S and 60S ribosomal subunits combine to form the 80S ribosome that participates in protein synthesis. Mitochondrial ribosomes have sedimentation coefficient of 55S, are smaller than cytoplasmic ribosomes, and are more similar to bacterial ribosomes than eukaryotic ribosomes. rRNAs in ribosomes exhibit extensive secondary structures.

What is the function of apoptosis?

Roles in Development and Homeostasis 1. Sculpting morphogenesis - helps to sculpt the shapes of developing organs; i.e., interdigital cell death (eliminates the cells between developing digits); hollowing out solid structures to create lumina during embryogenesis Bone morphogenetic protein (BMP) •Example of apoptosis-inducing extracellular signal •It is a TGF-B family member •Helps trigger the apoptosis that removes the tissue between the developing digits in the mouse paw. •BMP stimulates changes in the transcription of genes that regulate cell death. 2. Deleting unneeded structures a. structures that are required in one sex but not in the other: Mullerian ducts of mammals and birds are formed in both sexes. In females the Mullerian ducts develop into the uterus or oviduct, whereas in males they regress as a consequence of cell death; Wolffian duct forms the vas deferens, epididymis, and seminal vesicle in males, but is not needed in females and is eliminated. b. vestigial structures that were required in an ancestral species but not in the descendant Pronephric tubules form functioning kidneys in fish and amphibian larvae, but are not used in mammals and are eliminated c. Structures that are needed at one stage of development but not later Subplate neurons are required transiently during the development of the mammalian cerebral cortex and are subsequently removed by PCD; when a tadpole loses its tail at metamorphosis 3. Controlling cell numbers In many organs cells are overproduced and then culled by PCD to adjust their numbers. A. Vertebrate nervous system: both neurons and oligodendrocytes are generated in excess, and up to half or more are eliminated by PCD, i.e. about half of the original population of chick spinal motor neurons is eliminated during a critical period in development. (see next slide) B. Coordinate regulation of cell proliferation and cell death provides precise control over tissue size, ie., liver During homeostasis, cells that have already functioned die as younger cells are generated to replace them (thymus, prostate, liver, blood cells, skin, gut lining) 4. Eliminating cells that are abnormal, misplaced, nonfunctional or potentially dangerous to the organism Cells that develop improperly, i.e. in visual system of developing vertebrates, cell death preferentially eliminates neurons that have formed improper connections. Cells damaged by irradiation and other genotoxic agents often undergo apoptosis; this is an anticancer mechanism, but also seems to help prevent the birth of defective offspring. If pregnant mice are irradiated, the number of offspring produced decreases, as many of the irradiated embryos die. There is little increase in the occurrence of birth defects among those mice that are born.

How is SAM produce?

S-Adenosyl Methionine L-methionine + ATP - SAM via the L-Methionine adenosyltransferase enzyme SAM contains an "active" methyl group, with very high group transfer potential SAM ONLY methylates (FH4 more versatile). The methyl group came from the essential amino acid methionine The fate of SAM after donating the methyl group is S-adenosyl homocysteine (SAH), which is cleaved to homocysteine Some reactions that involve SAM are Norepinephrine to Epinephrine Creatine formation Phosphatidylethanolamine to Phosphatidylcholine Melatonin formation

Describe the smooth ER

SER (i.e., the sarcoplasmic reticulum) functions in the uptake and release of calcium in muscle cells Synthesis of steroid hormones Ovary - estrogen, progesterone. Testis - testosterone. Adrenal cortex - aldosterone, cortisol, sex hormones. Synthesis & break down of glycogen. Detoxification of drugs, metabolic wastes, etc. Formation of lipoproteins and production of bile. SMOOTH ER OCCURS IN STEROID-SECRETING CELLS, HEPATOCYTES,SKELETAL MUSCLE, etc. The enzymes involved in making steroid hormones are located in the SER membrane as are those that synthesize and break down glycogen in liver cells. ROLE OF SMOOTH ENDOPLASMIC RETICULUM: Scaffold on which enzymes reside that are involved in making steroid hormones.

How do steroid hormone receptors work?

SHRs are ligand-activated transcription factors that regulate many biological processes, including metabolism, reproduction, and development. The only class of hormones that penetrate cell membranes (except nitric oxide NO) Highly lipophilic molecules - carried by transport proteins in plasma In the absence of ligand, the SHR maintains a cytosolic inactive state by association with heat shock proteins and/or other proteins such as co-repressors. Thyroid hormone receptors are located in the nucleus. For a steroid hormone to regulate gene transcription, its receptor must: Bind to the hormone The SHR undergoes conformational changes and is released from the repressor proteins Bind to a second copy of itself to form a homodimer Move from the cytosol to the nucleus, Bind to its response element which is specific DNA sequences in the genes regulated by the hormone A response element is part of the promoter of a gene. Are DNA sequences that are bound by the complex of ligand-steroid receptor. äSequences are specific for each hormone Binding by the steroid-receptor complex activates or represses the gene controlled by that promoter. Steroid hormones turn on (or off) genes through this mechanism

What is the major insulin activated transcription factor?

SREBP1c (Steroid Response Element Binding Protein 1) Stimulates Glucokinase, Pyruvate kinase, Fatty acid synthase, Adenosine triphosphate and citrate lyase, Acetyl CoA carboxylase, Glucose-6 phosphate dehydrogenase SREBP1c-induced gene products: glycolysis, lipogenesis and pentose phosphate pathway. Glucose metabolism also stimulates ChREBP (Carbohydrate Response Element Binding Protein) an important player synergizing with SREBP1c on numerous promoters.

What is the purpose of single strand DNA binding proteins?

SSB is not enzyme and it is essential DNA replication, recombination and repair SSB prevents hairpins in DNA, protects against nucleases, and facilitates activity of other DNA metabolic enzymes (such as DNA polymerase) It binds Single Stranded DNA in a cooperative fashion and prevents that DNA from re-annealing with a complementary strand

How is damaged muscle repaired?

Satellite cells

What yields more energy unsaturated or saturated fatty acids?

Saturated

What is the difference between TEM and SEM?

Scanning Electron Microscope (SEM)- Very High Detail! Imagine you are in a dark room with a weak flashlight. To explore your surroundings, you might sweep the light across the room, much like someone reading a book: left to right and top to bottom. SEM functions similarly, sweeping the electron beam across the sample and recording the electrons that bounce back. This technique allows you to see the surface of just about any sample, from industrial metals to geological samples to biological specimens like spores, insects, and cells. While SEM cannot see features to the level of detail as a TEM can it is much faster, less restrictive, and can sometimes be performed with limited or no sample preparation. Transmission Electron Microscope (TEM) When a movie plays in the theater, light is transmitted through an image on a film. As the beam of light passes through, it is modified by the image and the contents of the film are then displayed. TEM works in the same way but with electrons, passing through, or transmitting, an ultrathin sample to a detector below. TEM allows you to observe details as small as individual atoms, giving unprecedented levels or structural information at the highest possible resolution. As it goes through objects it can also give you information about internal structures, which SEM cannot provide. TEM is, however, limited to samples that can be thin enough to let electrons pass through them. This thinning process is technically challenging and requires additional tools to perform.

Describe Mirabegron

Selective Beta 3 Adrenergic Agonist **Overactive bladder/ urinary incontinence Relaxation of detrusor muscle via β3-stimulation ⬆ AC Inhibits subfamilies of cP450 enzymes

What are the major phosphorylated amino acids?

Serine Threonine Tyrosine

What are the different strain designations?

Serovar (serotype) - distinguished by serological methods (antibodies) e.g. M types Biovar (biotype) - distinguished by biochemical means Morphovar (morphotype) - distinguished by morphology

What are the different function of glutamine in the blood?

Serves as fuel for intestinal epithelium, kidney Kidney - acid-base balance Muscle - capture of NH3, export to liver (and kidney) Brain - capture/export of NH3, glutamate-glutamine cycle N of glutamine used for biosynthetic reactions (nucleotide biosynthesis) Utilization of pool depends on conditions - acidosis, sepsis

What are the major types of receptors?

Seven transmembrane receptors (7-TMRs)also called G protein-coupled receptors (GPCRs) Ligand-gated ion channels Receptor tyrosine kinases Cytosolic receptors

What type of technology/method could be used to diagnose sickle cell disease?

Several tests are used when screening for sickle cell disease and other abnormal hemoglobinopathies. The most common tests used today are: Hemoglobin electrophoresis High performance liquid chromatography (HPLC) and Deoxyribonucleic acid (DNA) testing Hemoglobin S solubility test and sodium metabisulfite test— these tests may be used for screening individuals 6 months old or older. They are not diagnostic and are not used for newborn screening. The tests detect the presence of hemoglobin S but do not distinguish between sickle cell disease and trait.

How is elastin fibril stuctured?

Similar to collagen, high in glycine and proline Unlike collagen, no repeating patterns Alternating coiled-coil domains and hydrophobic domains create elasticity Covalent bonds provide strength Post-translational modifications of Lysine residues in Elastin fibrils Lysinorleucine is identical to covalent links found in collagen Desmosine results from identical chemical reactions, but is unique to elastin

How are transcription and translation related in bacteria?

Since bacteria do not have nuclear membrane, translation can occur shortly after transcription begins This allows for translational coupling For example, when translation stops secondary structures can form in the mRNA causes pauses in transcription Due to a lack of nutrients or bacterial stress responses secondary structures can form causing pausing r termination of bacterial transcription

What happens to ion concentration during an AP?

Since the concentrations of the ions inside and outside the cell don't change during an action potential, the equilibrium potentials don't change.

What are SNP, SNV, and CNV

Single Nucleotide Variant (SNV) -Single base pair change from most in population Single Nucleotide Polymorphism (SNP) -Special case of SNV -Present in >1% of the population -Considered "normal" genetic variation -A SNP is a SNV but not all SNVs are SNPs Copy Number Variant (CNV) -Change in number of copies of DNA -Insertions -Deletions Allele -different forms of a given gene (due to SNVs, SNPs, CNVs, etc)

Describe a simple squamous epithelium

Single layer of closely adherent polygonal cells Thinnest tissue of the body Bowman's Capsule in kidney, Respiratory spaces in lungs Lines blood and lymphatic vessels (Endothelium) Squamous Height <Width "Fried egg on the sidewalk" Simple Squamous Epithelium: Lining of the atria and ventricles of the heart- Endocardium Simple Squamous Epithelium: Lines the walls and covers the closed cavities of the body (abdominal, pericardial and pleural cavities) - Mesothelium

What are the functions of the three types of muscles?

Skeletal Muscle: Moves the skeleton and other structures such as precise eye movement. Strong, quick, discontinuous, voluntary contraction Cardiac Muscle: Propels bloods through the heart and lungs and into the aorta. Strong, quick, involuntary contraction Smooth Muscle: Contraction of blood vessels, viscera, intrinsic muscle of the eye, change shape of various organs. Weak, slow, involuntary contraction

What is McArdle syndrome?

Skeletal muscle glycogen phosphorylase or myophosphorylase deficiency Liver normal

What is the function of epinephrine?

Skeletal muscle vessel dilation (β2) Smooth muscle, relax &/or contract (β2/α) Urinary retention (mixed α/β) Metabolic ⬆ plasma glucose (α2) ⬆ glycogenolysis (β) ⬇ insulin secretion (α2); ⬆ (β2)

What is Ehlers-Danlos syndrome?

Skin Hyperextensibility Skin hyperextensibility should be tested at a neutral site (one not subjected to mechanical forces or scarring), such as the volar surface of the forearm. It is measured by pulling up the skin until resistance is felt. In young children, hyperextensibility of the skin is difficult to assess because of abundant subcutaneous fat Widened atrophic scars Joint Hypermobility Joint hypermobility (see Figure 3) depends on age, gender, and family as well as ethnic backgrounds. Joint hypermobility in classic EDS is general, affecting both large and small joints, and is usually noted when a child starts to walk. Types I and II (Classical) Genetic defects in collagen V and I Abnormalities in size and structure of collagen fibrils Hyperextensibility of skin, easy bruising Type III (Hypermobility) Genetic defects in collagen III or Tenascin-X no distinctive biochemical collagen finding has been identified Extreme flexibility in joints Type VI (Kyphoscoliosis) Lysine hydroxylase Decreased collagen crosslinks and lack of glycosylation Eyeball rupture, decreased muscle tone, scoliosis Type VII (Arthrochalasia) Procollagen peptide- protease or collagen I mutation Procollagen I not cleaved Lax ligaments, dislocation of major joints

What is the biofilm matrix composed of?

Slime layer Biofilm matrix = secreted layer embeds cells Functions of matrix: Carbohydrate reservoir Matrix for biofilm formation Polysaccharides Protein eDNA Amyloids

Describe regulators of Small G proteins

Small G proteins, such as Ras and Rho require Regulators of G protein signaling (RGS). Step 1: Guanine nucleotide exchange factor (GEF) facilitates dissociation of GDP from G protein. Step 2: GTP then binds spontaneously, and GEF dissociates yielding the active G protein-GTP form. Steps 3 and 4: Hydrolysis of the bound GTP to regenerate the inactive G protein-GDP form is accelerated a hundredfold by GTPase-activating protein (GAP).

How do bacteria differ from eukaryotic cells?

Smaller Lack nucleus Lack other organelles (membrane bound vesicles; Golgi complex, ER etc.) Different ribosome structure (70S vs 80S) Contain cell wall Lack sterols in membranes Some produce flagella and pili/fimbrae Some produce capsules and extracellular matrix for biofilms

Describe sonic hedgehog

Sonic hedgehog is a secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, SHH is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons. In the limb, SHH is secreted by the zone of polarizing activity (ZPA) organizing limb axis formation. SHH has still others roles in organ development in lung, pancreas, etc. When hedgehog binds to the patched protein it inhibits PKA and Slimb which allows GLi to bind to RNA and transcribe When hedgehog is not present patched inhibits smothered and PKA and Slimb cause GLi to be cut in half and acts as a repressor

What does the band 3 anion channel do?

Specific chloride-bicarbonate exchanger Also known as AE1; makes up 25% of the cell surface (1 million copies per RBC). Pumps out HCO3- generated by uptake and conversion of CO2. Its action results in the "Chloride shift", lowering pH in the RBC to facilitate oxygen dissociation. An isoform of AE1 is also present in kidney cells, where its function is critical in acidification of urine. Facilitates bohr effect- Bohr effect; inverse relation between O2 binding to Hb and acidity and CO2 levels

What are the types of sphingolipuds and what are they composed of?

Sphingomyelin and sphingoglycolipid Sphingosine is the backbone and is part of ceramide Ceramide is the compound when the amino group of the sphingosine is linked to an acyl chain, in which the acyl chain length and the degree of unsaturation vary over a wide range. The first C on sphingosine is linked to a phosphate (for sphingomyelin) or a sugar (for sphingoglycolipid) moiety. The second C (C2) is linked to an amino group. C3 is linked to a hydrocarbon chain.

What happens in Niemann-Pick disease?

Sphingomyelinase is responsible for breaking sphingomyelin (SM) down into phosphocholine and ceramide. Enzyme is located in lysosomes of cells. Also in the extracellular environment. It's a surface acting enzyme. Accumulation of sphingomyelin inside cells, it precipitates out to form oily droplets which can eventually impair cell functions. Sphingomyelin accumulates in lysosomes. This indicates type B Niemann-Pick disease. Both types A & C show profound neurological problems caused by an accumulation of sphinosylphosphocholine.

Where does spingosine come from?

Sphingosine is derived from the condensation of palmitoyl CoA and serine. These reactions occur on the cytoplasmic face of the endoplasmic reticulum (ER) in all cells. Ceramide can be converted to sphingosine by ceramidase and this reaction generates fatty acid. Sphingosine can be converted back to ceramide by ceramide synthase, which requires fatty acyl CoA (FA CoA).

What happens at the metaphase checkpoint?

Spindle Chromosome segregation is prevented if chromosomes are not properly attached to the mitotic spindle. Unattached kinetochores trigger signaling that prevents activation of the Anaphase Promoting Complex, preventing cohesin cleavage and chromosome segregation. The mechanism involves several spindle checkpoint proteins that detect the unattached kinetochore and assemble a complex that prevents activation of the APC/C

How are BCAA metabolized?

Step 1: Amino-transferases (3). Step 1 products called alpha-keto-BCAAs Step 2: decarboxylating dehydrogenase.- Branched chain keto acid dehydrogenase Step 3 & 4 NOT important

What happens during exercise?

Stimulate lipolysis Stimulate hepatic and muscle glycogenolysis Gluconeogenesis can contribute during prolonged exercise Glucose from blood G-6-P from glycogen Lactate, AA and glycerol to liver for gluconeogenesis Fatty acids oxidation predominates over time Creatine phosphate is composed of 3 amino acids (Arg Gly Met) and can donate it's phosphate to ADP to form ATP during high intensity exercise. Quickly depleted. Glucose is first metabolized to lactate. As exercise continues, glucose and fatty acids are oxidized to generate ATP as blood flow increases and O2 rises. Decrease in carbohydrate oxidation Increase in fatty acid oxidation Muscle glycogen levels fall over time Muscle triglycerides (IMTG) fall over time

What stimulates and inhibits glucagon?

Stimuli Hypoglycemia Amino acids (Ala and Arg) Secreted catecholamines (b2 adrenergic receptor)Exercise Neural input Exercise Vagal nerve Inhibitors Hyperglycemia Insulin

What stimulates and inhibits insulin?

Stimuli Ingested glucose Ingested amino acids GLP-1 (an incretin) enhances release Neural (cholinergic innervation) Inhibitors Catecholamines (a2 adrenergic receptor) secreted and neural (important for exercise!) Hypoglycemia

What are the functions of the basal lamina?

Structural attachment: Cells are anchored to the basal lamina by junctions and the basal lamina is attached to the underlying connective tissue by type VII anchoring collagen fibrils and fibrillin microfibrils. Breach of the BL by epithelial cells could result in the metastasis of tumor cells to secondary sites. Compartmentalization: Basal or external laminae separate the cells from the surrounding connective tissue. For molecules to move into cells they must cross the basal lamina. Filtration: The basal lamina regulates the movement of molecules and is best characterized in the kidney. Tissue scaffold: During would repair the basal lamina acts as a scaffold. Examples satellite cells in muscle, OR regeneration after nerve damage. Signaling: Molecules in the basal lamina interact with receptors at the base of the cell and thereby regulate process such as cell migration, proliferation and differentiation.

What type of amino acid is cysteine and what are its abbreviations?

Sulfur containing, Cys, C

What is the purpose of cartilage?

Support and Framework -Embryonic skeleton (bone growth), airways Shock absorption, resisting compression -Intervertebral disks, menisci, pubic symphysis Smooth gliding surfaces -Articular surfaces of bones within joints

What are satellite cells?

Surround nerve cell bodies - provide trophic support to neurons.

How do the sympathetic and parasympathetic divisions of the ANS differ from each other, functionally?

Sympathetic: "Fight or Flight" response Fear, strength, endurance Cutaneous/visceral vasoconstriction Parasympathetic: "Rest and Digest" response Homeostatic, protective, vegetative Secretomotor

How do the peripheral portions of the sympathetic and parasympathetic divisions of the ANS differ from each other, anatomically?

Sympathetic: Ganglia relatively near CNS Preganglionic fibers are short Postganglionic fibers are long Parasympathetic: Ganglia near or in target organ Preganglionic fibers are long Postganglionic fibers are short

What are the symptoms of biotin deficiency and what are ways to get it?

Symptoms: depression, muscle pain, dermatitis, hair loss, dry skin, dry eyes, insomnia It may arise from eating raw eggs, especially raw egg whites! It may arise from an overuse of antibiotics.

What are synbiotics? What is the proposed advantage of synbiotics?

Synbiotic products contain a blend of select probiotics and corresponding prebiotics that selectively favor the selected probiotics, alluding to a "synergy" between these components. Synbiotics were developed to overcome possible survival difficulties for probiotics, showing the improvement of survival of the probiotic bacteria during the passage through the upper intestinal tract, leading to increased levels of gut bacteria and more balanced gut microbiota.

How is GABA synthesized?

Synthesized from Glutamate using PLP GABA is an inhibitory neurotransmitter. Requires PLP; with vitamin B6 deficiency, failure to form GABA results in convulsions (esp. important in infant formula).

How is proline synthesized?

Synthesized from glutamate via glutamate semialdehyde Reversible process Glutamate to proline uses ATP and 2NADPH Proline to glutamate crates FADH2 and NADH

How is glucagon synthesized?

Synthesized in the alpha cells of the islets of Langerhans in the pancreas, enteroendocrine cells in the intestines and brain Glucagon is synthesized as a large precursor, preproglucagon, which is proteolytically cleaved and released in the blood Glucagon is degraded in the liver Preproglucagon expressed in enteroendocrine cells is precessed by different convertases forming alternate products GLP-1 and 2 which is stimulated by a high carb meal GLP-1 is an incretin and synergizes with glucose increasing insulin release

How do t-cells mature in the thymus?

T cells from the BM enter the thymic cortex without surface markers = double (-) After they interact with thymic epithelial cells (cTEC) they acquire unique TCRs and both CD4 and CD8 surface markers = double (+), [by somatic recombination]. These TCRs have the ability to bind and recognize different antigens. Those T cells that recognize self-MHC, mature and express either CD4 OR CD8= single (+), = positive selection [those that cannot recognize self-MHC or self-Ags are discarded]

Describe the TRIAD of muscle

T-tubule: Invagination of the plasma membrane. Terminal Cisterna:Specialized ends of SR, where networks meet. Sarcoplasmic reticulum: repeating network around myofibrils. Each network extends from one A-I junction to the next A-I junction. 1. Release of acetylcholine at the neuromuscular junction causes and electrical impulse to be generated in teh muscle cell plasma membrane 2. The electrical impulse is carried to the cell's interior by the t-tubules 3. The electrical impulse triggers the release of Ca2+ from the sarcoplasmic reticulum

What are some examples of drugs acting on SHRs?

Tamoxifen: selective estrogen receptor antagonist in breast tissue, used for treatment of estrogen-dependent breast cancer. Ethinyl estradiol and L-Norgestrel: acting on estrogen receptor and progesterone receptor, respectively. Used as combined oral contraceptives. Thyroxine (T4): a prodrug of tri-iodothyronine (T3). Used to treat hypothyrodism.

How does telomerase work?

Telomerase is a DNA polymerase that utilizes a bound RNA as a primer Telomerase is a ribonucleoprotein DNA polymerase that does not use an exogenous primer as a source of a free 3'OH, but rather has its dedicated RNA component (telomerase RNA; TER) that acts as a template to elongate the 3'OH of the parental strand The primer is the template not the source of the 3'OH Thus, the newly synthesized DNA is ss, and can subsequently be used as template to further elongate the lagging strand via the Okazaki fragment mechanism Telomerase is a reverse transcriptase because copies RNA into DNA

What are the differences and similiarities between telomerase and DNA polymerase?

Telomerase similarities to conventional DNA polymerases • It requires a 3'OH • Uses dNTPs • Uses a template • It is a processive enzyme Telomerase differences to conventional DNA polymerases • Has and RNA component • Does not require exogenous template • Elongates ssDNA (3' end of template strand)

How does fibrillar assemble in different tissues?

Tendon-Parallel Bundles Cartilage-No regular arrangement; associated with glycosaminoglycans Skin-Planar sheets of microfibrils layered wat many angles Cornea-Planar sheets stacked crossways for strength

Describe osteocytes

Terminally differentiated osteoblasts that become encased in the ECM. Make up over 90% of all bone cells. Dendritic processes maintain contact with other osteocytes, Haversian canals, the bone surface (periosteum) and the bone marrow (endosteum) - sites of vasculature.

What is tetanus in muscles?

Tetanus occurs when the frequency of action potentials is high enough to prevent any relaxation of contraction between action potentials and the force.

How is tethering and fusion facilitated?

Tethering / Fusion Steps Involve Rab GTPases, tethering proteins and SNARE proteins Rabs are small, Ras-like GTPases. There are over 60 Rabs, many of which localize to specific vesicles or membranes. Active (GTP-bound) Rabs bind tethering proteins which mediate initial (≈ 200nm) attraction to guide the incoming vesicle. Fusion involves recognition of v-(Vesicle)-SNARE and t-(Target) SNARE proteins, which interlock and force the donor and acceptor membranes together. Trans-membrane receptors are thus delivered to the donor membrane, and cargoes released into the donor lumen. 2 v-snares bind to 2 t-snares to zip and then fuse to the membrane

What is BH4

Tetrahydrobiopterin (BH4) is required for hydroxylation of phenylalanine (to make tyrosine) Tetrahydrobiopterin (BH4) is formed in our bodies from GTP; participates in: Phe to Tyr Tyr to Dopa (precursor of dopamine, norepinephrine and epinephrine) Trp to serotonin When BH4 is used it is converted to BH2 and needs to be recycled by a reductase.

Describe regulative development

The ability of cells to change their fate to compensate for missing part is called regulation. The limb field represents an "equipotent" system where a cell can be instructed to form any part of the limb.

How do steroid hormones work?

The action of steroid hormones are unique examples of combined signal transduction and transcription factor activation. The glucocorticoid hormone, cortisol, passes through the plasma membrane into the cytoplasm where it binds to the specific, high-affinity glucocorticoid receptor (GR). The resulting complex is the non-DNA-binding oligomer of the GR, in which the receptor is complexed with other proteins. Dissociation of the complex yields the free cortisol-receptor subunit in the DNA-binding form. The activated receptor forms a homodimer and is translocated to the nucleus. Inside the nucleus, the receptor complex binds to specific DNA responsive elements to activate gene transcription.

Describe acetylcholinesterase

The actions of acetylcholine are terminated primarily by degradation by acetylcholinesterase. Acetylcholinesterase inhibitors Reversible: Neostigmine (used to improve muscle tone and after anesthesia to reverse the effects of non-depolarizing muscle relaxants), physostigmine (used to treat glaucoma, Alzheimer's disease) Irreversible: nerve gases (Soman, Sarin)

Explain the palm model for DNA synthesis?

The active site of the polymerase is in the palm region. The finger domain interacts with the template forcing a 90° bend that exposes the first ss template base after the primer. The Thumb is not involved in catalysis, but interacts with the recently synthesized DNA facilitating correct position and lasting interaction allowing addition of multiple nucleotides

Why is the sympathetic division often called the thoracolumbar part of the ANS?

The cell bodies of the preganglionic neurons are located in spinal cord segments T1-L2

What is receptor desensitization?

The desensitization process depends on phosphorylation of the receptor, by PKA, PKC, or a member of the family of G-protein-linked receptor kinases (GRKs). Once a receptor has been phosphorylated by a GRK, it binds with high affinity to a member of the arrestin family of proteins. The bound arrestin can contribute to the desensitization process in at least two ways: Inactivates the receptor by preventing it from interacting with G proteins, an example of receptor uncoupling. It can serve as an adaptor protein to couple the receptor to clathrin-coated pits for sequestration or degradation (down-regulation) of the receptor.

How does PCR work?

The development of PCR in the mid 80's allowed researchers to pick out their sequence of interest from a complex mixture and clone directly into vectors. Isolation of DNA (only pg to ng amounts is needed). Set up PCR reactions with DNA, primers, nucleotides, and thermostable polymerase. Place reactions in machine that can quickly adjust temperatures. Gel electrophoresis to analyze PCR product. Each cycles doubles the copy number of the amplified product. 30 cycles (230), about 1 billion copies. The 3' end of the primers need to be oriented towards each other as nucleotides are added onto the 3'OH group of the preceding base. RFLP and VNTR analysis using primers that span the polymorphic restriction site or VNTR. Looking for mutations in known genes by PCR, followed by DNA sequence analysis of the PCR product. Embryo typing and genetic counseling for Huntington's disease: In vitro fertilization of multiple embryos , grow embryos to 8 to 16 cell stage, isolate one cell and DNA for PCR. Remission test in cancer patients. Virus detection. Design primers complementary to the sequences between the region of DNA you want to clone and containing restriction enzyme sequences for easy cloning. Perform the PCR reaction (we will go over that later). Limitations: o Can't amplify big DNA fragments (2-3 kb) in complex mixtures. If DNA of interest was already cloned, can use PCR to shuttle large regions between various vectors. o High mutation rate. DNA sequence verification required. Need to consider type of starting material depending on the goal of the cloning exercise (genomic for cDNAs-DNA copy of RNA)

What happens in a pyruvate kinase deficiency?

The metabolic pathway that is affected is the conversion of phosphoenolpyruvate (PEP) to pyruvate, which is the last step in glycolysis. This step is an ATP producing step, so we are diminishing the amount of ATP available to the RBC. This results in hemolysis. The method for hemolysis is not confirmed, but it is hypothesized that the reduced production of ATP causes the loss of K+ and water, leaving a rigid RBC that is more likely to be destroyed as it passes through the spleen. Her fatigue and lethargy may be caused by the hemolysis preventing her RBCs from delivering the required oxygen for oxidative phosphorylation in other tissues. Her spleen is enlarged because there is a large amount of blood that needs to be filtered and there are many damaged RBCs that need to be removed from circulation. She is jaundiced because her body is degrading many erythrocytes into bilirubin and the liver cannot successfully conjugate all of it to be excreted so instead, it inserts into tissues, causing yellowing. In RBCs, the glycolytic pathway is really the only way to supply ATP, so if we are preventing PEP from converting to pyruvate, we are starkly decreasing the amount of ATP available to the RBC. This defect is more serious in RBCs and not other tissues because other tissues use oxidative phosphorylation to produce the majority of their ATP and they have other mechanisms, such as the TCA cycle, to regenerate the intermediates needed for this production of ATP. Additionally, the liver cells are big users of PK, but they consistently make new enzymes to use, so the liver isn't as affected by PK deficiency. The RBCs continue to use the same enzymes throughout their lifetime. PK is 4 subunits.

What is KEGG?

The metagenome (all the genes in the microbiota - assembled into one giant metagenome) Metabolic pathways can be assess using programs such as KEGG The activity of the genes can be monitored by reverse transcriptase quantitative PCR (RT qPCR) Relative abundance of the genes can be determined by number of hits The number of different bacteria can be assessed by the number of homologs present The genes are not associated with a specific bacterium unless the bacteria has already been sequenced

What is omega-oxidation?

The methyl end of the fatty acid is oxidized by a mixed function oxidase, alcohol dehydrogenase, and aldehyde dehydrogenase. w-oxidation occurs in the ER of many tissues (liver and kidney) and may involve primarily medium chain fatty acids. The resulting dicarboxylic acid can be beta-oxidized from both ends in mitochondria.

What happens during downstroke

The voltage dependent K+ opens (Figure 9-4 & 5) 1.The voltage dependent K+ channel has only one gate called the n gate, which is the activation gate 2.The "n" gates open when the membrane is depolarized, but they open much more slowly than do the "m" gates of the Na+ channel. a.Thus, the Na+ channels are open before the K+ channels are. b.Because the K+ channels don't have any inactivation gates, the K+ channels do not inactivate -- they stay open as long as the membrane is depolarized. 3.When the n gate opens K+ flows out of the cell, restoring the membrane back to its resting potential

What are CD antigens?

These are surface markers that identify a specific group of T cells These markers are co-receptors to the main T cell receptor, that enable them to recognize different Ag-MHC combinations A Cytotoxic T cell expresses a CD 8 marker, while A Helper T cell expresses a CD4 marker and can be differentiated from a Cytotoxic T cell

What metabolic process in microbiota bacteria would produce acetate, propionate and butyrate? What do bacteria use this metabolic process for?

These end products would be produced via pyruvate fermentation. Bacteria use this process as a method to produce energy (ATP) as well as regenerate NAD+ to be used for Embden-Meyerhof-Parnas Pathway.

What is bistability?

These types of behaviors are all or nothing behaviors: motility, matrix production, sporulation and competence are not continuums, they are either on or off Other behaviors may include dormancy The entire population does not express the phenotype Bimodal Epigenetic Switches = bistable gene expression They are either on off Double negative feedback · A is a repressor of B and B is a repressor of A. · trigger 1 is an inducer (can be influenced by multiple signals); A expressed and B is repressed · trigger 2 is an inducer (can be influenced by multiple signals); B is expressed and A is repressed · so at any one time only A or B can be expressed biphasic switch may result from variability (noise) in [trigger] = not all the cells get the same signal

What is a consequence of too high a level of VLCFAS in the blood?

They have a deleterious effect on the brain (brain development), skeletal muscle, etc. They cause the break down of myelin throughout the body and the accumulation of toxic substances (e.g. iron, copper) in various tissues. Skeletal muscle weakness. Inability to nurse properly. Neurological disorders, Seizures, Enlarged Liver, Kidney Cysts, etc. Zellweger's Syndrome Cerebrohepatorenal syndrome A fatal disease due to the absence of peroxisomal enzymes

How are Thick and Thin Filaments Anchored and Kept in Register?

Thick: Titin - Stabilizes and centers the myosin containing thick filament to Z line C Protein - Holds thick filament in register at M line Thin: Alpha actinin - Bundles thin filaments and anchors them to the Z line. Nebulin - Helps α-actinin anchor actin filament to Z line. Tropomodulin - Actin-capping protein Regulates length of actin filament

How is acetyl CoA carboxylase regulated?

This enzyme is active in the dephosphorylated state. Dephosphorylation is catalyzed by an insulin-stimulated phosphatase. Therefore, fatty acid synthesis is active in the fed state. Low energy levels, via activation of the AMP-activated protein kinase, cause the enzyme to be phosphorylated and inactivated. The typical product of fatty acid synthesis, palmitate, is converted to its CoA derivative, palmitoyl-CoA, which inhibits the enzyme. A high-calorie diet increases the rate of transcription of the gene for acetyl-CoA carboxylase, whereas a low-calorie diet reduces transcription of this gene. Acetyl CoA carboxylase exists in two forms: polymer form (like a filament, active) and tetramer form (inactive). citrate causes it to polymerize. Palmitoyl CoA shifts the equilibrium to the tetramer form.

How polyunsaturated fatty acids synthesized?

Through various desaturases and elongases Humans lack enzymes to introduce double bonds between C10 and the w-carbon whereas the plants can.

What happens during the beginning of repolarization

Time-dependent Na+ channel inactivation-the beginning of repolarization Na+ channels inactivate soon after they are activated （that happens spontaneously): 1.The h gate closes; The Na channel is closed; The inward Na current drops to zero 2.The inactivated Na+ channel is closed but not available for activation. a.For relief the h gate, the membrane potential must return to about -80 mV.

Describe fibrocartilage

Tissue intermediate between dense connective tissue and hyaline cartilage On histologic sections, the border between dense connective tissue and fibrocartilage is not clear-cut Locations: intervertebral discs, attachments of certain ligaments, pubic symphysis, menisci Fibers: type I collagen and smaller amounts of type II collagen Growth: interstitial No distinct perichondrium

After 5 years of Gleevac treatment, the individual returns to the office with similar symptoms. Design and describe with a model a molecular test that would be used to assess a mutation in the domain of the protein that is known to confer resistance to the drug described in B.

To confirm the resistance of BCR-ABL to Gleevec, we should isolation protein from the blood cells of the relapsed patient and western blot for phosphorylated BCR-ABL target proteins. I would then sequence the mutated gene and transfect it into a cell line (e.g. MEF, or HeLA). I would first test its resistance to gleevec to test that it is the new mutation in the BCR-ABL fusion gene that is conferring the resistance. Then screen the other drugs in the class to determine which new drug to give to the patient.

What is the CRISPR Cas system used for in bacteria?

To prevent insertion of foreign DNA This prevents commensal strains from becoming pathogenic strains

What are bacterial siderophore used for?

To provide Fe2+ Bacteria require (iron; Fe) for growth They can obtain iron in multiple ways Some bacteria can take up human iron containing proteins such as ferritin (by lysing red blood cells), transferritin or hemin Some bacteria produce siderophores (iron-chelating proteins), which have a stronger avidity for iron that human proteins They secrete the siderophores, which scavenge iron and are taken back up by the bacterial cell

What is the function of topoisomerase?

Topoisomerases are needed to eliminate supercoils ahead of the helicase that would otherwise prevent the advancement of the replication fork Topoisomerases cut the duplex DNA and pass DNA though the break, without letting the end of DNA go (they cut one or both strands).

What is measured and what is calculated in a Lipid Panel?

Total Cholesterol, HDL-C, and Triglycerides are measured. LDL is calculated using the formula: LDL = Total cholesterol - (triglycerides/5) - HDL

What are balanced translocations?

Total amount of DNA unchanged Three dimensional nuclear location changed Common Usually no effect on health or development Reciprocol- Segments of two nonhomologous chromosomes break and are equally exchanged. Robertsonian- Two acrocentric chromosomes (13, 14, 15, 21, 22) fuse such that short arms are lost and long arms separated by centromere

What is autosomal dominant?

Trait or disease expressed regardless of whether homozygous or heterozygous for the dominant allele Approximate equal distribution between male and female family members Trait or disease appears in every generation with clear transmission from parent to child Risk to pass the trait to child is 50% with each pregnancy Without allele: almost no risk for transmitting the trait to their children Dominant Traits -Blood type A -Blood type B Disorders -Achondroplasia -Ehlers-Danlos syndrome -Familial adenomatous polyposis -Familial hypercholesterolemia -Hereditary nonpolyposis colon cancer (HNCC) -Huntington disease -Marfan syndrome -Myotonic dystrophy -Neurofibromatosis (types 1 and 2) -Polycystic kidney disease** (types 1 and 2) -Polydactyly -Porphyria -Retinitis pigmentosa** -Syndactyly von Willebrand disease

Describe transcription factors

Transcription factors (Trans-factors) are Gene Regulatory Proteins that Contain Structural Motifs That Can Read DNA Sequences. 1. Transcription factors are Gene Regulatory Proteins that Contain Structural motifs That Can Read DNA Sequences. 2. Upon the appropriate stimuli (often phosphorylation), Transcription factors recognize and bind to specific DNA sequence motifs in the promoter region of the target gene or genes. 3. Upon this binding, mRNA for that particular gene is transcribed, and accumulation of its gene product begins. 4. Many transcription factors transactivate sets of multiple genes related by a common function and can influence the progression of a pathological state.

What is HMG-CoA reducatse regulated?

Transcriptional control: synthesis of HMG-CoA reductase mRNA is enhanced by SREBP-NH3+. When [chol] is high, expression of HMG-CoA reductase is reduced Regulation by proteolysis: When [chol] is high, the reductase conformation is changed becoming more susceptible to proteolysis Regulation by phosphorylation: Insulin activates the reductase; glucagon does the opposite.

What is transformation?

Transformation is the uptake of DNA from the environment by competent bacteria Because the DNA is free in the environment the DNA is sensitive to DNase Inhibition of DNA uptake by DNase during laboratory experiments is a hallmark of transformation Only competent bacteria can take up the DNA o naturally occurring state o chemically induced in some bacteria Gram-positive bacteria take up any DNA Gram-negative bacteria take up own DNA DNA is integrated via homologous recombination or is degraded

How did streptococcus pnemoniae transformation lead of the discovery of DNA?

Transformation of competent cells lead to the discovery of DNA Streptococcus pneumoniae is a virulent bacteria that will kill mice S. pneumoniae requires a capsule to keep it from being killed by the immune system Without capsule it is avirulent (cannot cause disease) If killed encapsulated virulent bacteria are injected into a mouse along with live avirulent unencapsulated bacteria, the mouse will die because the live bacteria pick up the capsule gene via transformation

What is the function of Carnitine: Acyclar-nitrine translocase?

Translocates Fatty acylcarnitine with carnitine across the inner mitochondrial membrane

How does vesicular transport occur?

Transport vesicles bud from one compartment and fuse with another. The vesicle carries material (proteins, small biomolecules) in its lumen and membrane proteins and lipids in its membrane. 4 steps in vesicle transport 1. Budding 2. Movement (diffusion or motor driven) 3. Tethering 4. Fusion Budding: Adaptor proteins, coat proteins Transport: Microtubules and motor proteins (see Dr. Gallo's lecture) Docking: Rab proteins Fusion: SNARE proteins, on vesicles and target membrane.

Describe the the Na+/K+ pump

Transports 3 Na+ out of cells and 2 K+ into cells for every 1 ATP hydrolyzed

What is the function of tricarboxylate translocase?

Transports citrate from mitochondria to cytosol.

What does albumin do?

Transports long-chain fatty acids from adipocytes to other tissues

What is a lipoprotein?

Triglycerides, cholesterol, cholesterol esters and phospholipids form non-covalent aggregates with proteins forming a complex Hydrophobic lipids (triglycerides, cholesterol esters) form the core of the lipoprotein Amphipathic lipids (e.g., phospholipids) are at the interface between the aqueous medium and the hydrophobic core The apoproteins of the particle are amphipathic as well Different classes: Chylomicron, VLDL, IDL, LDL, HDL All have different components Chylomicron- Mostly triacylglycerol VLDL- Mostly triacyglycerol IDL- A good amount of everything LDL- Mostly cholesterol esters and cholesterol, but also phospholipids and proteins HDL- Mostly proteins but also cholesterol esters and phospholipids

What are two component regulators?

Two component regulators sense differences in the environment in different parts of the biofilm and can regulate gene expression These differences can include oxygen and osmotic differences Histidine kinase - a signal is sensed it autophosphorylates a histidine residue on the transmitter module The phosphate is transferred from the histidine kinase to an aspartate on the response regulator The response regulator is usually a DNA binding protein and can be an activator or a repressor, where phosphorylation can activate or inactivate its DNA binding The response regulator sometimes regulates other proteins as part of a phosphorylation cascade If the two-component regulator is a global regulator, it can regulate >50 genes and multiple systems Major pathogens can have Can both repress and activate EX: In Escherichia coli the Histidine Kinase EnvZ senses increases in osmotic strength It phosphorylates OmpR OmpR-P activates transcription of ompC (outer membrane porin, small pores) OmpR-P represses transcription of ompF (outer membrane porin, large pores) Where the regulator binds can influence it's affect on gene transcription The change in OMPs changes membrane permeability

How is Phosphoenolpyruvate carboxykinase (PCK) regulated?

Two isozymes; cytoplasmic (PEPCK-c or PCK1) and mitochondrial (PEPCK-m or PCK2) PCK1 is expressed in liver, kidney and small intestines. PCK2 expressed in most tissues. The gluconeogenic PCK1 is transcriptionally regulated: - Glucagon/catecholamines increases mRNA expression. - Glucocorticoid hormone cortisol increases mRNA expression (stress response) - Insulin inhibits expression by cytoplasmic localization of AKT phosphorylated FOXO Oxaloacetate is decarboxylated to phosphoenolpyruvate (PEP). Requires GTP and eliminates the CO2 added by Pyruvate Carboxylase. Note: PEP is not converted back to pyruvate because PKA inactivation of Pyruvate Kinase (prevents futile cycle).

Describe secondary active transport

Two or more solutes are transported Electrochemical potential is the energy source No direct involvement of ATP Reversible: depending on the electrochemical potential

How is glycogen synthase regulated?

Two separate isoforms encoded by unique genes with distinct tissue expression GYS1 is found in muscle and the other tissues capable of glycogenesis GYS2 is present in only in liver Both Glycogen Synthase isozymes are allosterically activated by G-6-P Both Glycogen Synthase isozymes are inhibited by phosphorylation G-6-P can induce full activity of phosphorylated protein GYS is bound to glycogen in both it's active and inactive states Insulin inhibits GSK3 which phosphorylates and inactivates glycogen synthase

Describe type 1 muscle fibers

Type I 1.Contraction time - slow 2.Resistance to fatigue - high 3.Aerobic metabolism - high 4.Mitochondrial density - high 5.Oxidative capacity - high 6.Glycolytic capacity - low 7.Major storage fuel - triglycerides 8.High myoglobin content 9.Myosin heavy chain - MYH7

What is type 1 diabetes?

Type I Insulin-dependent diabetes mellitus (IDDM)- primarily caused by autoimmune destruction of pancreatic β-cells. Type I diabetics are insulin-dependent and prone to ketoacidosis. Typically diagnosed in children or adolescents and require life-long exogenous insulin administration for glycemic control.

What is type 2 diabetes?

Type II Noninsulin dependent diabetes mellitus (NIDDM))-- most prevalent form and is characterized by both insulin secretion defect and insulin resistance. Diagnosis typically in older obese adults. Treatment initially can be weight loss and increased activity later may require drug therapy. Decrease in insulin-dependent GLUT4-mediated glucose uptake Decrease in insulin-dependent repression of hepatic glucose production Decrease in ability of insulin to either repress Hormone-sensitive lipase or increase expression of Lipoprotein lipase in adipose tissue.

Describe Type 2a muscle fibers

Type IIa 1.Contraction time - moderately fast 2.Resistance to fatigue - fairly high 3.Activity - long term anaerobic 4.High mitochondrial density 5.Oxidative capacity - high 6.Glycolytic capacity - high 7.Major storage fuel - creatine phosphate, glycogen 8.High myoglobin content 9.Myosin heavy chain - MYH2

Describe type 2b muscle fibers

Type IIb 1.Contraction time - very fast 2.Resistance to fatigue - low 3.Activity - short term anaerobic 4.Mitochondrial density - low 5.Oxidative capacity - low 6.Glycolytic capacity - high 7.Major fuel - creatine phosphate, glycogen 8.Low myoglobin content 9.Myosin heavy genes - MYH4

What are the non-essential amino acids?

Tyrosine (from phenyalanine) Alanine, arginine, aspartate, asparagine, glutamate, glutamine, glycine, proline, , cysteine, serine

What is tyrosine used to make?

Tyrosine is used to make two major types of products: the catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine), and the pigment melanin, both by initial dopa formation Synthesis of dopa for neurotransmitters (by tyrosine hydroxylase) occurs in neural tissue and adrenal medulla and requires BH4. Synthesis of dopa also occurs in melanocytes (by tyrosinase) and leads to the skin pigment melanin. Tyrosine hydroxylase and tyrosinase are completely distinct. Inborn defects in tyrosinase lead to albinism (1/40,000); high incidence (1/227) among Hopi tribe of native Americans.

Describe kinases and phosphatases

Tyrosine kinases phosphorylate proteins on tyrosines. These are more often associated with activated growth factor receptors, and are rapid and transient. Serine/threonine kinases phosphorylate proteins on serines and threonines. Generally associated with longer lasting phosphorylation. Phosphatases remove phosphate group from a substrate. "Resets" the system for future kinase activity.

Describe ubiquitin mediated protein degradation by lysosomes.

Ubiquitinated receptors bind to proteins that are known as epsins, which in turn interact with adaptor proteins that are bound to clathrin-coated pits. The ubiquitinated receptor undergoes endocytosis and becomes incorporated into endosomes, which are in turn sequestered into multivesicular bodies. The membrane of the multivesicular bodies becomes continuous with lysosomes, leading to degradation of the receptor.

What is conjugated bilirubin?

Unconjugated bilirubin is conjugated by reaction with 2 molecules of UDP-glucose, by two distinct enzyme to form bilirubin monoglucuronide, then diglucuronide. The process (conjugation) occurs primarily in the liver, but in part is catalyzed in bile duct. The bilirubin diglucuronide is water-soluble, and can be dumped into the intestine. In a further step the diglucuronide is hydrolyzed in the gut to reform bilirubin. Unconjugated bilirubin is referred to as "indirect bilirubin"; Conjugated bilirubin is referred to as "direct bilirubin" Normally, most serum bilirubin is unconjugated and bound to albumin (indirect bilirubin = ~0.9 x total bilirubin), so direct bilirubin in the blood is very low (near 0)

What is transmembrane asymmetry?

Under normal physiological conditions PS (phosphatidylserine) and PE (phosphatidylethanolamine) prefer to reside in the inner leaflet facing the cytosol; carbohydrate moieties are in the extra-cellular side. Under apoptotic conditions, PS is exposed on the outer leaflet of the cell membrane Scramblase (induced by apoptosis) Randomize trans-membrane lipid distribution Lipids can also undergo spontaneous flip-flop between the inner and outer leaflet. The transfer rate is high when membrane defect in donor membranes is abundant. Lipids can also be transferred between different membranes via protein-mediated processes. In addition to cholesterol spontaneous transfer, there exists protein-mediated cholesterol transfer, which is mainly responsible for the asymmetric distribution of cholesterol in cells (see Table II). Cholesterol is synthesized near endoplasmic reticulum (ER). However, cholesterol is most abundant in the plasma membrane, not in the ER.

What happens with lactose intolerance?

Undigested lactose passes to the colon where it's fermented into short chain fatty acids (SCFA) including acetate, butyrate and propionate. Fermentation also produces several gases (methane, hydrogen, CO2). Water enters into the colon as a result of the osmotic pressure of the undigested lactate leading to diarrhea.

What is the difference between dietary and functional fiber?

Undigestible CHO is dietary fiber and functional fiber Functional fiber generally is soluble and forms a viscous gel Soluble fiber lowers elevated blood cholesterol, improves glycemic control and is fermented. Insoluble cannot form a gel and passes through GI unfermented, adding bulk to stool

How is the rate of transcription determined?

Unlike DNA replication where all DNA is copied once during a round of replication, only specific genes at specific times and at variable rates are transcribed into RNA by a particular cell. The overall rate of transcription is dependent on the rate of recruitment of RNA polymerase, rate of initiation of transcription and rate of release of paused RNA polymerase. These events are directed by the unique DNA sequences of an individual gene's promoter and regulatory regions, and the transcription factors (proteins) available in the cell that bind to these DNA sequence.

How is glutamine used in different cell types?

Used as major fuel in intestinal epithelium (i.e. gut) and kidney Exported to carry excess NH3 away from muscle, brain

How does polyunsaturated fatty acyl CoA differ from monounsaturated oxidation?

Uses 2,4-Dienoyl CoA reductase and NADPH to turn two bonds into one

What laboratory tests would you use to diagnose Primary Ciliary Dyskinesia (PCD)?

Using electron microscopy identifying specific ciliary ultrastructural defects in biopsy samples is the main method of diagnosing PCD. It works by examining the dynein arms of the cilia. Other supportive tests include measurement of nasal nitric oxide in upper airways (in patients aged 5 years or more) and that tends to be low in PCD. PCD clinical genetic testing is available but is difficult because of the amount of genes involved (32 genes). Imaging studies can also be used to check the movement of the cilia.

What is refsum's disease?

Vegetables contain phytanic acid which contains beta-methyl which prevents beta-oxidation Therefore, phytanic acid needs to be initially oxidized by alpha-oxidation Individuals with this fatal disorder cannot carry out alpha-oxidation and thus cannot break down phytanic acid The branched methyl groups of phytanic acid disrupt the membrane structure of myelin that protects the nerve fibers in the brain tissue Symptoms include loss of vision, failure of muscle coordination, dry, rough, and scaly skin, impaired hearing and bone changes Treatment includes restricting foods that contain phytanic acid aka no green vegetables and no dairy

How is fuel utilized in muscle during intense exercise?

Very intense, short-term (10-15 sec sprint) - phosphagen system (ATP, creatine phosphate) When ATP and creatine phosphate stores are depleted, intense exercise can be sustained by anaerobic glycolysis for up to 2 minutes -Rapid accumulation of lactic acid in exercising muscles and circulation

Describe elastic cartilage

Very similar to hyaline cartilage except it contains a large network of fine elastic fibers Locations: auricle of the ear, walls of the external auditory canals, Eustachian tubes, epiglottis Fibers: type II collagen and elastic fibers Growth: appositional and interstitial

What is maple syrup urine disease?

Very typical of inherited disorders of amino acid metabolism. Disfunction of Step 2 in Branched Chain Amino Acid Metabolism: Branched chain dehydrogenase Accumulation of alpha-keto-BCAA's Incidence low in general population (1/200,000 worldwide), but higher in S.E. PA (1/200 births among PA Presents after first protein meal (milder forms seen later in life). Failure to thrive, feeding difficulties; brain development severely affected (though milder forms exist); convulsions Urine has odor of maple syrup (from alpha-keto-BCAA's MSUD Therapy Feed low protein diet, low in BCAA (but not completely BCAA-free). Need to have all essential AA, including BCAA, to make proteins, etc. Differing degrees of severity.

How does the HIV virus enter?

Via membrane rafts 1. HIV virus infects host cells by first binding to CD4 protein. 2. gp120 undergoes conformational change due to binding. 3. HIV virus binds to co-receptor which leads to raft clustering. 4. Lateral assembly of protein complex takes place in the raft to initiate fusion of the virus envelope with the cell membrane.

What is Werner syndrome?

Werner Syndrome (WS) a rare, autosomal recessive genetic disease that mimics premature aging. Patients with WS age rapidly following puberty, and are at increased risk of developing cancer and cardiovascular disease. Symptoms of WS include: premature graying, loss of hair, bilateral cataracts, osteoporosis, atherosclerosis, diabetes, scleroderma-like changes and ulceration of the skin. A single gene WRN identified on Ch 8 belongs to family of DNA helicases (RecQ proteins). This and other progeroid syndromes (Bloom syndrome, xeroderma pigmentosum, etc) result in elevated DNA damage burden, providing causal evidence for the links between lifelong increase in genomic damage and aging

What is the complement system?

What is complement? ~20 proteins synthesized in liver found in serum, become biochemically activated in a cell-free system to destroy pathogens. Role: Directly destroying pathogens by facilitating their removal via phagocytosis Alerting and activating other immune cells to sites of infection and inflammation. Cell lysis How is it activated? Recognizes pathogen bound to Abs Labels target pathogen for opsinization What happens next? It's a cascade of events resulting in opsinization of the pathogen/phagocytosis! Why are host cells not affected? Host cells have surface-anchored regulatory proteins that inhibit complement activation

What are targets for genome wide analysis and how do they worK?

Whole-genome/Exome First, the altered cancer genome is the direct cause of disease and precisely defines the tumour phenotype. Second, as we have access to both diseased tissue and normal samples from the same patient, and as most cancer genomic alterations represent somatic events, we can discern with confidence those changes specific to cancer. Third, in cancer, genomic alterations are progressive and in some cancer cases, changes related to disease stage, development of metastases and drug resistance are discernible. RNA-Sequencing: •Mutation detection in expressed genes •Integrating data on levels of RNAs •Transcriptional signatures may help in tumor classification

What is Fick's first law of diffusion?

Without Partitioning J = D • ∆C / ∆x Where: J = flux (mol cm-2 s-1), ∆C = concentration difference (mol cm-3), ∆X = membrane thickness (cm), D = diffusion coefficient (cm2s-1 Fick's law holds for diffusion through membranes and also diffusion in free solution.

Describe Wnts

Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Wnt genes and Wnt signaling are also implicated in cancer. Insights into the mechanisms of Wnt action have emerged from several systems: genetics in Drosophila and Caenorhabditis elegans; biochemistry in cell culture and ectopic gene expression in Xenopus embryos. Many Wnt genes in the mouse have been mutated, leading to very specific developmental defects. Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to b-catenin, which then enters the nucleus and forms a complex with TCF to activate transcription of Wnt target genes.

Does inactivation of BRCA2 and other genes in the same pathway provide an opportunity to design "precision medicine therapies" highly toxic to cancer cells that could spare normal dividing cells? What is the name of this concept?

Yes. For example, PARP inhibitors are used to stop the PARP enzyme from the repair of tumor cells after chemotherapy. They only work in people with the BRCA1/2 gene mutation. This is called "synthetic lethality" in which cancers with specific mutations are many times more sensitive to the drug than normal cancer cells. The BRCA deficient cells already can't do homologous recombination, so they are relying on the backup processes for DNA repair. The PARP inhibitors can inhibit one other DNA repair pathway (it impairs it in BRCA deficient and normal cells), which will cause the BRCA deficient cells to be unable to fxn, but the normal cells are okay, because they still have HR and the other DNA repair pathways to lean on.

Describe anchoring junctions

Zonula adherens ANCHORING JUNCTIONS: lateral adhesions using proteins that link into the cytoskeleton. Continuous belt that encircles the cell=belt junction Provides cell-cell attachment by linking the actin cytoskeleton of the adjacent cells Important for creating and maintaining the structural integrity of the epithelium Associated with Actin Cytoskeleton 50 different CAMs and are divided into 4 families: cadherins, integrins, selectins and the immunoglobulin superfamily. Afadin-nectin complex Cadherins are the main transmembrane components of Zonula adherens Cadherins are transmembrane proteins and are Ca+2 dependent Cadherins form homotypic calcium-dependent interactions (in the extracellular space ) with cadherins of the neighboring cell In the cytoplasm Cadherins interact with intracellular proteins. Catenins, vinculin and alpha-actinin link cadherin molecules to actin filaments of the cytoskeleton Cadherin-catenin- actin cytoskeletal network regulate the cell adhesion, growth and differentiation and are one of the main components responsible for folding epithelial sheets into tubes ducts and other related structures. In human disease, during epithelial-mesenchymal transitions (EMT), when epithelial cells switch to a fibroblast-like cell (mesenchymal) cadherins are down regulated while other molecules like vimentin are upregulated, resulting in cancer

Describe tight junctions

Zonula occludens Located apically within the lateral domain Encircles the cell Narrow region where the plasma membranes of adjacent cells come in contact to seal off intercellular space Not a continuous seal >>a series of focal fusions of the outer leaflets of plasma membrane Focal fusions>> Junctional proteins of adjacent cells traverse the plasma membrane and come in contact to occlude the intercellular space Occluding junctions are impermeable and allow the epithelium to function as a barrier. Limits the movement of water and other molecules in the intercellular space. Regulates selective passage of substances (blood brain barrier). Prevent the migration of lipids and membrane proteins from the apical surface and the lateral regions. Recruit various signaling molecules to the cell surface and link them to actin filaments of the cytoskeleton. Claudins, Occludins are transmembrane components of tight junctions and belong to the tetraspan family of proteins. Junctional Adhesion Molecules (JAMs) are transmembrane components of tight junctions and belong to the Ig superfamily of proteins Nectins are transmembrane components of tight junctions and belong to the Ig superfamily of proteins Uses F-actin TJ: A zipper to seal the intercellular space creating a barrier/regulating paracellular diffusion Paracellular transport occurs across the ZO. The amount of water, electrolytes and small molecules that are transported depends on the tightness of the seal generated by the ZO. Dependent on the molecular composition and ratio of claudins to occludins and other proteins and the aqueous channels in the seal.

Describe lysosomes

a. The hydrolytic enzymes are formed in the RER b. Enzymes have a terminal mannose-6-phosphate group as a marker to be packaged in lysosomes c. They are packaged at the trans face of the Gogi complex (termed the Trans Golgi Network -TGN) d. The newly formed vesicles that bud off are termed early endosomes or primary lysosomes. They are small and have homogeneous, electron-dense contents. e. The early endosomes (primary lysosomes) may fuse with phagocytic or other vesicle to form late endosomes or secondary lysosomes. Lysosomes: Are membrane bound organelles contain hydrolytic enzymes have acidic contents (pH 4.5-5.5) have electron-dense heterogeneous contents digest ingested material and aged or damaged organelles FUNCTIONS OF LYSOSOMES - THE DIGESTSIVE SYSTEM OF THE CELL: Heterophagy, e.g., phagocytosis & degradation of bacteria by (e.g., by neutrophils) Responsible for break down of bone during bone remodeling (by osteoclasts) Autophagy, e.g., destruction of worn-out organelles, e.g., mitochondria, ER, etc.

What is osteopetrosis?

a.k.a. Marble Bone Disease or Albers-Schönberg Disease: Genetic disorder caused by mutations of several genes that affect osteoclast development and/or function Results in a diffuse increase in bone due to decreased bone resorption Defects inherited in autosomal recessive pattern Symptoms: Increased fractures Cranial nerve deficits Anemia and infections Treatment: Bone marrow transplantation

What state favors fatty acid mobilization and fatty acid beta-oxidation in the mitochondria

beta-oxidation is inhibited by insulin so it would be active in the FASTING state Activated by glucagon and catecholamines

What are the major actions of second messengers?

cAMP- Protein Kinase A cGMP- Protein Kinase G Ca2+ Calmodulin-activated Protein Kinases DAG-Protein Kinase C

How does Viagra work?

cGMP is degraded by phosphodiesterase (PDE); different tissues have different PDE isoforms PDE5 is found predominantly in retina and corpus cavernosum; inhibiting PDE5 (with Viagra or related drugs) selectively enhances cGMP levels in c.c., leading to vasodilation (erection).

What are chondroblasts?

chondrocyte precursors capable of forming a cartilage-specific ECM, but not yet encased within the matrix.

Where in the cell does glycolysis occur?

cytoplasm of the cell

How does the PNS regenerate after injury?

i) Nerve is injured - perhaps by a cut, crush or gunshot wound. ii) Rapid 'Wallerian' degeneration of the distal axon, triggered by impaired transport of axon 'survival factors' past the injury site. Blood nerve barrier break- down allows influx of macrophages, which cooperate with Schwann cells to digest myelin. iii) Schwann cells dedifferentiate, then proliferate and line up. Aligned Schwann cells and remaining basement membrane forms tubes (bands of Bungner) that guide regenerating axons iv) Regenerating axon finally reaches target (here a muscle fiber) and re-establishes synaptic connection (='Re-innervation'). **i)In the CNS, myelin clearance is far less efficient and damaged oligodendrocytes often die. The uncleared myelin debris contributes to the failure to regenerate.

What is the equation for ionic current?

i=g(Em-Eion) g=1/R R=Resistance g=conductance

What is tRNA made from?

tRNA molecules carry amino acids to ribosomes and ensure that the amino acids are incorporated into the appropriate positions in the growing polypeptide chain; they are adaptors. Cells contain at least 20 different tRNA molecules, one for each amino acid Many amino acids have more than one tRNA tRNA molecules contain about 80 nucleotides. Each tRNA has one binding site for a specific sequence of three nucleotides in mRNA (the anticodon site) The sequence CCA, found at the 3' end, is the attachment site for the amino acid About 20% of the nucleotides are unusual and are produced by posttranscriptional modifications. The nucleosides dihydrouridine (D), ribothymidine (T) and pseudouridine are present in most tRNAs. Although their base sequences differ, tRNA molecules all form a similar cloverleaf structure.

What is contained in the outer membrane of gram negative bacteria?

·The outer membrane of Gram negative bacteria contains porins for transport Porins can be non-specific (water-filled channels allowing hydrophilic molecules of a certain size into the cell) or specific A number of active transporters are located in the cytoplasmic (plasma) membrane of Gram negative and Gram positive bacteria

What happens in Fabry disease?

α- galactosidase A is active in the lysosome and it catalyzes the lysosomal hydrolysis of globotriaosylceramide. It breaks the molecule down by hydrolyzing the galactosidic bond between two galactose residues. Reduced activity will result in an accumulation of globotriaosylceramide. The associated sphingolipidosis is Fabry disease, which is an X-linked, lysosomal storage disorder. When you have a build up of globotriaosylceramide, it builds up in the cells, especially in cell lining blood vessels near the skin and cells in the kidney, heart, and nervous system. It will also begin to remain in the blood circulation. As it accumulates in the lining of blood vessels and in the blood itself, the vessels become narrowed, decreasing blood flow throughout the body and to tissues such as the kidney, heart, and nervous system, eventually causing damage to these tissues. The acroparesthesias and anhidrosis as a child could be caused by the nervous system damage or build up in the blood vessels preventing good blood flow during activity. Because it mainly affects the small blood vessels near the skin, angiokeratomas occur due to the dilation of those blood vessels as the cells lining them expand due to accumulation of globotriaosylceramide. The corneal opacities are due to the buildup of globotriaosylceramide in the cells of cornea. The proteinuria may be cause by the beginnings of kidney failure because of the lack of blood flow to the tissue or by direct deposition of the molecule into the kidney tissues. The deposition of globotriaosylceramide into heart tissues can develop into heart disease, which would explain the findings on the ECG and ultrasound.

Describe Nebivolol, Metoprolol, Atenolol, Betaxolol, etc. ....

β1-preferring Adrenergic Antagonist Cardioselective **Hypertension, angina, and controlled CHF and migraines **Open-angle glaucoma ➠ Betaxolol (slight/no anesthetic properties) Pharmacodynamics - most selective for β1; [higher] block β2) ⬇ cardiac output, blood pressure, AV conduction Some inhibit Na+ channels ➠ anesthetic effect (metoprolol, pindolol, acebutolol) Some ↑ NO production ➮ vasodilation (nebivolol, carteolol, bucindolol, celiprolol, carvedilol, labetalol, betaxolol) ** Used for acute treatment of myocardial infraction, acute coronary syndromes, management of long term chronic heart failure Adverse effects Cognitive dysfunction, hypoglycemia, diarrhea Black box warning: angina will be exacerbated due to abrupt removal, risk of MI

What happens in Tay-Sachs disease?

β—N-acetylhexosaminidase A forms part of the complex that breaks down GM2 gangliosides, through the hydrolysis of the bond connecting a N-acetyl-D-galactoamine and a D-galactose residue in the polar head of the ganglioside. Reduced activity results in the accumulation of the GM2 galactoside in the lysosomes of cells in the brain and spleen. The associated sphingolipidosis is Tay Sachs disease. The accumulation or improper storage of the GM2 galactoside in the cellular lysosomes can lead to the destruction of the lysosomes. This destruction will empty the catabolic enzymes that are typically confined to the organelle, leading to death of the cell and damage to the surrounding tissue. The increased muscular tone suggests damage has occurred to CNS motor neurons. The increased startle response (i.e. exaggerated response to touch or noise) also suggests some nerve damage to inhibitory neurons in the CNS. Finally, the cherry red macula is a key indicator of Tay Sachs and can be attributed to progressive opacification of the inner retina. The foveola is devoid of the ganglion cell layer and hence remains transparent and allows transmission of the red color of the choroid and the retinal pigment epithelium (blood vessels are what looks red).

What are histone tails?

•Histone tails protrude out of the nucleosomes and are subject to several posttranslational modifications (acetylation, methylation, phosphorylation), which act as docking sites for other proteins that affect the level of chromatin condensation and modulate transcription Histone tail modification is also critical for epigenetic heritable control of gene expression Variant forms of histones work at particular parts of chromosomes (i.e. centromeres) or during specific processes (recombination or repair).

How is PKC activated?

•PKC is a serine/threonine kinase • PKC can directly phosphorylate cytoplasmic proteins and some transcription factors • Multi-protein family with distinctions in tissue specificity and activation requirements 1.Ligand-receptor binding, via G-protein activation, rapidly activates phospholipase Cb, 2.phospholipase Cb cleaves PIP2 (inositol phospholipid) into IP3 and DAG 3. IP3 binds to receptors on the ER and Ca2+ is released into the cytoplasm; Several PKC isoforms are activated by Ca2+ 4. DAG has two functions---as a precursor in arachidonic acid generation, and direct binding and activation of PKC

What are some of the genes involved in cancer?

•Protooncogenes: activators of the cell cycle -ABL: protein kinase -RAS: GTPase -MYC: nuclear DNA-binding protein -ERB-A: growth factor receptor •Tumor suppressors: repressors of the cell cycle -RB1 •DNA repair/recombination -MLH1, MSH2 -BRCA1, BRCA2 -ATM, FA, NBS, BLM, XP •Apoptosis BCL2, TP53

What are trans regulators of eukaryotic transcription?

•Transcription factors (TF) (or basal factors) bind to TATA box and facilitate binding of RNA polymerase. -TATA-binding protein (TBP) binds to TATA box. -TF A & B bind TBP -RNA polymerase binds, then factors E,F, & H bind. -Can transcribe at a basal level, essential, cannot be regulated Activator (Transcriptional transactivators), and possibly repressors, communicate with basal factors through coactivators (linked in tight complex to TBP

What happens to amino acid exchange after an overnight fast?

↓Blood glucose, ↑Glucagon (↑gluconeogenesis), ↓Insulin Protein synthesis in liver and other tissues occurs at a diminished rateNet degradation of protein occurs in skeletal muscle Muscle oxidizes branch chain amino acids (BCAA) to produce energy and glutamine (and alanine) Alanine and glutamine account for 50% of total amino acid nitrogen released from muscle Liver - ↑aa uptake, ↑gluconeogenesis, ↑urea output Kidney, gut major sites of glutamine uptake Brain uses glucose and BCAA's for energy

How is the palmitoyl chain from the fatty acid synthase complex released?

Thioesterase

How to release the palmitoyl chain from the fatty acid synthase complex?

Thioesterase

Describe loose connective tissue

"Loose" CT= Loosely arranged Cells/GroundSubstance/Fibers- Most Ground substance and cells Supports Epithelial tissue, Surrounds blood vessels, Fills spaces between Muscles Most common type with a gel-like consistency Flexible; Well vascularized; Cellular LCT (1) Diffusion of oxygen/carbon dioxide and nutrients/wastes (2) inflammatory and immune reactions (3) Provides structural support

What is a mutation vs a polymorphism?

"Mutation"= "a disease-causing change" "Polymorphism" = "a non disease-causing change" or "a change found at a frequency of 1% or higher in the population" PREFER "sequence variant" or "allelic variant" If disease associated= "Pathogenic variant" Variants for which a functional effect is unknown can together be called "variants of uncertain significance" (VUS).

How is beta-oxidation regulated?

(1) Hormones control the supply of fatty acids in the blood. (2) Carnitine palmitoyl transferase I is inhibited by malonyl-CoA, which is synthesized by acetyl-CoA carboxylase (ACC). AMP-PK is the AMP-activated protein kinase. (3) The rate of ATP use controls the rate of the electron-transport chain, which regulates the oxidative enzymes of β-oxidation and the TCA cycle.

What are the three irreversible steps of gluconeogenesis?

(1) conversion of pyruvate to PEP via oxaloacetate, catalyzed by pyruvate carboxylate (PC) (only in mitochondria!!) and Phosphoenolpyruvate carboxykinase (PCK) (2) Dephosphorylation of fructose 1,6-bisphosphate by Fructose-1,6-bisphosphatase (FBPase) (3) Dephosphorylation of glucose 6-phosphate by Glucose-6-phosphatase (G6Pase). These enzymes have been found in liver, kidney, small intestine and muscle.

What is the rate limiting step in DNA synthesis?

The rate limiting step is binding (1 s). Elongation is much faster (millisecond range).

What happens in hereditary lack of adenosine deaminase?

(Adenosine --> inosine + NH3) causes buildup of dATP in T-cells. dATP inhibits ribonucleotide reductase, resulting in failure to produce T-cell DNA. Disorder is one type of SCIDS (severe-combined immunodeficiency disease). Treatment: Bone marrow transplant

What is the location of smooth muscle?

Viscera Vascular System Arrector Pili muscle in the skin Intrinsic muscle of the eye

What is the function of Carnitine: Palmitoyl-transferase 1?

(CPT I) Converts Fatty acyl CoA to fatty acylcarnitine and CoA so it can be transported to the mitochondrial matrix

What is the function of Carnitine: Palmitoyl-transferase 2?

(CPT II) Converts Fatty acylcarnitine and CoA into Fatty acyl CoA for beta-oxidation

What is pinocytosis?

(Cell drinking) small invaginations of the cell membrane form and entrap extracellular fluid . Vesicles pinch off and eventually fuse with lysosomes or as in capillaries may move to the surface of skeletal muscle cells where they fuse with the cell membrane and transfer material to the muscle cell.

What is phagocytosis?

(Cell eating) remove foreign bacteria, extracellular components, damaged cells etc. After a bacterium binds to the surface of a macrophage , cytoplasmic processes are extended which surround the bacterium enclosing the bacterium in an intracellular phagosome.

What is coenzyme A and where does it come from?

(CoASH) Coenzyme that carries acyl groups and comes from pantothenic acid aka vitamin B5

How do you calculate a z value?

(Value-Mean)/Standard Deviation

What is the importance of the Na+/K+ pump?

(a)Responsible for creating the high K+ concentration and low Na+ concentrations in the cytoplasm. This is necessary for: (i)resting membrane potential (ii)action potential possible (iii)the secondary active transport: Na+/Ca2+ exchange keeps cytosolic Ca2+ concentration very low. It also makes the transport of glucose, fatty acids and amino acids possible. (b)Responsible for maintaining the high K+ concentration and low Na+ concentrations in the cytoplasm. (i)During an action potential, K+ leaves the cell and Na+ enters the cell. The pump returns these ions so the cellular concentrations are maintained. (ii)When the cell is at its resting potential, there is a continuous flux of K+ from the cell through channels and a continuous flux of Na+ into the cell through channels. (iii)These fluxes are smaller than those in the action potential, but still important. The pump returns these ions so the cellular concentrations are maintained.

What is the synthesis and fate of VLDL?

***Associated with high carbohydrate diet Proteins synthesized on the rough endoplasmic reticulum (RER) (are packaged with triacylglycerols in the ER and Golgi complex to form VLDL. VLDL are transported to the cell membrane in secretory vesicles and secreted by exocytosis. In the blood HDL gives lipoproteins C2,E and CE to VLDL. It is then digested into IDL, FA and glyerol by LPL Some IDL goes to receptors on the liver where it is endocytosed and then degraded by lysosomes into cholesterol, amino acids, FA and glycerol Some IDL goes to the HGTL enzyme where it creates FA, glycerol and LDL Some LDL is oxidized and taken up my macrophages and made into foam cells Some LDL is is taken up by the liver and peripheral tissues where it is endocytosed and then degraded by lysosomes into cholesterol, amino acids, FA and glycerol The Fatty acids and glycerol produced by the LPL and HTGL enzymes in the blood go to muscle for energy and adipose tissue for storage

What regulates the Pyruvate Dehydrogenase Complex?

+ Pyruvate, ADP, Dephosphorylation, Ca+-Inhibits pyruvate dehydrogenase kinase (uses ATP), Activates pyruvate dehydrogenase phosphatase- Dephosphorylates - NADH, ATP, Acetyl CoA, Fatty Acids, Phosphorylation (Pyruvate dehydrogenase kinase)

How does mitochondrial DNA differ from nuclear DNA?

-- Circular shape -- mtDNA has few, if any, repair mechanism and no noncoding regions (introns), thus more prone to mutation -- All mtDNA are maternally derived

What is produced in the TCA cycle?

1 GTP 3 NADH 2 CO2 1 FADH2

What is the concentration of Ca2+ in the extracellular fluid?

1 mM

How are peroxisomes targeted?

1) Most peroxisomal matrix proteins contain a C-terminal Peroxisomal Targeting Sequence (PTS1). 2) PEX5 recognizes fully folded proteins with a PTS1 C-terminus. 3) PEX5 takes the PTS1-containing protein to a multi-protein complex in the peroxisomal membrane. The members of the complex are collectively referred to as PEX proteins, or Peroxins. 4) PEX5 accompanies the folded protein into the peroxisomal membrane, and forms a channel with other Peroxins, which allows the PTS1-containing protein to translocate into the matrix. 5) After releasing its cargo the PEX5 is either recycled or degraded.

What are the steps of ketone body formation?

1. 2 acetyl CoA for acetoacetyl CoA via the enzyme thiolase 2. Acetyl CoA to 3-hydroxy-3-methyl glutary CoA (HMG CoA) via the enzyme HMG CoA Synthetase 3. HMG CoA goes to acetyl CoA and acetoacetate via the enzyme HMG CoA lyase 4. Acetoacetate spontaneously creates Co2 and acetone Acetoacetate to beta-hydroxybutyrate via the beta-hydroxybutyrate dehydrogenase enzyme creates NAD+ from NADH, requires phosphatidylcholine (PC) for functioning

What are the different stages of karyotyping?

1. Amniocentesis (Embryonic cells or lymphocytes) or venipuncture + PHA (Mitogen) 2. Colchicine (Mitosis blocker) then centrifuge 3. KCL (Hypo-osmotic) 4. Centrifuge 5. Fixation 6. Centrifuge 7. Transfer to plate 8. Heating and Drying 9. Giemsa dye (Chromosome staining) 10. Microscopy

How does the cross bridge cycle end?

1. Calcium is removed from the sarcoplasm by calcium pumps (SERCA). - Ca2+ pumps are located on the longitudinal portion of the SR membrane. - Ca2+ is pumped from the sarcoplasm into the SR against a concentration gradient SERCA in an active transport system which utilizes ATP directly - Ca2+ diffuses to the terminal cisternae where it binds to a storage protein, calsequestrin. 2. The removal of calcium from the myoplasm causes calcium to dissociate from TnC. - TnI separates from TnC and rebinds to tropomyosin. - Tropomyosin returns to its position covering the myosin binding sites on actin. - Cross bridge cycling stops.

How is the TCA cycle regulated?

1. Citrate Synthase + ADP - High citrate, low OAA, ATP, NADH, Succinyl CoA 2. Isocitrate dehydrogenase - Rate limiting step + ADP, NAD+, Ca+ - ATP, NADH 3. Alpha-ketoglutarate dehydrogenase + Ca+ - Succinyl CoA, NADH, ATP

What are the steps of fatty acid synthesis?

1. Conversion of glucose to mitochondrial acetyl CoA Pyruvate dehydrogenase is present only in the mitochondria. The reaction catalyzed by pyruvate dehydrogenase has a large negative DG0' and is irreversible. Acetyl CoA cannot be converted back to pyruvate 2. Transfer of acetyl CoA from mitochondria to cytosol with the aid of citrate A membrane-bound tricarboxylate translocase transports citrate from mitochondria to cytosol 3. Carboxylation of Acetyl CoA to Form Malonyl CoA by Acetyl CoA Carboxylase This is the rate-limiting step in fatty acid synthesis Biotin serves as a carrier of activated CO2 4. Chain Elongation on the Fatty Acid Synthase Complex. This protein is a homo-dimer. Each monomer contains 7 enzymes plus an acyl carrier protein ACP. 5. Further Elongation and Desaturation of Fatty Acyl Chains

What does arachidonic acid break down to?

1. Cyclo-oxygenase to create PPG2 which will create prostaglandins and thromboxanes 2. Lipoxygenase to create HPETE which will create Leukotrienes, HETE, and lipoxins 3. Cytochrome P450 to create epoxides which will create diHETE and HETE

How is calcium released from the sarcoplasmic reticulum?

1. Depolarization of the T-tubule membrane causes Ca2+ channels on the SR to open. 2. The T-tubule contains a dihydropyridine receptor, which acts as a voltage sensor. 3. The SR membrane contains a calcium channel, called the ryanodine receptor. 4. The DHP receptor is coupled to the ryanodine receptor by a protein which blocks the Ca2+ release channel when the membrane is polarized. 5. Depolarization of the T-tubule causes the charged protein to move towards the DHP receptor, unblocking the Ca2+ release channel within the ryanodine receptor.

What are the 4 dimensions of a limb?

1. Dorsal-Ventral axis: palm is ventral, knuckles dorsal. 2. Anterior-Posterior axis: thumb is anterior, little finger is posterior. 3. Proximal-distal axis: stylopod ------ autopod. 4. Time: time-dependent change in cells of the progress zone determines the type of structures that can be formed in the proximal-distal axis

What are the 3 distinct types of protein targeting?

1. Gated transport (not covered in detail here) 2.Targeting via transmembrane transport (blue arrows). 3.Targeting via vesicular transport (green arrows). We will focus on the biosynthetic route i.e. 'forward trafficking'.

What determines the rate of aging?

1. Genetic factors 25% of the variation in lifespan is caused by genetic differences. Evidence that longevity clusters in some families. Human genetic premature aging syndromes 2. Environmental factors: inflammation, radiation, oxygen, chemicals, etc life style: diet, malnutrition, alcohol, drug abuse etc. Environmental factors: inflammation, radiation, oxygen, chemicals, etc life style: diet, malnutrition, alcohol and drug abuse etc. Caloric Restriction-Caloric restriction without malnutrition extends lifespan and delays the onset of age-associated diseases in many species

What is located in the thymus of the medulla?

1. Maturation of T cells completed here. 2. Medullary thymic epithelial cells form swirls called Hassals corpuscles (lymphopoietin) 3. Thymic dendritic cells complete maturation of T cells

What is array comparative genome hybridization?

1. Patient and control DNA labeled with fluorescent dyes and applied to the microarray 2. Patient and control DNA compete to attach or hybridize to the microarray 3. The microarray scanner measures the fluorescent signals 4. Computer software analyzes the date and generates a plot

Describe AP propagation

1. Positive charge (Na+) enters the cell at the point called x=0 where the action potential is in its rapid upstroke. 2. Positive charge carried by K+ flows in both directions along the length of the axon inside the axon. 3. Positive charge carried by K+ flows out of the axon through membrane K+ channels all along the length of the axon. 4. Positive charge carried by Na+ flows through the extracellular solution along the axon back to the point x=0. This completes the circuit.

What are the functions of the epithelium?

1. Protection/Barrier The epithelial cells act as a barrier by joining with adjacent epithelial cells Outer surface- Skin Inner surface- All body cavities, linings of the tubes and ducts e.g. digestive tract, blood vessels 2. Absorption Nutrients, Ions etc. 3. Secretion Exocrine and Endocrine glands Exocrine e.g. Sweat gland produce sweat to control body temperature 4. Receptors for smell, taste, hearing and vision Specialized epithelial cells

What are the generalized signal transduction scheme?

1. Receptor-ligand interactions Initial formation of signaling complex, 2. Early biochemical events: G-protein activation; Ras protein Family involvement 3. MAPK family cascade. Integration of signals 4. Transcription factor activation

Describe the adaptive immune response

1. T cells encounter antigen presented on Ag-presenting cells and become activated. There are two types: T helper cells and Cytotoxic T cells. 2.The T helper cells become activated by Ag presentation on MHC class II, interact with B cells, to drive B cell differentiation and proliferation, and to further stimulate the T cells themselves. Some T helper cells will also become memory T helper cells 3. Activated B cells then differentiate either into plasma cells and secrete antibodies which target the antigen, or they become memory B cells for future encounters. 4.Cytotoxic T cells, also become activated by Ag presentation by MHC class I following interaction with infected cells, undergo rapid expansion, assisted by cytokines secreted by activated helper T cells. 4.CTLs then directly target and kill infected cells by secreting factors that induce apoptosis.

How do you determine the sample size?

1. The magnitude of difference you wish to detect (d ) 2. The alpha level desired (type I error rate) 3. The desired power (type II error rate). Required sample size increases as: - desired detectable difference decreases - desired alpha level decreases - desired power increases

What are the functional domains in regulatory . (Activator/Repressor) proteins?

1. Transactivation Domain-ALL 2. DNA Binding Domain-ALL 3. Ligand Binding Domain-Some 4. Dimerization Domain-Some

What what points or regulation of gene expression?

1. Transcriptional initiation of transcription, RNA polymerase pausing 2. Post-transcriptional alternative splicing, 3' end cleavage, RNA editing, nuclear export, RNA localization, mRNA half-life 3. Translational initiation of translation, regulation of translation 4. Post-Translational modification of proteins, protein targeting, protein half-life

What are the different ways cartilage grows?

1.Appositional growth: Differentiation of chondrocytes from the perichondrium (chondrogenic layer of cells) n 2.Interstitial growth: Results from mitotic division of pre-existing chondrocytes within the cartilage matrix Examples: epiphyseal (growth) plate for increasing long bone lengths, articular cartilage regeneration since it lacks a perichondrium

Phosphorylation is the currency of growth factor signaling, Why?

1.Phosphorylation is a covalent modification that changes protein conformation 2. Exposes catalytic domains, and protein-protein interaction domains 3. is rapid—catalyzed by protein kinases 4. Is reversible—catalyzed by protein phosphatases 5. A chain of phosphorylation reactions is referred to as a signaling cascade

What are the different types of DNA damage?

1.Spontaneous 2.Alkylation 3.Oxidation 4.Irradiation 5.Mismatch

What is the concentration of Cl- in the extracellular fluid?

105 mM

What is the concentration of Na+ in the extraceullar fluid?

142 mM

Under physiologic conditions where does G-6-P go?

2/3rds converted to glycogen and 1/3 enters glycolysis In glycolysis 80-90 percent is converted to carbon dioxide and water whereas the remaining 10-20 percent is converted to lactate

What is the osmolarity of the extracellular fluid?

290 milliosmoles/L

Describe hyperpolarization-activated cyclic-nucleotide-gated (HCN) cation channels

4 members Have four similar or identical α-subunits, each with a single domain. Sensitive to cAMP and cGMP, which alter the voltage sensitivity of the channel opening. Permeable to the monovalent cations K+ and Na+. Function as pacemaking channels in the heart, particularly the SA node.

What is the concentration of H+ in the extracellular fluid?

40 nM

What is trisomy X?

47,XXX 1/1000 newborn females Normal and fertile, few are ever diagnosed Inactivation of 2 of the 3 X chromosomes most likely reason for the normal phenotype Affected females taller than average

What is cori disease?

4:4 Transferase and/or 1:6 glucosidase deficiency

Which enzyme is the major producer of leukotrienes?

5-lipoxygenase

Where is most of the bodies protein located?

60% is located in skeletal muscle

What is the pH of extracellular fluid?

7.4

How do you tell the difference between a lysosome and a peroxisome in a EM?

???

What is the distributed gene hypothesis?

A bacterial species with a supragenome (pan genome) will have a core genome that will be shared by all the bacteria (comprises 60-70% of the genome) It will then have distributed genes o genes present in only some of the bacteria in the population o gives rise to different strains o genes encoded unique functions - alternate metabolism, virulence factors, etc. Transformation is one genetic mechanism that can give rise to this type of genome structure in a species

What is a polarized cell?

A cell is termed polarized when its organelles are arranged in a way that facilitates its job (function). For example, e.g., a cell that makes digestive enzymes starts out by assembling the animo acids. Into a protein in the rough ER, moving them to the Golgi complex, where sugars are added to the proteins. Lastly, the proteins are stored In secretion granules at the top (apex) of the cell. Until they are needed e.g., after a meal. Then the contents of the secretory granules are released from the cell.

What is platelet count?

A count of the number of platelets (thrombocytes) per cubic milliliter of blood Reference range -150,000 to 450,000 platelets/uL Decreased number of platelets -Thrombocytopenia Increased number of platelets -Thrombocytosis

What is white blood cell count?

A count of the total WBC, or leukocytes, in 1 mm3 (uL) of peripheral blood Reference range -3,500 to 10,500 cells/ul Decreased WBC -Leukopenia Increased WBC -Leukocytosis

Define resting membrane potential

A difference in electrical potential (a voltage difference) between the inside and the outside of the cell. Resting membrane potential is a steady state but NOT an equilibrium state A.The inside of the cell is negative in relation to the outside. B.This voltage difference varies according to cell type but is usually between -50 and -90 mV. C.The importance of resting potentials 1.The resting potential affects whether solutes enter or leave the cell. 2.creating a driving force for the entry of Na+ into the cells, which is coupled to the transport of many other molecules into or out of the cell. 3.In cells, such as neurons, skeletal muscle and cardiac muscle cells, the presence of a membrane potential enables the production and transmission of action potentials.

What is a fasicle?

A fasicle is a functional unit of myofibers that work together.

What is the definition of cisternae?

A fluid-containing sac or cavity

What genetic methods could be used to make a diagnosis of down syndrome?

A karyotype could be used to confirm the diagnosis by spilling the chromosomes out of a cell and then laid out on a slide to be organized using microscopy. FISH could be used as well by creating a fluorescent probe with a known DNA sequence on the 21st chromosome and then counting how many chromosomes show up with that fluorescent probe. Array cGH could also be used. In array cGH, patient and control DNA are labeled with fluorescent dye and applied to a microarray, which they compete to attach to. A scanner will measure the differences in the fluorescent signals and then a computer can generate a plot that would show the gain of chromosome 21 DNA.

What happens to nucleobases?

A lot of energy goes into making nucleobases, and ones made in cells are typically recycled The ones we ingest are metabolized and excreted PRTase recycle nucleobases uses PRPP

What happens during mismatch repair?

A mechanism that corrects mismatched, but undamaged, bases in DNA (spelling error by DNA polymerase) A cut and patch type of mechanism is used to identify the mismatch. Cut the younger (i.e. most recently synthesized) DNA strand, excise the mismatched base, resynthesize the DNA, and ligate the patch to the contiguous DNA strand Enzymes: MSH2, MSH6 MLH1, PMS2 Exonuclease DNA Pol, Ligase

What is exocytosis?

A membrane limited structure fuses with the plasma membrane resulting in the release of the content into the extracellular space. Since structures enclosed in membranes repel each other (highly negatively charged) exocytosis is mediated by fusogenic proteins, process regulated by calcium.

How do you tell if 2 bacteria are closely related?

A molecular chronometer needs different regions: 1. highly conserved regions; these regions are the same in most bacteria except the most distantly related 2. highly variable regions; these regions are different in almost all bacterial species allowing differentiation of closely related bacteria

How do DNA polymerase gamma and epsilon work?

A multiprotein machine with 5 subunits called the "clamp loader" attaches and detaches the sliding clamp from DNA polymerase. Collision with a downstream Okazaki fragment prompts the clamp loader to remove the clamp and release the polymerase, allowing it to recycle Uses ATP

What is the difference between and nucleotide and a nucleoside?

A nucleoside doesn't have any phosphates

What are alternate pathways for bacteria to metabolize sugars?

A number of alternative sugars can be used by bacteria including: o hexoses o complex sugars o citrate These sugars usually enter glycolysis at Fructose 1,6 diphosphate Hydrolases, esterases and lyases liberate metabolizable sugars from complex polysaccharides such starch, and components of fruits and vegetables; inulin, pectin, cellulose, arabinoxylan These are referred to a MACs (microbiota accessible carbohydrates)

What are transposons?

A piece of self perpetuating DNA that makes copies of itself and spreads from host to host (only a small proportion retain the transposing capacity) Transposons & remnants of transposons comprise ~45% of the DNA in the human genome LINES (Long Interspersed Nuclear Elements). Encode RT and endonuclease (orf2) and an RNA binding protein that is a chaperon. 6Kb. In euchromatin, mostly in extragenic regions, introns, NTRs, some in coding regions. Autonomous SINES (Short Interspersed Nuclear Elements). Much smaller. Non autonomous, depend on Lines or other transposons. Share 3' sequences with lines. Alu is the most abundant (only in primates). GC rich and found in non-coding regions. Non-atonmous *Copy and Paste

What is Fibrodysplasia Ossificans Progressiva (FOP)?

A rare autosomal dominant genetic disorder of ectopic bone formation. Most cases are sporadic resulting from new mutations in the gene (people with no history of the disorder in their family). A few examples of inheritance within a family. The mutated gene is the ACVR1 gene responsible for encoding the bone morphogenetic protein (BMP) type I receptor. BMPs (many subtypes) belong to the transforming growth factor-beta (TGF-β) superfamily of proteins and were originally identified as the active components of bone extracts capable of inducing bone formation at ectopic sites. Activating mutations in the type 1 receptor cause progressive endochondral ossification in skeletal muscle, tendons, and ligaments with progressive loss of joint mobility. Trauma to soft tissues can trigger more rapid ossification of the injured area.

How does receptor-ligand interaction initiate a cascade of signals?

A receptor transduces mechanical energy in the form of a conformational change on the outside, into biochemical energy in the form of phosphorylation/second messenger generation on the inside A receptor needs to: • specifically identify its ligand, • turn this interaction into a signal (bring it inside) • act as a hub for the beginning of a signaling complex There are three main families of cell-surface receptors, each of which transduces extracellular signals in a different way. 1. Ion-channel-linked receptors are transmitter-gated ion channels 2. G-protein-linked receptors indirectly activate or inactivate plasma-membrane-bound enzymes or ion channels via trimeric GTP-binding proteins (Gproteins). 3. Enzyme-linked receptors either act directly as enzymes or are associated with enzymes; the enzymes are usually protein kinases that phosphorylate specific proteins in the target cell.

How do lysosomes degrade glycogen?

A small amount of glycogen is continuously degraded by lysosomes The lysosomal enzyme a-1,4 glycosidase (GAA) degrades glycogen Homeostatic role is uncertain Deficiency in lysosomal GAA results in lysosomal accumulation of glycogen in muscle Pompe disease presents as infantile or late-onset adult

How is glycogen primed?

A small fragment of preexisting glycogen may act as a primer to initiate glycogen synthesis In the absence of a pre-existing glycogen primer, a specific protein, Glycogenin, can accept glucose from UDP-Glucose The initial glucose unit is linked to the hydroxyl group of tyrosine in Glycogenin Glycogenin is a glycosyltransferase transferring glucose from UDP-G to itself Glycogenin forms a primer of 10-20 glucose residues that is then extended by glycogen synthase and branching enzyme.

Describe a Transitional Epithelium

A specialized stratified epithelium Typical Location: Bladder, Ureter, Urethra Impermeable to salts and water

What is the definition of an action potential?

A sudden, transient, depolarizing deviation from the resting potential. Has a threshold -- once the cell is depolarized to this level, an AP will be generated, about -55 mV. All or nothing, once the stimulus threshold is reached the AP will be generated. An increase in the stimulus amplitude will not change the amplitude of the AP Refractory period - A time in which another AP cannot be generated »Prevents back (retrograde) propagation of AP »Limits the maximum frequency of APs »In the heart it reduces the chance for arrhythmias to occur Self-regenerating as it propagates along the membrane without decrement.

What is the cytoskeleton?

A system of protein polymers that provide for the architecture, shape, and motility of cells and for the directed movement of organelles and molecules within the cell Components: microtubules, microfilaments (aka Actin filaments), intermediate filaments, and a host of accessory and regulatory proteins

What is thrombophilia and what test would you order for inherited thrombophilia?

A thrombophilia is an inherited or acquired disorder of the blood that causes abnormal clotting Genetic testing would be able to determine whether the patient has inherited a mutation in a variety of genes that would cause a thrombophilia. Genetic testing would be able to differentiate between methylenetetrahydrofolate reductase (MTHFR) mutation, Factor V Leiden mutation, and prothrombin 20210 mutation.

How does histone acetylation occur?

A transcriptional activator and coactivator bind which results in acetylation of H3K9 and H4K8. Then another coactivator with histone kinase activity binds and phosphorylates H3S10 followed by the acetylation of H3K14. This then allows TFIID and a chromatin remodeling complex to bind to the promote and subsequent initiation of transcription.

What is the integrin?

A transmembrane heterodimer that works as cell-cell adhesion molecule or cell-matrix adhesion Different subtypes such as Laminin receptors, RGD receptors, collagen receptors, leukocyte-specific receptors Integrin signalling is bidirectional

Where are the three aldolase genes expressed?

A, highest muscle but present most tissues, major role in glycolysis, A only cleaves F-1,6-bP B, highest liver, kidney and intestines (gluconeogenic), active in fructolysis glcolysis and gluconeogenesis, B cleaves F-1-P as well as F-1,6-bP C, highest in CNS.

What are the major function of apoproteins?

A-I structural; activator of LCAT; cholesterol pickup B-100 structural; ligand for LDL receptor; secretion of VLDL C-II activator of lipoprotein lipase E ligand for LDL receptor and chylomicron remnant receptor

What cells do glycolysis?

ALL cells generate ATP from glucose by glycolysis

What is the sliding filament theory?

A. The sliding filament theory is used to explain the contraction of skeletal muscle fibers. B. When skeletal muscle contracts, the thin filaments slide over the thick filaments. The movement of the thin filaments over the thick filaments is produced by the cross bridge cycle. C. Each cross bridge cycle consists of four steps. 1. Binding of the cross bridge with the actin molecules on the thin filament. 2. Binding of the cross bridge towards the center of the skeletal muscle fiber. 3. Detachment of the cross bridge from the actin molecule. 4. Return of the cross bridge to its original position.

What is the function of AcylCoA: Cholesterol Acyltransferase?

ACAT Intracellular enzyme that esterifies cholesterol

What are the different types of tissues?

A. Tissues with permanent cells Cell types that are not subject to cell turnover •Auditory hair cells •Photoreceptor cells of the retina in the eye - Although individual cells of these types persist, very little of the adult body consists of the same molecules that were laid down in the embryo. (nerve and cardiac muscle cells were once thought to belong to this class). (both from the ectoderm like the skin) Common characteristics •long life spans •cannot be replaced if lost placed in protected environments B. Cell renewal in tissues Most differentiated cells are not permanent. Typically differentiated cells die after some time and then are replaced. • Simple duplication • Stem cells B1. Renewal by simple duplication Liver Regeneration •Processing of nutrients for other tissues: synthesis, degradation and storage of a large amount of substances. •Protected environment, so cell turnover is slow as compared to the gut (last about 1 year). •Hepatocytes proliferate in response to damage: [HGF=mitogen] increases in blood. Survival factors also control hepatocyte number. •Stems cells have also been identified in liver. •As result the liver has relative high regeneration capacity after injury or hepatectomy (70% in rodents). •However, chronic damage to a specific cell type, might result in the outgrowth of other cell types, damaging the structure of the organ irreversibly (HBV and HCC). B2. Renewal by stem cells Stem cells are required to produce new cells to replace differentiated cells which are unable to divide and exhibit a limited life span. Examples of incompatibility with cell division: • Outermost layers of the skin • Red blood cells • Skeletal Muscle cells • Senescent cells Terminally differentiated neurons

What is Eion?

AEventually the electrical force caused by the negative charge in the cell exactly counterbalances the effect of the chemical force (caused by K+ being in higher concentration inside the cell than outside the cell) The membrane potential (Em) at which the sum of the electrical and chemical forces on an ion is zero

What is aneuploidy?

Abnormal number of chromosomes.

How long does mitosis take?

About an hour

What is the beta 1 selective adrenergic antagonist/partial agonist?

Acebutolol

What are selectins?

Adhesion molecules Selectins mediate the carbohydrate-protein interaction with specific ligands and interrupt the rapid flow of leukocytes in the circulation by initiation of rolling and tethering on endothelial cells.

Descrie to aldehyde dehydrogenase enzyme

Acetaldehyde is oxidized to acetate by Aldehyde Dehydrogenase (ALDH) generating NADH Three different ALDH genes, the isozymes differ in cellular localization and Kms. ALDH acts as a tetramer. A cytoplasmic ALDH1 in human liver also has a higher Km than ALDH2 and is thought to be a minor contributor. Mitochondrial ALDH2 has a low Km for acetaldehyde and is the predominant enzyme responsible for liver acetaldehyde oxidation. Normally the activity of the ALDH isoforms far exceeds the levels of acetaldehyde produced and keeps plasma levels are very low. There is an ALDH2 variant ALDH2*2 with a single amino acid change decreasing Vmax 10-fold and increasing Km > 250 fold. Basically it's dead. It's almost impossible to find a homozygotic ALDH2*2 alcoholic

Why is acetaminophen a toxin and how is it detoxified?

Acetaminophen reacts with GSH, thereby depleting GSH cellular concentration in the liver. In the presence of ethanol: Acetaminophen is metabolized into NAPQI which is toxic GSH can neutralize NAPQI, but depletion of GSH can lead to accumulation of NAPQI Liver failure can ensue, particularly for individuals with existing liver damage. N-acetyl cysteine can help replenish GSH stores, antidote for acetaminophen poisoning.

What happens with a acetyl CoA carboxylase deficiency?

Acetyl CoA carboxylase is the rate-limiting enzyme in the synthesis of fatty acids that converts acetyl CoA to malonyl CoA. Malonyl CoA is an important factor for the synthesis of fatty acids as it elongates the fatty acyl chain by adding two additional carbons each cycle. Therefore fatty acid synthesis would be the primary process that is affected. Malonyl CoA is also an inhibitor of the CPT1 enzyme which regulates the uptake of fatty acids into the the mitochondria to be processed by beta-oxidation. No inhibition of CPT1 causes enhanced beta oxidation. Therefore, beta-oxidation of fatty acids would also be affected if there was a deficiency of acetyl CoA carboxylase

What enzymes in the fatty acid synthesis chain are induced after a high carbohydrate diet?

Acetyl CoA stimulates pyruvate carboxylase Pyruvate dehydrogenase, malic enzyme, citrate lyase, acetyl CoA carboxylase, fatty acid synthase and G-6-P dehydrogenase are also induced

What are microfilaments?

Actin filaments Composition: -Non-hollow polymers of the globular protein actin -Actin is an ATPase -Helical in structure (two chains wrapping around each other) -Roughly 7 nm in diameter Properties -Highly dynamic if not stabilized; undergo rapid bouts of assembly and disassembly -Huge array of configurations regulated by accessory proteins -Act as substrate for members of the myosin family of motors to move along and carry cargo -Unlike microtubules actin filaments do not have specific organizing centers like the centrosome and can be nucleated almost anywhere in the cell Structure -Polarized filament with barbed end and pointed end -Barbed end favored for assembly over pointed end -Myosin motors read the polarity and move toward one end or the other (most myosins move toward plus end) Functions -Concentrated in cell cortex for various functions -Cleavage furrow for pinching off cells in final stages of mitosis -Cell motility -Short-range organelle transport Contractility (in both muscle and non-muscle) 3 Actin isoforms: Alpha Beta Gamma Alpha actin is muscle specific Beta and gamma are found in most cells Helical structure bound by accessory proteins Actin must be ATP loaded for nucleation and polymerization

What are the purines?

Adenine and Guanine

Describe Yohimbine

Adrenergic α2-receptor antagonists Yohimbine previously used as aphrodisiac, erectile dysfunction; postural hypertension (off label). Veterinary use to reverse α2-agonist (xylazine) sedation Pharmacodynamics - sympathomimetics Oppose α2-inhibition of NE release ➠ ⬆ NE and 5-HT release **Increase blood pressure and heart rate Adverse effects CV, restlessness Mirtazapine ⬆ cholesterol Sedation with toxicity

What is Wernicke-Korsakoff syndrome?

Affects the hypothalamus and the thalamus and they may look atrophied on an MRI. Atrophy because these areas of the brain really need glucose to produce more ATP but they aren't getting any. Mammillary bodies may look shrunken on an MRI as well. Low thiamine is what's causing brain encephalopathy because its inhibiting the use of glucose Pyruvate dehydrogenase dysfunction

How are amino acids metabolized in the muscle?

After a high-protein meal, insulin promotes amino acid uptake and protein synthesis During fasting and other catabolic processes, there is a net degradation of protein and release of amino acids Muscle is a major site of glutamine synthesis (satisfying demand for amino acid during the post-absorptive state, metabolic acidosis, septic stress and trauma) Amino acid degradation accompanied by formation of alanine (glucose-alanine cycle)

What is the function of thiotransferase?

After beta-hydroxybutyrate and NAD+ is turned into Acetoacetate and NADH in a tissue that utilizes ketone bodies for energy, thiotransferase (Not in liver, also called succinyl CoA/acetoacetate CoA transferase which makes succinyl CoA into succinate) and succinyl CoA activates the ketone body by converting it into acetoacetyl CoA Thiolase can then be used to convert aceoacetyl CoA into 2 acetyl CoA Activation leads to loss of 1 ATP because succinyl CoA is reacting with acetoacetate instead of making a GTP Makes 23 ATP Acetoacetate Makes 26 ATP beta-hydroxy butyrate

Acyclovir and related drugs are non-toxic to uninfected cells. What prevents acyclovir from becoming a nucleotide analog in uninfected cells?

After intracellular uptake, it is converted to acyclovir monophosphate by virally-encoded thymidine kinase. This step does not occur to any significant degree in uninfected cells and thereby lends specificity to the drug's activity. Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase or viral DNA polymerase, altering substrate sensitivity

What are some drug-drug interactions involving beta antagonists?

Agent decreasing absorption (i.e., aluminum salts, cholestyramine & colestipol) Agents inducing hepatic enzymes (i.e., phenytoin, rifampin & phenobarbital, smoking) β- antagonists may impair clearance of other drugs (i.e., lidocaine) Antihypertensive effects of β receptor antagonists can be opposed by indomethacin and other NSAIDs

What are some agonists for GPCRs?

Agonists for GPCRs include neurotransmitters, hormones, light, tastants, odorants

Who is Liver Function tested?

Alanine Aminotransferase (ALT) -Formerly called serum glutamic-pyruvic transaminase (SGPT) - α-ketoglutarate + alanine ⇌ glutamate + pyruvate Asparate Aminotransferase (AST) -formerly called serum glutamic-oxaloacetic transaminase (SGOT) -Aspartate + ⍺-Ketoglutarate ⇌ Oxaloacetate + Glutamate In acute liver injury, i.e., viral hepatitis, both ALT and AST used as measure of degree of liver inflammation or damage

What are the amino acids released from muscle protein degradation?

Alanine and glutamine

Why is alkaline phosphatase tested?

Alk Phos or ALP Present in a number of tissues, including liver, bone, kidney, intestine, and placenta Each tissue contains distinct isoenzymes -Bone -Liver Often increased when bile ducts are blocked and when cancers spread to bones ALP isoenzyme analysis can pinpoint tissue of origin

How is the mitochondria targeted?

All Cells & Tissues Oxidative phosphorylation Apoptosis Cell/Tissue-specific Roles cholesterol metabolism amino & organic acid metabolism fatty acid beta oxidation sex steroid synthesis heme synthesis hepatic ammonia detoxification neurotransmitter metabolism Signal sequence (for import into the matrix) is often an amphiphilic alpha helix (charged amino acid residues are clustered in one side) •Signal recognized by specific receptors in mitochondria = TOM & TIM complexes (Translocase of the Outer and Inner mitochondrial membrane, respectively), which then actively import the proteins into the mitochondrion. Translocation is post-translational but the imported protein is kept unfolded prior to and during translocation by chaperone proteins. TOM and TIM complexes are multi-protein and contain recognition and translocase components (as also seen for Peroxins). The signal peptide is then cleaved to make the mature mitochondrial protein

What is the function of DNA polymerase?

All DNA Polymerases -Require a template -Require a primer (DNA or RNA) (no de novo synthesis) -Synthesize 5'→ 3' -Use dNTPs as substrate -Incorporate dNMPs into new DNA

Describe adrenergic receptors

All are G protein-coupled receptors A1: a1A, a1B, a1D. Gq-coupled, most drugs are not selective among the three. A2: a2A, a2B, a2C. Gi-coupled, most drugs are not selective among the three B: b1, b2, b3. Gs-coupled, most drugs are not selective among the three. Agonists and antagonists are used clinically

How has cancer evolved?

All cancers originate from a single cell Cancers follow a Darwinian path of evolution on a microscopic scale Tumors are genetically and phenotypically heterogeneous

What is RNA -seq?

Allele specific expression: prevalence of transcribed SNPs Identification and quantitation of alternatively spliced RNAs, novel transcripts and edited RNA Gene expression profiling, i.e. determining gene activity of all genes in cells under different conditions Single cell RNA seq: to identify heterogeneous cell populations in a given sample (e.g. tumor heterogeneity in a single biopsy).

Describe elastic fibers

Allow tissues to respond to stretch and distension Elastic fibers are the main components of elastic tissue Elastic fibers are responsible for elasticity, resilience, shape control. Found in walls of large blood vessel and ligaments. Desmosine and Isodesmosine are two uncommon amino acids in Elastin responsible for cross-linking elastic fibers and enable their stretch and recoil like rubber bands

Describe Methyldopa

Alpha-2 adrenergic agonist Pharmacodynamics ➱ sympatholytic α2 -selective ⇣ CNS sympathetic outflow via inhibition of presynaptic NE release Possible ⇣ NE release at peripheral presynaptic α2 Lower efficacy at peripheral postsynaptic α2 sites **Lowers blood pressure Pharmacotherapeutics: **Hypertension in pregnancy Adjunct for ADHD Adverse effects: Dry mouth, sedation, constipation Lupus-like syndrome Hypertensive crisis (sudden withdrawal)

Describe Clonidine

Alpha-2 adrenergic agonist Pharmacodynamics ➱ sympatholytic α2 -selective ⇣ CNS sympathetic outflow via inhibition of presynaptic NE release Possible ⇣ NE release at peripheral presynaptic α2 Lower efficacy at peripheral postsynaptic α2 sites **Reduces blood pressure, decrease in sympathetic tone Pharmacotherapeutics: *Hypertension, especially in urgent situations Adjunct for ADHD Tourettes Adverse effects: Dry mouth, sedation, constipation Hypertensive crisis (sudden withdrawal)

Describe Guanfacine

Alpha-2 adrenergic agonist Pharmacodynamics ➱ sympatholytic α2 -selective ⇣ CNS sympathetic outflow via inhibition of presynaptic NE release Possible ⇣ NE release at peripheral presynaptic α2 Lower efficacy at peripheral postsynaptic α2 sites (*selective α2A central agonist) Pharmacotherapeutics: **Hypertension Adjunct for ADHD Adverse effects: Sedation, constipation Hypertensive crisis (sudden withdrawal)

What is a type 1 error?

Alpha= False positive Probability an investigator is willing to accept of saying there is a difference when no difference exists (false positive) Reject the null hypothesis when it is true Probability of concluding a difference when, in fact, the null hypothesis is true

What is osteogenesis imperfecta?

Also known as brittle bone disease, this genetic disorder is characterized by fragile bones that break easily. The majority of cases are caused by a dominant mutation to type I collagen (COL1A1 or COL1A2) genes. OI affects ~ 50,000 people in the United States. People with mild OI may experience a few fractures and normal life expectancy while those with severe OI may experience hundreds of fractures and shortened life expectancy. There is currently no cure for OI but there are available treatments for the clinical management of patients with OI.

How many GAG's are needed to define a protein as a proteoglycan?

Although the brush-like structure is typical, it is not universal ie the presence of only 1 GAG is sufficient to define a protein as a proteoglycan

How are amino acids transported across the cell membrane?

Amino acids are transported across the cell membrane by Na+-coupled transporters Specificity: basic, dipeptides, aromatics etc. There are about 5 specificity groups. Same families of transporters are found in gut and kidney.

How is nitrogen turned into urea?

Ammonium is transferred to alpha-ketoglutarate to make glutamate and then released by glutamate dehydrogenase to relase ammonium to make urea

Why is blood urea nitrogen (BUN) tested?

Amount of urea nitrogen in the blood -Nearly all renal diseases can cause an inadequate excretion of urea. -The BUN is usually interpreted in conjunction with creatinine test.

How is pancreatic function tested?

Amylase Tests-Lipase(triacylglycerol acylhydrolases) Hydrolyze glycerol esters of long-chain fatty acids (triglycerides) sequentially into β-monoglyceride and two free fatty acids Serum amylase about half salivary and half pancreatic form- lipase more specific. -3X the upper reference range

What is the function of ARS?

An ARS is an enzyme that attaches the amino acid to the correct tRNA molecule in a process known as 'charging'. The amino acid is attached to the CCA sequence found at the 3' end of the tRNA and must correctly match up with the anticodon sequence associated with that amino acid. Each ARS represents one individual amino acid and will be able to charge ALL of the tRNAs that contain an anticodon associated with that amino acid. There are far fewer amino acids than three base pair combinations, and therefore several anticodons might code for the same amino acid. Often, these anticodons differ at the 3' position due to the 'wobble hypothesis'. Heterozygous individuals are symptomatic because the mutation has almost completely obliterated the function of the enzyme to transfer amino acids to the tRNA molecules. This impedes the ability of the cell to produce protein as the only functional enzyme is produced by the WT copy contained on the paired chromosome. The mutant enzyme effectively acts as a competitive inhibitor to the functional enzyme.

What is Glanzmann thrombasthenia?

An autosomal recessive bleeding disorder caused by mutations in the platelet integrins, which prevent aggregation.

What is argininemia?

An autosomal recessive disorder of the arginase 1 (ARG1) gene The last step in the urea cycle, the conversion of arginine + H2O → urea + ornithine, is done by arginase and that is the enzyme affected. With arginase damaged or missing, urea can't be produced normally and arginine and ammonia accumulates in the blood. Too much ammonia becomes toxic to the nerve cells and cause things like demyelination of neurons.

How do you analyze the structure and expression of genes and genomes?

Analysis of specific molecules: DNA Southern blotting PCR RNA Northern blotting RT-PCR Protein Western blotting Immunohistochemistry Global Analysis : DNA Genome sequencing SNP arrays RNA RNA seq Protein Proteomics

What is cholesterol used for?

An important precursor of steroid hormones A precursor of bile salts A major component in cell membranes and myelin sheath A regulator of membrane activities including cellular signaling

What is a case report?

Anecdotal Reports of Interesting Observations Unusual cluster of symptoms Departure from a normal pattern of known disease Repetitive disease occurrence among people with a specific exposure Cluster of observations in short time period or small geographic area New epidemic of known disease New disease occurrence New cause of existing disease

Does aneuploidy cause cancer?

Aneuploidy (numerical abnormality of chromosomes) is consistently seen in tumors The imbalance causes abnormal gene dosages; self-perpetuating by destabilizing disjunction, selection of aggressive variants Specific chromosomal abnormalities are consistently associated with some cancers "Philadelphia Chromosome" in CML

What do you use for the treatment of glaucoma?

Angle-closure: physostigmine (in combo with pilocarpine) Open-angle: physostigmine, demecarium (only after pilocarpine or carbachol)

What are the domains of the epithelium?

Apical domain exposed to the lumen or external environment Lateral domain in contact with neighboring cells by junctional complexes and adhesion molecules Basal domain attached to the basement membrane

What are Hassall's corpuscles?

Are Type VI ERCs wrapped concentrically, often keratinized. Secrete interleukins for T cell maturation.

What is the fate of proteins synthesized in the RER?

Are destined for secretion or incorporation into various subcellular organelles (lysosomes, ER, Golgi complex) or cellular membranes (ie, plasma membrane) Proteins that enter RER have signal peptides near N-termini These signal peptides don't have common amino acid sequence, but contain several hydrophobic residues ; are 15-30 aa long.

Describe mast cells

Arise from multipotent hematopoietic stem cells in the bone marrow Cirulate in undifferentiated state Oval to round cells with microvilli Nucleus centrally located, surface express IgE receptors Cytoplasm filled with dense basophilic secretory granules containing heparin, histamine, vasoactive mediators & chemotactic factors. Release of chemical mediators promotes allergic reactions known as immediate hypersensitivity reactions.

What causes albinism?

Arises from heritable defect in tyrosinase activity. Leads to lack of pigment (melanin). Also photosensitivity, visual impairment, due to role of melanin in development of iris/retina/optic nerve.

What happens in arsenic poisoning?

Arsenic allosterically can inhibit PDH through binding to the thiol groups in the E3 subunit which will in turn cause a build up of lactate because pyruvate cannot be turned into acetyl CoA and NAD+ still needs to be regenerated (and it can't be regenerated from ox phox) so it goes through anaerobic respiration, which will cause acidosis by formation of lactic acid. Arsenic binds a thiol group on lipoic acid on pyruvate dehydrogenase, which inhibits the enzyme action. A thiol group on the chelating agent DMSA binds to arsenic and makes it water soluble and nontoxic so that it can be dispelled from the body in the urine. Arsenic will produce arsenate (oxidized derivative) (AsO4) to inhibit the oxidative phosphorylation of ADP to ATP by ATP Sythase. This will uncouple the Hydrogen gradient from the production of ATP.

How is the polyA tail added?

As RNA polymerase continues to transcribe the DNA, enzymes cleave the transcript (hnRNA) at a point 10 to 20 nucleotides beyond an AAUAAA sequence, just before a run of Us (or Gs). Approximately 250 adenine nucleotides are then added to the 3'-end of the hnRNA, one at a time, by poly(A) polymerase. A poly (A) sequence is added one nucleotide at a time to the 3'-end by poly(A) polymerase. It should be noted that not all eukaryotic mRNAs contain a poly (A) tail.

What is more easily absorbed the ionized or the non-ionized version?

As a general rule, the non-ionized form of the drug is more lipid soluble and therefore, better crosses membranes The ionized form is most likely excreted

How does sepsis differ from hypercatabolism?

As sepsis progresses severe hepatic dysfunction leads to hypoglycemia and decreased glucose production Impaired ketogenesis and the activity of lipoprotein lipase is supressed-Hyperlipidemia

Describe Transient receptor potential channels (TRP channels)

At least 28 members Subdivided into 6 subfamilies based on homology: classical (TRPC), vanilloid receptors (TRPV), melastatin (TRPM), polycystins (TRPP), mucolipins (TRPML), and ankyrin transmembrane protein 1 (TRPA). TRPV: activated by capsaicin, active ingredient in hot pepper. Capsaicin is used topically to treat muscle and joint pain. Very diverse in its method of activation: Some constitutively open, while others are gated by voltage, intracellular Ca2+, pH, redox state, osmolarity, and mechanical stretch. Vary according to the ion(s) they pass, some being selective for Ca2+ while others are less selective, acting as cation channels.

What is the name for vitamin C and what does it do?

Ascorbic acid Cofactor for for prolyl- and lysyl-hydroxylases. Increases absorption of iron. Required for epinephrine synthesis, collagen synthesis, degradation of Tyr, absorption of dietary iron, and adrenal cortex hormone synthesis.

Where does the N for AMP and GMP come from?

Aspartate and glutamine

Which amino acids make up purines?

Aspartate, FH4 (Ser/Gly), CO2 make up peripheral carbons Glycine makes up the purine backbone including a nitrogen Glutamine provides the other 2 nitrogens

What inhibits cyclo-oxygenase?

Aspirin, acetaminophen, and other nonsteroidal anti-inflammatory drugs

What is immunohistochemistry?

Assesses protein abundance in cells or tissue, including disease tissue. Very little material is needed. Need highly specific monoclonal antibodies for this analysis.

What do babies reach pulmonary maturity?

At around 35 weeks when phosphatidyl choline reaches a high peak relative to sphingomyelin

Describe voltage gated sodium channels

At least 9 members. largely responsible for action potential creation and propagation All are blocked by local anesthetics Alpha subunit is formed from a single polypeptide that consists of four domains (I-IV), each of which has six transmembrane segments (S1-S6). The S4 of each domain contains positively charged arginines that are primarily responsible for voltage sensing The S5-pore loop-S6 region forms the pore domain through which sodium ions flow. The β-subunits, β1/3 and β2/4, are single transmembrane proteins that have an immunoglobulin-like extracellular domain that co-assembles with the Nav α-subunit.

How does long term potentiation occur?

At resting membrane potentials, the pore of NMDA receptor is occluded by Mg++. When glutamate binds to AMPA receptor, the pore is open allowing Na+ influx which causes depolarization. Depolarization in turn leads to repulsion of the Mg2+ from NMDA receptor out into the extracellular space, allowing the pore to pass Na+ and Ca++. Ca2+ influx leads to persistent modifications in the strength of synaptic transmission. This results in a long-lasting increase in EPSP size underlying long-term potentiation (LTP). LTP is the basis of learning and memory.

What are the cholinergic antagonists?

Atropine Pralidoxime Scopolamine Homatropine Tropicamide Ipratropium Benztropine Dicyclomine Glycopyrrolate Tolterodine Oxybutynin Darifenacin Trimethaphan Botulinum toxin

What is Marfan syndrome?

Autosomal dominant Patients exhibit numerous elastin-associated problems •Spontaneous pneumothorax - escape of air into pleural space •Dislocation of the lens within the eye •Numerous cardiovascular problems (heart murmur, aortic aneurysm) Caused by genetic defect in Fibrillin (depicted above). Fibrillin forms ubiquitous microfibrils Binds many growth factors; Fibrillin mutations in Marfan Syndrome lead to a failure to bind TGFβ. Resultant increases in TGFβ lead to stimulation of cells that release proteases to degrade elastin fibers. Most apparent symptom is Elongated bones (not related to elastin). Arachnodactyly

What are the main functions of the epithelium?

Avascular Cover exterior body surface Line internal cavities Forms secretory portion of glands Receptors for special senses

What happens to bilirubin in a bile duct obstruction

Bile duct obstruction, causes bilirubin to accumulate; can results in bilirubin excreted in urine instead of feces Urine bilirubin will be elevated

How do B cells mature in the bone marrow

BM stromal cells produce interleukin-7 ......promotes maturation of B cells B cells express immunoglobulin receptor (IgM or IgD) B cells also express immunoglobulins Igα and Igβ with an ITAM-intracellular domain (ITAM=immunoreceptor tyrosine-based activation motif) Self-antigen with strong binding affinity to two or more receptor molecules induces apoptosis of the B cell. Self-antigen with weaker binding affinity results in maturation of the B cell, which enters into the blood

What is the embden-meyerhof-parnas pathway?

Bacteria use the Embden-Meyerhof-Parnas pathway to convert glucose to pyruvate. 2 high energy phosphates are consumed: o ATP o high energy phosphate PEP from the phosphotransferase system (PTS) system transfer of phosphate from PEP to the sugar during transport (group translocation) 4 ATP are produced. NADH+H+ is produced and must be oxidized by either reduction of pyruvate (fermentation/oxidation) or by being used in an electron transport system (respiration).

What is the structure of DNA in bacteria?

Bacterial DNA is largely free of proteins or other structures and tethered to the membrane.•Bacterial DNA is largely free of proteins or other structures and tethered to the membrane.

What are metacentric, submetacentric and acrocentric?

Based on the position of the centromere with respect to the arms chromosomes are classified as Metacentric: has the centromere near the middle of the chromosome (1,3,16,19,20) Submetacentric: has the centromere away from the center but not at the ends Acrocentric: has the centromere at the end of the chromosome (13,14,15,21,22,Y)

What is the basement membrane made out of?

Basement Membrane: Basal Lamina - Collagen IV, Laminin, nidogen/endactin, perlecan Reticular Lamina - Connective tissue made from Collagen III fibers

What is a complete metabolic panel?

Basic -Sodium -Potassium -Chloride -Carbon Dioxide Content -Blood Urea Nitrogen -Creatinine -Glucose Plus -Total Protein -Albumin -Total Bilirubin -Total Calcium -Alkaline Phosphatase -Aspartate Aminotransferase (AST) -

What are cultures used for?

Because only a small percent of the bacteria can be cultured and many different kinds of growth medium are used, the use of culture to characterize microbiota is limited Culture techniques are useful for screening for carriage of pathogens as part of the microbiota (e.g. MRSA)

What does it mean when an organism is auxotrophic?

Because they are highly adapted to live as commensals in the human microbiota many bacteria are auxotrophic and cannot synthesize essential cellular components Scavenged from lysed human cells or other bacteria: oamino acids oNAD nucleotides

Describe FGF

Belongs to the FGF family of proteins that are involved in proliferation and differentiation of several cell types. It binds to receptors belonging to the tyrosine kinase family. FGF is a group of growth factors. There are at least 19 distinct members of the FGF family, which interact with at least 4 distinct types of cell-surface receptors. Growth factors (GF) are small protein chains, commonly known as polypeptides that bind to cell surface receptor sites and exert actions directly on the target cells.

What is required for TG digestion in the small intestine?

Bile salts, pancreatic lipase, co-lipase, bicarbonate

What does IgA do and where is it found?

Bind to epithelial cells Passive Immunity in neonates Protects mucosae- Prevents pathogens from adhering to mucosal surfaces

What does IgM do and where is it found?

Bind to macrophages and neutrophils Activates phagocytosis and complement cytotoxic response Oponization

Describe smooth muscle cells?

Bindle or sheets of elongated Cells Communicate via gap junctions Enclosed in reticular fibers and basal lamina Shorten and contract Closely packed Organized in bundles or sheets Tapered ends 20-500uM long, 5-10um wide Hypertrophy and hyperplasia Smooth Muscle One Direction on One Side Opposite Direction on the Other Side Staggered in parallel No central bare zone Allows for thin filament to be pulled over the entire length of the thick filament Contractile filament bundles are oriented obliquely to the long axis of the cell. Their contraction shortens the cell.

What does the initiator do?

Binds and unwinds DNA and recruits replication proteins such as the helicase

How is UDP-metabolized?

Biosynthetic precursor for: Glycogen Lactose UDP-Glucuronate Carbohydrate chains on glycolipids, glycoproteins and proteoglycans

What is blood serum?

Blood plasma without clotting factors

Describe bone marrow

Bone marrow consists of: 1)Developing & mature blood cells 2)Fat cells 3)Sinusoids 4)Stroma (connective tissue) FUNCTIONS: 1)Store mature blood cells 2)Develop and release new blood cells 3)Destroy old RBCs 4)Store iron from displaced hemoglobin Blood cell formation occurs extravascularly - in the spaces between sinusoids. The stroma, which supports the forming blood cells, mature blood cells and sinusoids (blood vessels), consists of stromal (reticular cells), reticular fibers, fibronectin, hemonectin, laminin, various collagens, proteoglycans, ground substance, etc. Fibronectin, laminin and hemonectin, which bind to receptors on developing blood cells, may anchor them to the matrix. BM consists of two microenvironmental domains, the vascular niche and the endosteal niche that provide soluble factors (cytokines) and cell-mediated interactions which regulate the renewal, differentiation and quiescence of HSCs. The vascular niche consists of the blood vessels and surrounding stromal (reticular cells), mesenchymal stem cells, adipocytes, macrophages and endothelial cells. The endosteal niche includes osteoprogenitors cells, osteoblasts and osteoclasts and is regarded as a site for long-term storage of quiescent HSCs. These cells produce multiple hematopoietic cytokines such as G-CSF, M-CSF, GM-CSF, and various interleukins.

What is in bone marrow?

Bone marrow has a framework of reticular CT. Islands of developing & mature blood cells (red & white). Megakaryocytes, fat cells, sinusoids, macrophages, etc.

How is NADPH produced?

Both the malic enzyme pathway and the pentose-phosphate pathway can lead to the production of NADPH.

What does 2,3-bisphosphoglycerate do?

Bound by hemoglobin and lowers the affinity for O2 If there is an increase in BPG in the blood hemoglobin will have a lower affinity for O2 and will release more O2 into tissues

What is the origin of the preganglionic parasympathetic nerve fibers and what general areas do they supply?

Brain stem nucleii of cranial nerves III, VII, IX, and X supply visera in the head, thorax and part of abdomen. Parasympathetic nerves from spinal cord segments S2-S4 supply pelvic, perineal, and some abdominal organs.

What happens during the second step of degradation of branched chained amino acids?

Branched chain dehydrogenase All three alpha-keto BCAA's are oxidized by a single alpha-keto acid dehydrogenase It is a multi-subunit enzyme, homologous (i.e. similar) to pyruvate- and ketoglutarate-dehydrogenases Site of defect in maple syrup urine disease (MSUD) Also present in liver, but appears to be of metabolic importance mainly in muscle. These require thiamine, lipoate, CoA, FAD, NAD Produce CO2

What is the structure of proteoglycans?

Brush-like structure (left) is typical of most proteoglycans Typically, 1 polypeptide is found in the center, while multiple GAGs point outward in all directions This shape reflects the negative charges of GAGs ie the sugar chains repel each other

What are the selective adrenergic beta 2 antagonists?

Butoxamine

How is arachidonic acid released from the cell membrane?

By phospholipase A2 or phospholipase C

How is PKF2 regulated?

By serine phosphorylation status PFK2 kinase active when dephosphorylated by an insulin-dependent pathway PFK2 phosphatase active when phosphorylated by a glucagon/catecholamine-dependent pathway Liver PFK2 has a single Ser that regulates both functions in mutually exclusive manner (on/off binary). Ser m-issing in muscle isoform

What are syndecans?

Cell surface co-factors Syndecans function as modulators of ECM-cell interactions, ligand-receptor interactions. Also function as regulators of blood coagulation. Critical roles in development and inflammation. Differences in GAG structure contribute to pathological situations (cancer, liver fibrosis).

What is the function of triacylglycerol lipase?

Fat mobilization from adipocytes Breaks down triacylglycerol to glycerol (to liver) and fatty acids (to liver and other tissues) Can be stimulated by glucgon through adenylate cyclase or caffeine

Can fatty acids be converted into glucose?

Fatty acid CANNOT be converted into glucose

What are some pharmacogenetics?

CAD/Stents/TIA: Clopidogrel (CYP2C19) Afib/Valve: Coumadin (CYP2C9+VKORC1) Hypertension/Arrhythmia: Beta blockers, Ca Ch Blockers, ARBs (CYP2D6, CYP2C9, CYP3A4/5) Hyperlipidemia: Statins (CYP2C9, CYP3A4, CYP3A5, SLCO1B1)

What are the major differences between fatty acid oxidation and synthesis?

CO2 required for fatty acid synthesis Fatty acid oxidation uses the coenzymes FAD, NAD+ and carnitine Fatty acid synthesis uses the coenzymes NADPH and biotin

Describe catechol-o-methyl transferase

COMT inhibitors: used with DOPA for treatment of Parkinson's disease V158M single nucleotide polymorphism is associated with reduced dopamine metabolism. It may be related to altered emotional processing and executive functions.

What are the vesicular trafficking proteins?

COP1: Golgi-to-Golgi; cis-Colgi-to-ER COPII: ER-to-cis-Golgi Clathrin: trans-Golgi-to-lysosomes; plasma membrane-to-endosomes COP: coatomer proteins

What are the differences between carbamoyl phosphate synthetase 1 and 2.

CPS1 is part of the urea cycle and is located in the mitochondria It gets nitrogen from NH3 and is regulated by NAG+ CPS2 creates pyrimidines and is located in the cytosol It gets nitrogen from glutamine and is positively regulated by PRPP and negatively regulated by UTP

What are beta antagonists used for?

CV: angina, hypertension, cardiac arrhythmias, CHF Pheochromocytoma (in addition to 𝞪-blocker) Portal hypertension/variceal bleeds Ocular hypertension/open-angle glaucoma* Migraine prophylaxis Hyperthyroidism Catecholamine-induced tremor Situational anxiety Substance abuse withdrawal

What is clopidogrel?

CYP2C19 Clopidogrel (Plavix) is a PRODRUG Active metabolite elicits the desired antiplatelet response ~30% of patients have deficiency in CYP2C19 Decreased amount of active metabolite High on-treatment platelet reactivity Different dosing needed for different gene variants

What is the 2nd stage of fracture healing?

Callus Formation Soft Callus Formation: -Development of a fibrous and cartilaginous callus (collar) that surrounds the fracture -Callus progressively widens and stiffens to ultimately immobilize the fractured ends of the bone Hard Callus Formation: -Initial bone formation in the callus -Endochondral ossification of cartilage -Intramembranous ossification directly on bone surface -Proportions of ossification processes depends on fracture displacement (and fixation)

Besides sphingosines, what can ceramide be created into?

Can be converted to a galactocerebroside through UDP-Galactose Can be converted to a glucocerebroside through UDP-Glucose and then to a ganglioside through other UDP-sugars and CMP-NANA

What happens at each of the carbons on the DNA base?

Carbon 1': mediates the N-glycosidic bond to the nitrogenous base. Important for fidelity. Carbon 2': OH in RNA and H (deoxy) in DNA. DNA more stable. RNA hydrolyzes in an alkali environment. Carbon 3': An OH is essential for replication. Nothing else can be extended. Carbon 5': Phosphates are bound. Hydrolysis of the γ and β phosphates provides the energy required for the NMP addition reaction.

How doe CO2 bind to hemoglobin?

Carbon dioxide is carried by hemoglobin by reversible covalent attachment to the amino termini, forming carbamates. Hemoglobin carbamates are not especially stable, but they do favor the deoxygenated form of hemoglobin (i.e. they promote the release of oxygen). This is distinct from the Bohr effect. CO2 does not occupy the heme Fe2+ (CO does, though). Only some of the CO2 generated in tissue is carried back to lungs as carbamate; the majority is carried in blood (serum) as HCO3-. Again: CO2 is NOT on heme! In contrast, the poison (and signaling molecule) CO does bind to Fe2+, as does NO (nitric oxide, signaling molecule). Cyanide binds well to cytochrome c oxidase Fe, or to met-hemoglobin Fe3+. This is why cyanide and CO are bad for you (compete with oxygen).

How is cysteine metabolized?

Carbons for cysteine are provided by serine; sulfur from methionine. Degradation of cysteine produces pyruvate, nitrogen(urea) and sulfate. Sulfate can generate sulfuric acid and is eliminated in the urine Sulfate also used to generate 3'-phosphoadenosine-5'-phosphosulfate (PAPS) which is used in glycosaminoglycan (heparin) and proteins Cys makes sulfate and pyruvate (glucogenic), SO4 di-anion needs to be excreted Aside from use in proteins, Cys is used to form glutathione (used in drug metabolism) and taurine (major component of bile)

What are the mixed Beta adrenergic antagonist/agonists?

Celiprolol Carteolol

How do you isolate or clone individual genes or gene products (cDNAs) that encode for proteins?

Cell-based DNA cloning (old school, early 70's). Use E. Coli as the host to isolate and amplify from a single source. PCR based cloning (more recent, mid 80's). Order from catalogue if available (current).

What is Stratified squamous epithelium keratinized/cornified?

Cells at the surface are dead and have lost their nuclei and tend to peel off Cells in the outer layers contain abundant keratin Found in skin

What are the consequences of an impaired Na+/K+ pump?

Cells lose K+ Cells gain Na+ Cells swell Digitalis, by slowing the pump, causes increased intracellular Na+ concentrations, lessening the energy for Na+/Ca2+ exchange. As a result, the intracellular Ca2+ concentration increases. The pump is electrogenic - it contributes to the membrane potential because it pumps 3 positive ions out for every 2 it pumps in. This "pump current" is hyperpolarizing. May change the resting potential by as much as 10-20 mV. May be important in some kinds of smooth muscle.

What are the components of the connective tissue?

Cells: Fibroblasts Adipocytes Mast cells Adult stem cells Lymphocytes Plasma cells Eosinophils Neutrophils Basophils Monocytes Macrophage Mast cells Fibers in the EM: Collagen fiber system Collagen Fibers Reticular Fibers Elastic fiber system Elastic Fibers Ground substance in the EM: Glycosaminoglycans (GAG's) Proteoglycans Structural Glycoproteins (Fn,Laminin) Water

What evidence is there that cancer is a genetic disease?

Cellular level: cancer cells divide and produce more cancer cells Chromosomal level: recurrent cytogenetic abnormalities are found in some cancers Familial level (pedigrees): there are heritable cancer syndromes Gene level: mutations in genes can drive proliferation

What is the function of sphingomyelin synthase?

Ceramide + Phosphatidylcholine goes to Sphingomyelin + DAG group

Why is chloride tested?

Chloride is the major extracellular anion Hyperchloremia and hypochloremia are rarely isolated phenomena - Usually part of shifts in sodium or bicarbonate to maintain electrical neutrality

What enzyme converts a cholesterol ester to a cholesterol

Cholesterol esterase

Describe Pralidoxime

Cholinergic antagonist Regenerates cholinesterase and muscarinic and nicotinic receptors **Doesn't reach into CNS so you need atropine for that

What are the adrenergic alpha 2 agonists?

Clonidine Brimonidine Methyldopa Guanfacine

What are different types of vectors/plasmids?

Cloning vectors: Phagemids, cosmids, bacterial artificial chromosomes, yeast artificial cosmids: used for cloning and sequencing of larger DNA pieces and for functional studies. Expression vectors: can do all kind of things, expression in bacteria to make recombinant proteins and in mammalian cells for functional studies. Vector contain promoter that allow for expression of downstream sequences in various host organisms and other components that provide useful properties (example to follow). Gene targeting vectors: used to knock-out genes in cells via homologous recombination.

What different roles do different types of collagens play?

Collagen 1- Fibril forming collagens , most common Collagen 9-Connects collagens to cells and other matrix components Collagen 10- Produced by chondrocytes, required for normal bone growth Collagen 4- Unique to basement membranes Collagen 6- Associated with muscular dystrophy Collagen 7- Connect epidermal BM with dermal connective tissue Collagen 17- Expressed in connective tissue-producing cells Collagen 18- Proteoglycan expressed in endothelial and epithelial cells

How do competitive and non-competitive antagonists affect a drug?

Competitive antagonist decreases the potency EC'50= 1 + [I] EC50 Ki EC50 - agonist concentration EC'50 - agonist concentration in the presence of antagonist [ I ] - fixed concentration of antagonist Ki - affinity of the antagonist for the receptor Non-competitive antagonist decreases the efficacy Degree of competitive antagonist inhibition depends on its concentration. The response in the presence of the antagonist is dependent upon the [agonist]

How are differentiated cells maintained?

Complex supporting apparatus to maintain the primary specialized cell type: keratinocytes, melanocytes, contractile muscle cells, secretory gland cells, etc. Different cell types (same genome) coexist in the same environment Cell memory: Differentiated cells "remember" their essential characteristics in a novel environment. Modulation by the environment: Changes in the environment modulate the differentiated state of some cells (i.e.: fibroblasts). The majority of adult tissues are composed of a number of distinct irreversibly determined cell lineages. Largely, differentiated cells do not transform into each other.

What are microtubules?

Composition -Polymers of tubulin dimers made up alpha-tubulin and beta-tubulin -Tubulin is a GTPase -Hollow with an outside diameter of 24 nm -Accessory proteins called microtubule-associated proteins (MAPs) stabilize and space the polymers and regulate interactions between cytoskeletal elements Properties -Highly dynamic if not stabilized; can undergo rapid bouts of assembly and disassembly -Act as substrate for microtubule-based motor proteins to transport cargo (e.g., organelles) Structure -Polarized polymer with a plus-end and a minus-end -Plus end is dynamic (lengthens and shortens) -Motor proteins read the polarity and move to one end or the other of the microtubule Functions -Make up the mitotic spindle -Provide railways for organelle transport in most interphase cells -Key determinant of cell shape -Very important in neurons for cell shape and axonal transport -Provide the backbone for cilia and flagella Microtubules are Composed of 13 (+) Protofilaments Protofilaments are 'stacks' of tubulin dimers

What is mean cell hemoglobin concentration?

Concentration of hemoglobin per RBC Calculated as HGB/HCT Reference range 32 - 36 g/dL Of little clinical or diagnostic use

What is conduction velocity and what are its determinants?

Conduction velocity is the speed of an action potential - how fast it travels down the axon (m/sec) Velocity ∝ l / t, where t is time constant, l is length constant Time constant (t ): The time at which it reaches 63% of the final voltage is called the time constant. It is a measure of how rapidly a voltage disturbance settles down. t = Rm Cm The length constant (l): the distance where the voltage is only 37% of that at x=0. l describes how far along the axon a voltage disturbance is felt. -In both types of axons, increasing diameter will lead to increased conduction velocity.

What are does petidoglycan do in bacteria>

Congers shape and arrangement Basic bacterial shapes: cocci bacillus vibrio fusiform (tapered ends) spirochete (e.g. Treponema) filamentous (e.g. Streptomyces) pleomorphic (e.g. Corynebacterium) Basic bacterial arrangements: diplo tetrad sarcinae strepto- staphylo-

What are conjugative transposons?

Conjugative transposons encode type IV secretion systems (T4SS) Cut and paste transposons with a circular intermediate that move by conjugation They are commonly referred to as ICE (integrative and conjugative elements) They can encode virulence factors and antibiotic resistance genes (accessory genes) Recombination is the excisase and integrase

What does villin do?

Connects actin to the membrane

How does pyruvate kinase function?

Converts phosphoenolpyruvate (PEP) to Pyruvate+ATP Substrate Level Phosphorylation Irreversible 4 PK isoforms PKM2 ubiquitously expressed while the others show tissue specific expression (PKM1, muscle/brain; PKL, liver; and PKR, rbc) PKM2/PKR activated by F-1,6-P and inhibited by ATP and alanine PKR: deficiency results in hemolytic anemia. PKM2: insulin-mediated increase in gene expression. PKL: insulin-mediated dephosphorylation stimulates PKL: glucagon/catecholamine-mediated Ser phosphorylation inhibits

What are phosphoglycerides?

Coplanar C1 and C2 are the first and second carbon in the acyl chain counting from the carboxyl carbon. R is an acyl chain containing varying numbers of carbons and double bonds. Sphingolipids: Derivatives of ceramide

What cells are located in the medullary cords and sinuses?

Cords: lymphocytes, macrophages, APCs, reticular cells Sinuses: processes from macrophages and reticular cells, slow-moving lymph, transformed (cancer) cells

What are the two types of covalent crosslinks in collagens?

Covalent bonds in collagen are formed between lysines that come in close proximity using either of the schemes outlined above Bonds form both within 1 triple helix and between adjacent triple helices The allysine route predominates in skin, cornea and sclera The hydroxyallysineroute predominates in bone, cartilage, ligaments and tendons

What is articular cartilage?

Covers the articular surfaces of bones Lacks a perichondrium Diffusion of oxygen and nutrients from the synovial fluid

What are the analytic case designs?

Cross-Sectional Survey Case-control Study Cohort Study Clinical Trial

How are second messengers removed?

Cyclic AMP and cyclic GMP phosphodiesterases - targets of drugs Calcium - pumps - to storage sites and to extracellular medium Diacylglycerol - converted back to phosphatidyl inositol IP3- degraded by phosphatases

What are pyrimidines?

Cytosine, Thymine, and Uracil

How is pyrimidine synthesized?

De novo pyrimidine synthesis starts with aspartate Note carbamoyl phosphate. It is cytoplasmic, and gets N from glutamine, NOT NH4. CPS-II (CPS glutamine) is cytoplasmic, regulated by UTP (-), and PRPP (+). Pyrimidine atoms derive from Asp, Gln FH4-C1 is used to make dTMP

Describe proteosomes

Deal with proteins as individual molecules (lysosomes digest bulk material) Recognize proteins with ubiquitin molecules

How is histidine metabolized?

Deamination Break imidazole ring; FIGLU Donation of formimino group (CH=NH) to FH4 Deamination: Methylene-FH4 etc.

What are the components of the cytoskeleton?

Microfilaments: made of actin, diameter (d) ~ 7 nm (red) Intermediate filament: made of certain proteins, d ~10 nm Microtubules: polymers of tubulin, 50 mm long, d ~25 nm (green)

How do you clinically manage pediatric tumors?

Decide when presentation of cancer predisposition warrants further investigation How to discuss this with the family How genetic testing helps in managing the patient and the extended family •Retinoblastoma •von Hippel-Lindau •Familial adenomatous polyposis •Multiple endocrine neoplasia types 2A/2B Genetic testing is the standard for management of the affected individual and at-risk family members, for disease surveillance or prevention

What is Duchenne Muscular Dystrophy (DMD)?

DMD is caused by a mutation at the Xp21 site on the X-chromosome -This part of the human genome encodes for the sarcolemmal protein dystrophin Impairs function of skeletal muscles, also cardiovascular and respiratory systems Dystrophin-associated protein (DAP) complex -Dystrophin -Dystroglycan (2 subunits) -Sarcoglycan (6 subunits) Function is to reinforce and stabilize the sarcolemma during the stress of muscle contraction -Muscle cells transmit large forces to tendons Resulting fragile membrane is subject to tears/damage and cell death -Tears in membrane result in altered Ca2+ homeostasis

How does DNA polymerase distinguish deoxyribonucleotides and ribonucleotides?

DNA polymerases distinguish deoxyribonucleotides from ribonucleotides very efficiently via steric exclusion of rNTPs from the active site

What are some sources of anemia?

Decreased production of red blood cells: Iron deficiency -> microcytic anemia. Folate/B12 deficiency -> megaloblastic anemia. Increased loss (including destruction) of rbc: Bleeding (incl. ulcer, tumor) Immune hemolysis Sickle cell anemia Pyruvate kinase or hexokinase deficiency Glucose 6-phosphate dehydrogenase deficiency

What are issues present in an LDL receptor mutation?

Decreased transcription of receptor A decrease in LDL intracellular trafficking Decreased incorporation into cell membrane A decrease in LDL binding Abnormal endocytosis Increased plasma cholesterol Premature atherosclerosis

What is Fructosuria?

Deficiency of hepatic fructokinase. A benign, asymptomatic metabolic anomaly.

What is the function of sphingomyelinase?

Degrades sphingomyelin to phosphatidylchiline and cermide

What is ANGELMAN SYNDROME?

Deletion (15q11 to 15q13) of MATERNAL chromosome 15 -Deficient expression of UBE3A 1/10,000 to 15,000 births No obvious birth defects Developmental delay Children learn to walk but usually have unsteady or clumsy gait with jerky motions The child smiles and laughs frequently regardless of circumstances Easily excited personality and hand waving or flapping motions, formerly termed "happy puppet" syndrome In normal individuals, UBE3A is expressed from both the paternal (blue) and maternal (magenta) chromosomes 15 in most tissues. In neurons, the paternal UBE3A allele is silenced by the process of genomic imprinting. As a result, only the maternal UBE3A allele is expressed in neurons from normal individuals. In the case of AS, the maternal UBE3A allele is absent (deletion) or inactivated (mutation) and only the paternal allele is expressed in most tissues. UBE3A is not expressed in AS brain.

What is WAGR SYNDROME?

Deletion (del 11p13) Wilms' tumor Aniridia -Children born without an iris Genitourinary (GU) malformations Severely reduced cognitive function (mental Retardation)

What is CRI DU CHAT SYNDROME?

Deletion (del5p) Translates from French as "cry of the cat." Affected infants and children have a distinctive cry that sounds like that of a cat Microcephaly -Moderately to severely reduced cognition Cleft lip and palate Widely spaced eyes (hypertelorism)

What are sphingolipids?

Derivatives of ceramide When phosphorylcholine is linked to -OH on C1 of ceramide, the compound is called sphingomyelin. When galactose is linked to -OH on C1, it is galactocerebroside. When an oligosaccharide is linked to -OH on C1, it is called ganglioside. NANA = N-acetylneuraminic acid; GalNAc = N-acetylgalactosamine The allylic OH and the carbons in the trans double bond are coplanar. Atoms involved in the amide bond are coplanar. An acyl chain with varying chain lengths and degrees of unsaturation A hydrocarbon chain with 15 carbons

What is the hardy-weinberg equilibrium?

Describes frequency of alleles in a population Two-allele system (normal and variant allele) Frequency of "A" allele out of all chromsomes is p Frequency of "a" allele out of all chromsomes is q Frequencies of diploid genotypes (individuals) are: P2= AA, 2pq= Aa, and q2=aa Frequencies remain stable from generation to generation in a large stable population with random mating

Describe desmosomes

Desmosome ("Spot weld") Desmosome, specialized structure for cell-to-cell adhesion Localized spot-like adhesions, randomly arranged on the lateral sides of plasma membranes (not a continuous structure around the cell) Desmosomes form super strong attachments The protein components are attached to intermediate filaments

Describe natural killer cells

Destroy virus-infected and tumor cells. Recognize cells lacking self-MHC Not dependent on Ag activation Express CD56 receptors, activating and inhibitory receptors Excess of activated ligand

What are the different types of collagen?

Determined by the nature of the alpha chains in the tropocollagen molecules Type 1: Fibril forming collagen, Dermis, Tendon, Bone, Fibrocartilage, Resistance to tension Type 2: Fibril forming collagen, Hyaline cartilage Intervertebral disc, Resistance to Pressure Type 3: Fibril forming collagen, Reticular Connective Tissue, Maintenance of expansible organs Type 4: Network forming collagen, Basal Lamina, Support delicate structures and filtration Type 7: Anchoring Collagen, Basal Lamina, Connect collagen fibers to basal lamina

What is the treatment for CML?

Development of a tyrosine kinase inhibitor for treatment of CML Lead compound identified as PKC inhibitor. Modification and re-screening against a variety of kinases. Identified compound that could block tyrosine kinases (namely abl, KIT, and PDGF). Modified for solubility and oral viability. Great selectivity towards BCR-ABL: only 90 tyrosine kinase in the genome. However, structure of ATP binding domain very similar as evolved from single gene. Gleevec preferentially inhibits BCR-ABL, KIT and PDGF, which is excellent specificity. Preferentially kills BCR-ABL positive cells: preferentially destroyed tumor cells harboring BCR-Abl fusion in culture and in animal models at low concentrations. Pharmokinetics-oral availability and stability of drug in blood. Gleevec is stable. Metabolism-how the drug is broken down in liver ; good variability between individuals. In the case of Gleevec, the breakdown product is also active against the kinase. Relapse rate after 7 years in CML: 81% in remission with 90% survival.....thus still a problem for 20% Western blot analysis revealed that cells resistant to Gleevec had restored tyrosine phosphorylation of BCR-ABL substrates. Sequence analysis of PCR product revealed mutations in the kinase domain of BCR-ABL. Cells transduced with recombinant viruses expressing these mutants displayed resistance to Gleevec. Structure studies using recombinant protein revealed the nature of how these mutation affect binding to Gleevec and not ATP. Generation of new drugs: one being in the same class as Gleevec (Nilotinib), just binds better and one in a different class (Desatinib) that are potent inhibitors to mutant BCR-ABL. Desatinib FDA approved based on good response in Gleevec resistant CML (54% partial response, 25% stable disease).

How do you strip DNA of histones?

Dextran sulfate and heparin

Describe T-cells

Differentiate in thymus to produce: Helper cells OR Cytotoxic cells Respond to cell bound Ags presented by specific molecules Kill intracellular pathogens Adaptive Immunity Two types of T cells: both have TCR and co-receptors Helper T cells (TH) CD4 and CD3: stimulate nearby B cells to produce antibody, call in phagocytes, activate other T cells. Cytotoxic T cells (TC) CD8 and CD3: directly kill infected cell.

How are diffusion and osmosis different?

Diffusion means dissolving in the phospholipid bilayer. Osmosis means moving through membrane pores (aquaporins) as hydraulic flow.

What are common DNA synthesis targets for cancer medications?

Dihydrofolate reductase (FH2-FH4), thymidine synthetase are targets for anticancer/anti-inflammatory drugs

What are the two major types of cholinergic agonists?

Direct acting - (receptor agonists) Muscarinic receptor agonists (choline esters, pilocarpine) Nicotinic receptor agonists (nicotine) Indirect acting - Inhibitors of cholinesterases (carbamates, organophosphates) Stimulators of ACh release (Black Widow Spider Venum, metoclopramide)

What is the difference between direct acting and indirect acting drugs?

Direct acting drugs directly activate the receptor while indirect work elsewhere

What is autosomal recessive?

Disease or trait expressed only when both alleles are present -i.e., homozygous for the recessive alleles Expressed in approximate equal distribution between male and females Carriers may not express any level of the disease or trait Unaffected carriers 50% chance of transmission of allele/variant to offspring Two unaffected carriers have 25% chance of homozygous transmission, i.e., affected offspring Commonly associated with a reduced level of activity of a gene product, i.e., reduced protein level/function Loss of half activity in heterozygotes usually does not cause effects -cystic fibrosis -sickle-cell anemia -phenylketonuria (PKU) Some carriers may have very mild manifestations Example- Sickle cell trait carriers more vulnerable to rhabdomyolysis when subjected to strenuous exercise

How do phosphoglycerides and sphingolipids make a lipid bilayer?

Dispersed in an aqueous phase, they aggregate to form bilayer or monolayer structures. The acyl chains or hydrocarbon chains are aligned "in parallel" as a result of hydrophobic and van der Waals interactions. Cholesterol molecules by themselves do not form bilayer structures, however, they can insert into lipid bilayers formed by phosphoglycerides and sphingolipids.

How is replication initiated in e.coli?

DnaA-ATP initiator binds 9-mer elements. DnaA binds single strand DNA within the 13-mer sequences melting the origin. This allows loading of DnaB helicase, which unwinds DNA allowing recruitment of the primase by the helicase and synthesis of the first RNA primer

What are coactivators and corepressors?

Do not contact DNA but rather make protein/protein interactions that are critical for control of transcription.

What do you use to treat Alzheimer's Disease?

Donepezil (Aricept) and Rivastigmine (Exelon) are available for treatment of cognitive deficits associated with AD. They are noncompetitive reversible cholinesterase inhibitors, relatively selective for memory loss of Alzheimer's Disease.

What is the mechanism of homologous recombination during collapsed DNA replication forks?

Double strand breaks may arise from forks that became stalled or broken. A DNA nick ahead a a fork will result in a double strand break when the newly synthesized strand reaches the nick. . An exonuclease degrades the 5'-end to generate a 3'. This initiates strand invasion pairing with the complementary strand previously synthesized from the other template. New DNA synthesis progresses and the looping strand breaks and rejoins to repair the fork. Normal DNA synthesis resumes.

What is trisomy 21?

Down syndrome 1/800-1000 births (increases with age) Found among all races and ethnicities Decreased intellectual development Congenital heart defects Classic facial changes -epicanthal folds with upslanting palpebral fissures

At which state does ketogensis occur?

During FASTING, fat mobilization is enhanced and consequently ketogenesis is increased. In the STARVED state ketone bodies are the major energy fuels (1) The supply of fatty acids is increased. (2) The malonyl-CoA inhibition of CPTI is lifted by inactivation of acetyl-CoA carboxylase. (3)β-Oxidation supplies NADH and FAD(2H), which are used by the electron-transport chain for oxidative phosphorylation. As ATP levels increase, less NADH is oxidized, and the NADH/NAD+ ratio is increased. (4) Oxaloacetate is converted into malate because of the high NADH levels, and the malate enters the cytoplasm for gluconeogenesis. (5) Acetyl-CoA is diverted from the TCA cycle into ketogenesis, in part because of low oxaloacetate levels, which reduces the rate of the citrate synthase reaction.

When does recombination occur?

During prophase 1 of meiosis 1

What are the affinities and potencies of Epinephrine, Norepinephrine and Dopamine?

EPI threshold concentration for β2 is lower than α At high [EPI] effects of α predominate Relative affinities EPI α1 = α2; β1 = β2 NE α1 = α2; β1 >> β2 DA D1 = D2 >>β >> α α : EPI ≥ NE β1: EPI = NE β2: EPI >> NE

What are the catecholamine mediated effects on the heart?

EPI ⇒ vasodilation predominates (β2) NE ⇒ vasoconstriction predominates

What is ecological fallacy?

Ecological fallacy results from making causal inferences about individual phenomenon based on observations of a group.

What is telomere shortening-induced senescence?

Ectopic expression of telomerase (TERT) in normal human fibroblasts as well as other primary cells leads to immortalization! Telomere maintenance occurs in 85/90% of all types of malignant human cells (in most cases via telomerase activation). Telomeric shortening leads to DNA (chromosome-end) damage and chromosomal alterations RECALL: DNA damage (including telomeric DNA damage) induces p53 activation which in turn induces the CDK inhibitor p21, inhibition of CDKs and activation of the tumor suppressor (p53 can also trigger apoptosis if repair does not occur) 1- Telomere shortening (detected as DNA damage) induces the p53 and pRB pathway in human cells leading to growth arrest and senescence. Thus, this prevents cells with deleterious mutations from expanding. 2- Critically short telomeres facilitate tumor progression by two mechanisms in cells defective in the p53 and/or pRB pathways: - Selection of immortal clones - Acquisition of other genetic alterations Chromosome stabilization depends on telomerase activation (or ALT). Therefore, cell senescence is a tumor suppressor mechanism as it prevents that a cell becomes tumorigenic. However, there is clear evidence that accumulation of many senescent cells in tissues is detrimental. Evidence at the organism level: Loss of proliferative capacity with age

What is trisomy 18?

Edward syndrome Second most common trisomic condition 1/3000 to 5000 births, affecting many more females than males Severe developmental and functional abnormalities Most affected children are stillborn Of those that are born alive, more than 90% die in first year of life

What is the ED50?

Effective dose for 50% of the population TD50 = lethal dose in 50% of the populations

What are eicosanoids and what do they regulate?

Eicosanoids (including prostaglandins, thromboxanes, and leukotrienes) are 20C fatty acids and powerful physiological regulators. Derived from the essential fatty acid arachidonic acid that can be derived from linolic acid They regulate inflammatory response, muscle contraction, blood pressure, bronchodilation, bronchoconstriction, water/sodium excretion

What is elimination?

Elimination=Metabolism+Excretion

What is the chord conductance equation?

Em=TkEk+TnaEna The transference equation says that the membrane potential -is a weighted average of the equilibrium potentials of the permeable ions -the transferences are the weighting factors.

What are the different types of connective tissue?

Embryonic Connective Tissue Adult Connective Tissue Specialized Connective Tissue •Adipose Tissue •Blood •Bone and Cartilage

What are the layers of the heart?

Endocardium = intima: endothelial lining VSMCs CT Purkinje fibers Autonomic nerves Myocardium = media : Cardaic myocytes Fibroblasts Myoendocrine cells (ANF=Atrial Natriureitic Factor) Increases sodium excretion and decreases blood pressure and blood volume by inhibiting renin secretion by the kidney and aldosterone secretion by the adrenal gland and inhibiting vascular SM cell contraction Epicardium = adventitia: Fibrous CT Mesothelium Vasa vasorum Nerves Adipose tissue

What are the three general mode of signaling?

Endocrine: Travels from a cell into the blood and then reaches a target cell some distance away. Paracrine: some signaling molecules act locally Autocrine: some cells respond to signaling molecules that they themselves produce.

How does cholesterol get into the cell?

Endocytosed by LDL receptor LDL-receptor is present in liver and other tissues LDL-receptor binds LDL, VLDL, IDL, and chylomicron remnants There are > 1100 mutations in LDL-receptor, which cause high LDL

What are the endoneurium, perineurium, and epineurium

Endoneurium: connective tissue Perineurium: tubular sheath, composed of specialized concentrically oriented layers of flattened (perineurial) cells, surrounded by continuous basement membrane (basal lamina). Makes up blood-nerve barrier. Epineurium: dense irregular connective tissue (often also containing adipose tissue) that surrounds the nerve and also fills spaces between the nerve fascicles.

What is required for bacterial growth?

Energy Carbon Source Bacteria in the human host are almost always chemoorganotrophs Although some can use inorganic compounds like H2 for generation of energy using an alternative ETS But, these organisms still use organic compounds as a carbon source, so they are not technically chemolithotrophs Bacteria of the microbiota scavenge nutrients from the human host Many of the glycolytic pathway and TCA cycle intermediates are used for biosynthesis (you do not need to know the biosynthetic pathways in bacteria - only information in color as mentioned below) These intermediates can also be obtained by the microbiota through nutrient scavenging from the human host Some bacteria will produce proteases to degrade proteins to supplement metabolism

What are properties of enhancers in eukaryotic mRNA synthesis?

Enhancers: •sequences are dissimilar •may be located thousands of base pairs from start point of transcription •orientation independent •position independent •bind proteins (transcriptional tranactivators) which cause loops to form in DNA (thus brought into proximity with promoter) •Transcription transactivators bound to enhancer sequences stimulate transcription via coactivators

How is fuel mobilized for muscles?

Epinephrine stimulates energy mobilization in the liver, muscle, and adipose cells Liver: elevated glucose output during exercise Muscle: β-adrenergic receptors in non-exercising muscle Adipose: release fatty acids

Describe the blood-thymic barrier

Epithelial reticular cell + dual basal lamina + endothelial cell. Regulates exchange between the circulatory system and thymus, providing a sequestered environment for immature T cells to develop.

What are the effects of ethanol on the central nervous system?

Ethanol acts on the CNS as a depressant, similar to volatile anesthetics Currently its proposed that the primary site of action is on specific proteins that are part of the ion channels and receptors embedded in the membrane

What are euchromatin and heterochromatin?

Euchromatin is less compressed in interphase and includes genes that are actively transcribed. In interphase most chromatin is in this extended, diffused state, but it is not uniform. (Weak binding of H1 and acetylation of core histone tails) •In mitosis much more coiling occurs. A human chromosome is compacted to 1/10,000 its length and becomes visible under the optic microscope. Heterochromatin: The chromatin fiber is highly condensed through the cell cycle and is primarily unexpressed (stains dark). -Constitutive (centromeres and telomeres). -Facultative (may be de-condensed (inactive X chromosome; X and Y chromosomes condensed during meiosis)

What is the difference between heterochromatin and euchromatin?

Euchromatin=Transcriptionally active Heterochromatin=Transcriptionally inactive

What are the major DNA repair mechanisms?

Excision repair Direct repair Double strand break repair Translesion synthesis Mismatch repair

What is creatinine tested?

Excreted by the kidneys and blood levels are therefore proportional to renal excretory function Plasma creatinine is a function of glomerular filtration rate Measured using 24 hour urine specimen and plasma/serum creatinine collected during the urine collection Uncorrected creatinine clearance (ml/min)= Urine Creat (mg/dL) x 24 hr Urine volume (mL) 1440 minutes x Plasma Creat (mg/dL) Should then be corrected for height and weight

What effect does exercise have on Glut4 transporters?

Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease. The most well established mechanism is through the AMP activation of AMPK which will inhibit the GAP enzyme and cause translocation of the GLUT4 vesicles to the cell membrane. It also increases skeletal muscle expression that can lead to improved insulin action.

What are the proteases?

Exoproteases: cleave from the ends of the chain; Endoproteases cleave at specific amino acids within the chain Pepsin: activated by H+ in stomach; cuts at Phe, Tyr, Glu, Asp Trypsin: activated by enteropeptidase; cuts at Arg, Lys Trypsin activates a lot of other enzymes

What are some uses of muscarinic agonists and what are some contraindications?

Eye surgery Glaucoma Nonobstructive atony of the bladder Paralytic ileus Xerostomia Diagnosis of bronchial hyperreactivity In patients with peptic ulceration, bronchial asthma, and hyperthyroidism.

What happens in CPEO?

Eyes possibly dependent on oxidative phosphorylation Mitochondrial myopathy which affects complex I, III, IV and V and can slow down the electron transport chain. This causes an accumulation of NADH through the conversion of pyruvate to Acetyl COA by pyruvate dehydrogenase. Pyruvate becomes elevated because there is a decrease in NAD+ needed for the formation of Acetyl COA. In order to generate NAD+ the cell produces lactate from pyruvate causing the elevated levels of lactate. The slow progression of the disease is due to accumulation of the mutant form of the gene over time.

What are in mixed micelles?

FA 2-MG Bile salts Dietary cholesterol Lipid soluble vitamins

What are the non-mobile electron carriers?

FAD (Bound to complex II), Fe-S, Heme

How is the early limb bud induced?

FGF10 secreted by cells from the lateral plate mesoderm initiates interactions between the ectoderm and mesoderm to induce early limb bud growth. When mesenchyme cells enter the limb field they secrete FGF10 that induces the overlying ectoderm to form a structure called the AER. This ridge runs along the distal margin of the limb bud and is called the AER.

What does glycine cleavage yield?

FH4-C1, NADH, CO2 and NH4+

How is FISH used in bacteria?

FISH (fluorescent in situ hybridization) can be used to determine the distribution of the different species in tissue. Example of FISH · tissues are collected, fixed and sectioned · bacteria are labeled by 16S rRNA probes labeled with different fluorescent tags · confocal or fluorescent microscopy is used to image the tissue specimens reveals location and organization of bacteria

What is Factor V Leiden?

Factor V Leiden is the name of a specific gene mutation that results in thrombophilia, which is an increased tendency to form abnormal blood clots that can block blood vessels. The mutation occurs in the F5 gene that normally makes coagulation factor V, which can be inactivated (to stop clotting) by activated protein C (APC). The mutated protein cannot be inactivated by APC, so clotting process will remain active longer than usual, which can lead to clots.

What is a factors in the fidelity of DNA?

Factors Watson-Crick base pairing: 102 The physical constraints of the active site: 105 Exonuclease proofreading activity: 107-108 The actual accuracy of 1 mistake in 1010 bp is attained via post-replication mismatch repair DNA polymerase can sense right base pairing based on the diameter of the double helix (1nm); Pitch 3.6 nm The level of accuracy required for DNA synthesis cannot be attained solely on Watson-Crick base pairing and the physical constraints of the active site: DNA polymerases exhibit exonuclease proofreading activity

What is hypercholesterolemia?

Familial Dyslipidemias Type II Patients with very high LDL (> 300 mg/dL) and with a family history of high-LDL. FH is an autosomal dominant disorder caused by an abnormality in one or more alleles responsible for the formation of LDL receptors (defects in LDL receptors or ApoB-100). To treat the heterozygotes, statins and cholestyramine are commonly used. Statins are competitive inhibitors of HMG-CoA reductase, and cholestyramine is a bile salt sequestrant.

How would you describe heritable cancers?

Family history of the same or related cancer Manifest earlier (but after reproductive age or don't affect reproduction) Multiple tumors Poor long-term survival Associated with a single gene (~2 dozen syndromes identified) Variable penetrance

How does tissue remodeling occur by TIMP?

Family of four different members whose role is to irreversibly inactivate extracellular proteases There is a common feature - the sequence VIRAK is essential for TIMP/MMP binding TIMP/MMP interaction is non-covalent, but strong enough to resist separation by SDS-PAGE

Why would blocking acyl CoA hydrogenase by unripe frut from the ackee tree cause hypoglycemia?

Fatty acid oxidation is blocked and the production of acetyl CoA is reduced Sufficient ketone bodies cannot be produced Patient must then rely only on glucose for energy in the brain In starving state not enough glucose to supply to brain and it will lead to coma and death

What are the precursors of acetyl CoA

Fatty acid, palmitate, ketone bodies, glucose, pyruvate, ethanol, alanine

Where does Acetyl CoA come from?

Fatty acids Carbohydrates Amino acids Ketone bodies Ethanol

What are the functions of the tonsils?

Filtration Lymphocyte production (mostly B) Immunological responses B cells à IgA T cells/APCs à TGF-β

What is FISH?

Fluorescence in situ hybridization Probe DNA, labeling with flourescent dye, denature and hybridize

What are the final steps of BCAA metabolism?

For Leu, and part of Ile, acetyl CoA and acetoacetate are produced, these are ketogenic. For Val, and part of Ile, propionyl-CoA is produced. So these are glucogenic.

How does pyrosequencing work?

For pyrosequencing (deep sequencing) single fragments of DNA are attached to beads, PCR amplified and sequenced. This also can be used to determination of relative abundance of the genes.

How is transcription regulated in eukaryotic cells?

For regulated transcription in an eukaryotic cell other factors are required in addition to the pre-initiation complex 1.Activator/repressor proteins that bind other cis-acting DNA sequences within the gene sequence 2.Mediator, coactivators and corepressors 3.Chromatin remodeling complexes 4.Histone-modifying enzymes

What is Ellis-van Creveld syndrome?

Form of dwarfism -short stature -polydactyly -abnormalities of the nails and teeth -cardiac defects Much more frequent in Old Order Amish population of Lancaster County, PA Traced back to one couple, Samuel King and his wife, who came to PA in 1744 Mutation in EVC gene

Describe ubiquitin mediated protein degradation by autophagy

Formation of Lysine 63 linked chains on aggregates. Transport to the aggresome (trash can). Ubiquitin binding protein p62 recruits autophagic membranes around the aggregate material. Maturation and fusion with the lysosome. Degradation by lysosomal proteases.

What is a charged amino acid?

Formation of aminoacyl-tRNA (tRNA with amino acid covalently attached to 3'-end)

What does aminoacyl-tRNA synthetase do?

Forms ester bond that links amino acid to appropriate synthetase, one for each amino acid Each recognizes a particular amino acid and ALL the tRNAs that carry that amino acid

What is the function of myoglobin?

Found in muscle, bound to O2, carries (or "buffers") O2 from blood to mitochondria in oxidative muscle. Role was thought to be essential. BUT: mouse Mb knockouts seem fine, can exercise and reproduce normally. Myoglobin is not cooperative Note that Mb would fail as an O2 carrier from lungs to tissue: Does not let go at ordinary partial pressures of O2. Turns out Mb also carries NO, and has essential roles in development. Mb KO mice develop differently to evade effects. Most meat packers now treat beef with carbon monoxide to keep it looking red and fresh (Mb-CO is red), even long after it has expired.

Where does alpha oxidation occur?

Found in the microsomes of brain tissue Produce one carbon shorter than the original fatty acid No need to convert free fatty acid to fatty acyl CoA Uses the enzyme monooxygenase, O2 and Fe2+ Then creates NADH from NAD+ and CO2

When does homologous recombination occur?

Only available at G2 before mitosis

What are the origins of the musculoskeletal system?

From the ventral somite cells migrate away to form the sclerotome Sclerotome forms the axial skeleton: gives rise to: vertebral bodies intervetebral discs neural arches and proximal ribs dorsomedial sclerotome spinous process distal portion of the ribs Dorsal somite is made up of the dermatome and myotome referred to as the dermamyotome. Dermamyotome: dorsal dermis (dermatome) and skeletal muscle (myotome) Myotome: epaxial myotome-back muscle hypaxial myotome-depends on the level of the somite: at the level of the limbs-limb and limb girdle muscles between the limbs-body wall and abdominal muscles

What happens during DNA damage by alkylation?

G turned into O6-methyl-G which bind to T and results in a A:T mutation

When does non-homologous end joining occur?

G1

When does single strand annealing occur?

G1

What are different phase of eukaryotic cell division?

G1: cells prepare for S phase 2n/2C S: synthesis phase (DNA replication) Early: 2n/2C Late: 2n/4C G2: cell prepare for mitosis 2n/4C G1 + S + G2: Interphase M: Chromosomes segregate into daughter cells 2n/4C-4N/4C-2n/2C

What happens with Glucose-6-Phosphate Dehydrogenase (G6PDH) Deficiency.

G6PDH deficiency is one of the most common inherited enzyme disorders, occurring in 100 million people. Most individuals are asymptomatic. Clinical manifestations are related to hemolysis resulting from the inability to produce sufficient amounts of cytosolic NADPH. In individuals with G6PD deficiency, hemolysis is often an acute response to environmental oxidative stresses: - treatment with anti-malarial drug primaquine. - consumption of fava beans (divicine)

How is GABA synthesized and degraded?

GABA made in neurons from Glutamate; Glu decarboxylase (GAD) is sensitive to low PLP. Synthesis linked to TCA cycle (bottom right): a-KG is transaminated to make Glu (-> GABA), product succinic semialdehyde oxidized to succinate ---> a-KG Reuptake by presynaptic cell, glia, both important GABA recycling involves glial metabolism to produce glutamine which is sent back to neurons for GABA formation.

What are the key steps in the biosynthesis of GLUT4 and trafficking of the transporter protein to its initial destination in resting adipose or muscle tissue?

GLUT 4 is made by the ribosomes of the rough ER (RER) GLUT 4 then goes to the Cis golgi --> through the golgi --> secretory vesicles / technically referred to as Glut4 Storage Vesicles (GT note: Glut4 only goes to plasma membrane after stimulus (insulin))

What do the different GLUT transports do?

GLUT5 is a Na-independent facilitated transporter for fructose in the small intestine GLUT3 is primarily in neurons and together with GLUT1 allows glucose across the BBB GLUT2 low-affinty glucose transporter present in pancreatin beta cells, liver, intestine and kidney GLUT4 mostly in muscle, heart and adipose, sequestered in specialized storage vesicles. The MAJOR insulin-responsive transporter GLUT1 high in blood cells and in endothelial cells lining blood vessels of brain. Expressed in skeletal muscle and fat and up-taken there

What is glutathione and how is it used?

GSH is made up of glycine, cysteine, and glutamate GSH+HSG uses glutathione peroxidase to create GSSG and in the process converts H2O2 to 2H2O Cysteine can be limiting for formation of GSH With large amounts of drug / toxin, GSH is consumed and can be exhausted Glutathione reacts with xenobiotics through its sulfhydryl group, catalyzed by glutathione S-transferases (GSH's) GSH adducts lose Glu and Gly portions, and are acetylated to form mercapturic acids, which are excreted via urine.

What causes galactosemias?

Galactosemia results from the inability to metabolize galactose. Deficiency of any 1 of the 3 enzymes leads to symptoms. Most common cause is Galactose-1-P-Uridyl Transferase (GALT) deficiency Can cause cataracts

What is post-translational modification?

Gene transcription and translation of RNA leads to the production of proteins in cells. Post-translation modification of proteins is a rapid and reversible way of modulating protein function (activating, inactivating, fine-tuning) in response to intracellular or extra cellular signals in the absence of de novo protein synthesis or protein degradation. Numerous types of post-translation modifications. Reversible An individual protein can be modified by the same "tag" at numerous sites, some of which play opposing roles in the regulation of protein function. Most proteins have the potential to be modified by a number of different post-translation modifications, which have varying impact on their expression and/or activity. A protein can be sequentially modified by the same or different tags. Can directly induce changes in the confirmation of a protein an alter its activity. Can promote new protein interactions or negatively control existing ones, which regulate the activity or expression of the protein.

What is SNP genotyping using arrayed allele specific oligonucleotides?

Genomic DNA is cut with restriction enzyme. Universal adaptors (in blue) are ligated to the fragments, allowing them to be amplified using a single pair of PCR primers. PCR products are fragmented, fluorescently labeled, and hybridized to a microarray (small glass slide) which contains in sets, a 25 oligonucleotide of each polymorphism.

How are transcription factors activated?

Gene transcription is the final step in the signal transduction process. 1. A cell must alter its protein content by changing the Expression of Its Genes in Response to External Signals as the end result of Signal transduction pathways. 2. The DNA sequences that control the expression of a gene are concentrated in a control region called the promoter, where the general transcription factors and the RNA polymerase assemble. 3. Specific nucleotide sequences, called cis elements, each typically less than 20 nucleotide pairs in length, function as fundamental components of genetic switches by serving as recognition sites for the binding of specific gene regulatory proteins. 4. Transcription factors (Trans-factors) are Gene Regulatory Proteins that Contain Structural Motifs That Can Read DNA Sequences. Transcription factors have multiple modes of stimuli and activation 1- De-novo synthesis: Egr-1 2- Translocation: NF-kB 3- Phosphorylation: p53 4- Protein-protein interaction (homo and heterodimerization): E2F

What is transcription initiated?

General transcription factors + RNA polymerase forms the pre-initiation complex. This is essentially the same for all genes that are transcribed. Formation of the pre-initiation complex is the rate limiting step in the initiation of transcription. The pre-initiation complex is responsible for basal transcription and NOT regulated transcription.

Describe generalized transduction

Generalized transduction occurs during the lytic phase The phage packages a piece of chromosome rather than the phage genes It can be any gene in the chromosome The DNA is injected by the phage Integration of the DNA into the chromosome requires RecA-mediated homologous recombination Because the virus packaged chromosomal DNA, not viral DNA, the transduced bacteria is not infected with the bacteriophage

What are bacterial collective behavior?

Generally regulate collective behaviors o bioluminescence (original description) o antibiotic production o conjugation - pheromone inducible conjugative plasmid transfer o virulence factor expression biofilm formation and behaviors

What is the pentose phosphate pathway?

Generate reducing equivalents, in the form of NADPH, for reductive biosynthesis reactions within cells Provide the cell with ribose-5-phosphate for the synthesis of the nucleotides and nucleic acids The cytoplasmic pathway is present in a wide variety of cells. it is an alternative pathway for the oxidation of glucose and does not generate ATP. In erythrocytes the pathway is critical to protect against oxidative damage, in macrophages it is essential for generating ROS to kill pathogens, in rapidly dividing cells it provides nucleotides, in adipocytes and it is required for fatty acid synthesis, and in the adrenal gland it's essential for synthesis of both steroid hormones and catecholamines.

What are the hallmarks of aging?

Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.

What is mosaicism?

Germline mosaicism -Spontaneous DNA base change occurs during germ cell development -At risk of having affected children despite of not being affected with the trait Somatic mosaicism -May express mild manifestations of the phenotype -May express the phenotype in a restricted region of the body -Variant may also be present in the germline

What is mass spectrometry?

Global analysis of protein Determine relative expression profiles of proteins in and out of cells Also can determine differences in protein modification. Sensitivity, quantitation (in patient samples) and coverage still not there yet for diagnostic purposes. However, very powerful in defining pathways in which proteins function.

What are global regulons?

Global regulons are genetic regulatory networks where a single gene affects the transcription of multiple genes Direct effects are when the regulator binds to the operator of a genes or operons in the regulons Indirect effects are when the global regulator influences the transcription of another regulator, which regulates other genes Spore Formation- Sigma factors, promoters; Caused by starvation/stress SOS Response- LexA Repressor, Rec-A-stimulated proteolysis; Caused by DNA damage, ssDNA, replicaiton fork, stalling (starvation) Two-Component System- Histidine kinase, response regulator

What is the mechanism of glucagon action?

Glucagon binding activates the cell surface G protein-coupled Receptor (GPCR) GPCR activates G-alpha-s and adenylate cyclase cAMP is formed which activates the Ser/Thr kinase Protein Kinase A (PKA) PKA phosphorylates a wide variety of substrates including phosphorylase kinase to degrade glycogen Glucagon regulates gene expression by activating the transcription factor CREBP (cAMP response element binding protein) and the transcriptional co-activator PGC-1. CREBP target genes include PEPCK and Glucose-6-phosphatase.

What happens during the post-absoptive state?

Glucagon released and sends signal to the liver to release glucose into the blood Fatty acids are released from the adipose tissue to go to the liver Increasing free fatty acid levels (catecholamine-mediated lipolysis) Cortisol and growth hormone levels rise as glucose levels continue to decline. Increased gluconeogenesis flux and provide substrates (amino acids and glycerol) Renal gluconeogenesis accounts for about half of de novo glucose production during the post-prandial state. Increasing free fatty acid levels (catecholamine-mediated lipolysis) GLUT4 levels in cell membranes decrease. Oxidation fatty acids excess acetyl CoA levels. Acetyl CoA inhibits PDH AND stimulates PDH kinase activity AND PDH phosphatase is inactive (low insulin). Accumulation of citrate in the cytoplasm inhibits PFK1. Blood glucose sparing: less uptake, less glycolysis through hormonal and allosteric mechanism. Muscle energy source shifts to fatty acid oxidation.

What do glucocorticoids do?

Glucocorticoids inhibit the formation of all kinds of eicosanoids; thus bronchoconstriction is greatly reduced Glucocorticoids induce the expression of phospholipase A2 inhibitory proteins, which make phospholipase A2 inactive. Adipose tissue - Increase in lipolysis Muscle - Increase in protein degradation Liver - Increase in gluconeogenesis

What is Von gierke disease?

Glucose-6-phosphatase deficiency or Glucose-6- Phosphatase translocase deficiency Affects liver and kidney Fatty liver Renal disease Growth retardation and delayed puberty

What reaction happen in red blood cells?

Glycolysis: glucose to lactate, Cori cycle Pentose phosphate shunt to ribose 5-P and PRPP Formation and metabolism of glutathione Interconversion and salvage of nucleotides NOT: TCA, Ox-Phos, gluconeogenesis, nucleotide synthesis, protein synthesis, lipid synthesis

What are glycosominoglycans?

Glycosaminoglycans: may have >100 sugar residues/attachment site linear polysaccharide structure repeating sugar dimer sugars are O-linked May also carry small, branched sugar structures Within the organism, the role of GAGs is structural (probably do not play a role in folding of the associated protein). Five out of six disaccharides are sulfated Glucosamine and chondroitin are sold over-the-counter.

What is the function of the golgi complex?

Glycosylation of proteins Protein sorting Synthesis of glycolipids and sphingomyelins

What reaction is catalyzed by phospholipase C?

Gq protein coupled receptor activates phospholipase C PLC catalyzes DAG and IP3 IP3 releases Ca2+ from intracellular storage sites DAG activates protein kinase C in the presence of Ca2+

What are membrane structures found in gram positive bacteria?

Gram positive membrane structure: Lipoproteins Lipoteichoic acid Membrane proteins Electron transport chains (metabolism lecture) Transporters

Describe the extracellular matrix

Ground substance and Fibers Ground substance: •Extracellular substance, Colorless, Hydrated (high water content) •Fills the space between cells and fibers •Due to its viscosity serves as lubricant •Allows diffusion of water soluble molecules and provides a path for cell migration •Anchors cells through cell-ECM adhesion •Binds and retains growth factors •Transmits information from the ECM across the plasma membrane Macromolecules of Ground substance: Glycosaminoglycans (Dermatan sulfate Keratan sulfate Hyaluronic acid), Proteoglycans (Aggrecan Syndecan Decorin) and Glycoproteins (Fibronectin Laminin) Multi-adhesive glycoproteins facilitate attachment between Cell-CT element OR CT element-CT element

What is located in the cartilage extracellular matrix?

Ground substance: ECM contains large proteoglycan aggregates, such as aggrecan, that interact with collagen. Glycosaminoglycans (GAGs): negatively-charged side chains (chondroitin sulfate and keratan sulfate) on proteoglycans that bind water. Creates a shock absorber, due to its stiffness and elasticity!

What happens during DNA damage by oxidation?

Guanine converted to OxoG or A transversion Commonly found in cancer

What is guanylate cyclase regulated?

Guanylate cyclase is not regulated by guanine nucleotide regulatory proteins? Two Mechanisms: Integral part of receptor and directly activated by ligand binding Cytoplasmic form which is activated by nitric oxide

How are amino acids metabolized during a high protein meal?

Gut and liver use most of the absorbed amino acids 6-9 fold increase in amino acids in blood Stimulation, release of glucagon above fasting levels, increasing aa uptake in liver and gluconeogenesis Insulin release also stimulated (2-3 fold), but not high enough to inhibit gluconeogenesis Carbohydrate content of meal affects metabolism BCAA's are taken up by skeletal muscle/other tissues

What are the effects of acidosis?

Impaired metabolism Impaired proton pumps Decreased cardiac output and thus less O2 for tissues Glutamine for acid excretion aka muscle wasting

What are some examples of genotype directed therapies?

HER2-positive breast cancer: trastuzumab (Herceptin) BCR-ABL-positive CML: imatinib (Gleevec) EGFR-positive lung cancer: gefitinib (Iressa)

What is the rate limiting enzyme in ketone body formation?

HMG CoA Synthetase

Describe voltage gated calcium channels

Have a similar topology to Nav channels in their α-subunits. 10 different a subunits, Cav1.1-1.4, Cav2.1-2.3 and Cav3.1-3.3 Can have up to four associated auxiliary subunits: a disulphide-linked α2δ-complex, an intracellular β-subunit, and an occasional γ-subunit with four transmembrane segments. L-Type (Cav1.1-1.4): present in skeletal muscle, smooth muscle, bone (osteoblasts), ventricular myocytes (responsible for prolonged action potential in cardiac cell; also termed DHP receptors), dendrites and dendritic spines of cortical neurons L-type calcium channel blockers are used as antihypertensive drugs, including dihydropyridine type of drugs, e.g. Nifedipine

What are structural motifs of regulatory proteins?

Helix-Turn-Helix Zinc Fingers Leucine Zipper Transcriptional regulatory proteins recognize specific enhancer or silencer DNA sequences and make a series of contacts that involve hydrogen bonds, ionic bonds and hydrophobic interactions. Most transcriptional regulatory proteins bind to the major groove of DNA. Even a single base mutation in a enhancer/silencer DNA sequence of a gene or single amino acid change in a regulatory protein can reduce the ability of the transcriptional regulatory protein to bind its appropriate DNA sequence and regulate transcription rate.

What is hemolysis?

Hemolysis-rupture of red blood cells Can be due to improper collection End result is release of cellular contents into blood. Significant increase in potassium, magnesium, phosphorous

What is erythoblastosis fetalis?

Hemolytic Process causes hemolytic anemia (hypoxic injury to the heart and liver causing edema) and jaundice (damage to the CNS). Rh-negative mothers are given anti-D antibodies to mask the D-antigen on fetal RBCs that leaked into the maternal circulation and prevent long-term sensitization to the D-antigen.

What is the function of hepatic lipase?

Hepatic triglyceride lipase HTGL Converts IDL to LDL

What are epigenetics?

Heritable (from parent cell to daughter cell) alterations in gene activity that are not caused by changes in gene sequence.

What are the major regulatory enzymes in glycolysis?

Hexokinase (Glucokinase)- Inhibited by G-6-P Phosphofructokinase 1 (PFK1)- Inhibited by ATP and Citrate, Stimulated by F-2,6-bisphosphate and AMP and ADP, Irreversible, no transcriptional regulation, 3 isoforms Pyruvate Kinase- Stimulated by fructose 1,6-bisphosphate, inhiited by ATP and Acetyl-CoA

What are the differences between hexokinase and glucokinase?

Hexokinase is found in most tissues while glucokinase is only found in the liver and beta cells of the pancreas Only hexokinase is inhibited by G6P Deficiency in hexokinase causes hemolytic anemia Hexokinase is involved in maintaining intracellular glucose concentration while glucokinase is involved in maintaining blood glucose concentration Glucokinase is inducible Hexokinase has a low Vmax and Km while glucokinase has a highVmax and Km Hexokinase makes glycogen and uses energy to make CO2 and lactate Glucokinase makes glycogen, fat and induced metabolic signals Hexokinase is co-expressed with GLUT 1/3/4 Glucokinase is co-expressed with GLUT2

What is leukocytosis?

High WBC Causes: Increased production, greater release from storage, change in the proportion of circulating and marginated WBCs.

How is cholesterol levels in the cells regulated?

High cholesterol inhibits HMG COA reductase that facilitates cholesterol synthesis High cholesterol promotes the ACAT enzyme creating cholesterol ester stores High cholesterol inhibits LDL receptor transcription so less cholesterol will be released into the cell

What is hutchinson-gilford syndrome?

Hutchinson - Gilford Syndrome (Progeria)(autosomal dominant): Mutation on the gene encoding the lamin A protein. Most children with Progeria do not live beyond teenage years (one or two lived to be 20 or 21). Children suffering from this disease tend to have similar appearance. Generalized atherosclerosis and cardiovascular problems. Small face and jaw , delayed tooth formation, dwarfism wrinkled and aged-looking skin, hip dislocation, baldness, pinched nose. Mental growth equivalent to children of the same age. Appears to be associated with defects in nuclear architecture that can cause genetic instability. (There are other related genetic disorders).

What are the functions of specific glycosaminoglycans?

Hyaluronic Acid Cell migration in: Embryogenesis, Morphogenesis, Wound Healing Component of cartilage (aggrecan) Chondroitin sulfate proteoglycans Formation of bone, cartilage, cornea Heparin Anti-coagulant Causes release of lipoprotein lipase from capillary walls Heparan sulfate Component of skin fibroblasts and aortic wall; impacts FGF/receptor binding affinity Anti-coagulant

What is the function of RNaseH?

Hydrolyzes the ribonucleotides on the RNA primers of the Okazaki fragments

What are the therapeutic applications of sympathetic drugs?

Hypotension (Shock) Asthma Allergic reactions/ anaphylaxis Nasal decongestion Glaucoma Mydriatic Narcolepsy ADHD Weight loss Overactive bladder/ urinary urgency

What is the biological consequence if 8-oxo-G lesions are not removed from DNA?

If 8-oxo-G lesions remain in DNA, it can base pair with an A instead of C. This can result in a transversion mutation from G:C to T:A, if the DNA replicates and incorporates a T to match with the A. This transversion mutation can present as a point mutation, which can result in an amino acid change or introduction of a stop codon which can negatively affect the protein that the damaged DNA codes for

What is the methyl trap hypothesis?

If B12 is deficient or if methionine synthase is defective, N5-methyl-FH4 accumulates. Eventually, most folate becomes "trapped" in the N5-methyl form, effectively resulting in a folic acid deficiency

How is blood serum and how is it retrieved?

If whole blood is allowed to contact glass, it will clot. After centrifugation, the fluid portion is SERUM. Essentially same as plasma BUT NO clotting factors Blood Clot -Comprised of clotting factors (Fibrin, etc) -RBCs, WBCs, and PLTs

What is illegitimate recombination?

Illegitimate recombination involves no homology between the participating DNA molecules: •Insertion of a mobile genetic element into a target chromosome. •Some viruses designated retroviruses integrate a DNA version of their genome into chromosomes (HIV and retroviruses). One partner in transposition is the transposable genetic element, sometimes referred to simply as a "transposon Transposons can move from one location to another on the same chromosome or can move from one chromosome to another.

What is a fatty liver?

Imbalance between hepatic triglyceride synthesis and VLDL secretion

What are the functions of astrocytes?

Important role in neurovascular coupling (linked to Blood Brain Barrier) Regulation of intercellular fluid composition in brain Metabolic cooperation with neurons Regulation of cerebral blood flow Astrocytes Provide Neurons with Neurotransmitters and Energy: Astrocytes also mobilize glycogen (stored from glucose) to produce lactate. Neurons take up lactate and convert it to pyruvate in order to generate energy via the TCA cycle. This allows glucose to be used for other metabolic pathways and/or can protect neurons from low glucose. Astrocytes express glutamate transporters, which take up excess glutamate from the synaptic cleft and recycle it by converting it to glutamine.

What is burkitt's lymphoma

In Burkitt's lymphoma, t(8;14/2/22): fusion between c-MYC and regions coding for immunoglobulin genes, resulting in overexpression of c-MYC In some promyleocytic leukemias, t(15;17) chromosomal translocation generates the PML-RARα fusion protein (treated with retinoic acid) Fusion genes are interesting targets for therapy because they are specific to the tumor.

What is an isotonic contraction?

In an isotonic contraction, the muscle develops force and shortens. 1.The load lifted by the muscle when it shortens is called the afterload. 2.An isotonic contraction consists of three phases • It contracts isometrically until the force developed is equal to the afterload. • It shortens isotonically at a constant velocity until it shortens as much as it is capable of shortening. • It contracts isometrically until it begins to relax. 3.The velocity of shortening during an isotonic contraction is inversely proportional to the afterload. 4.The amount of shortening that occurs during an isotonic contraction is inversely proportional to the afterload. The greater the afterload, the greater the number of myosin molecules that must be bound to actin. The greater the number of myosin cross bridges involved in the contraction, the slower the velocity of shortening.

What is stress-induced senescence?

In cell culture stresses might include: Hyperoxia- It has been demonstrated that both murine and human cells cultured in more physiological conditions survive longer. Disruption of cell-cell contacts Lack of interactions between different cell types as it occurs in tissues Persistent mitogenic activation Absence of appropriate survival and trophic factors Adherence to an artificial surface

What are the classifications of 7TMRs?

In common: 7 TMs, a disulfide bond between top of TM3 and e2 loop, basic residues at the cytoplasmic end of TM6 Three main families (A, B, C) of 7TMRs in mammals. Within each family, >25% homology within 7 TMs, a distinctive set of highly conserved residues and motifs Rhodopsin (Family A): 672, rhodopsin and rhodopsin-like, by far the most important GPCR family as drug targets. some are orphan receptors (unknown ligands). further divided into α, β, γ and δ groups. olfactory receptors 388, in the δ group. Secretin/Family B: 15, glucagon/VIP/calcitonin, large N-terminal domains (~350AA) with conserved cysteine residues, mainly coupled to Gs to stimulate AC. Adhesion/Family B: 33, large N-terminal domain Glutamate (Family C): 22, metabotropic glutamate receptors (mGluRs), GABAB receptors and chemosenors. very large N-terminal domain, crucial for ligand binding and receptor activation. Frizzled (Family F): 11, large N-terminal domain, cell polarity, embryonic development, formation of neural synapses, cell proliferation Taste2 (Family O): 25, large N-terminal domain

How is eukaryote cell cycle progression triggered?

In eukaryotes the proteins that replicate DNA or mediate mitosis are different from the proteins that regulate progression through the cell cycle. Cell cycle progression is orchestrated by protein kinase complexes named Cyclin Dependent Kinases (CDKs), which phosphorylate other regulatory and structural proteins thereby controlling expression and activities of replication enzymes and cell cycle factors. CDKs are only active when bound to cyclins, which are expressed at particular phases of the cell cycle. There are 4 main types of cyclin/CDK complexes: The expression of cyclins, the positive regulatory subunits of the CDKs that trigger cell cycle progression, is cyclic

In what phase does replication occur in eukaryotes and how?

In eukaryotes, multiple Origins of replication are fired during S phase Only a fraction of replication origins fire, but they do it only once per cycle

What is the function of fatty acyl CoA synthetase?

In intestinal epithelial cells, free fatty acids are converted to the active fatty acyl CoAs Activation of fatty acid which uses ATP to form AMP which is exchanged for CoA

What is the molecular mechanism of CF?

In most Cystic Fibrosis (CF) patients, the CFTR channel protein is functional, but mislocalized 87% of CF patients have a mutant CFTR protein that would have reasonably normal channel function but never reaches the plasma membrane Cystic Fibrosis can thus be considered as a disease of impaired protein trafficking

How do action potentials propagate in muscles?

In muscles that act as a syncytium, cells are connected by gap junctions and action potentials propagate between cells.

How is bacterial rRNA and tRNA produced?

In prokaryotes, rRNA is produced as a single, long transcript that is cleaved to produce the 16S, 23S and 5S ribosomal RNAs. tRNA is also cleaved from a larger transcript. RNaseP, one of the cleavage enzymes, is a protein containing an RNA molecule. This RNA actually catalyzes the cleavage reaction.

What do bax-like proteins do?

In response to cytotoxic signals, Bax & Bak undergo conformational change and form membrane-associated homo-oligomers. This can be blocked by Bcl-2 over-expression. Once activated, Bax-like proteins appear to cause membrane damage. Disruption of the outer membrane of mitochondria releases apoptotic mediators: 1. cytochrome c, which activates Apaf-1 [which activates caspase 9, an initiator caspase] 2. Pro-apoptotic regulators Smac/Diablo and Omi/HtrA2, which antagonize inhibitors of apoptosis [IAPs {inhibit activated caspases}];

What is demyelination disease?

In several diseases the myelin sheath of a neuron is attacked and broken down. The axial current leaked out at more places and may not reach the next node of Ranvier. Sodium channels may diffuse away from the node Neural transmission (AP conduction) does not work properly (slowed down or blocked). These are called demyelinating diseases. Most common of these is multiple sclerosis.

What is lesion by-pass (Translesion) DNA Synthesis?

In some cases, low fidelity DNA polymerases will insert nucleotides across from a DNA lesion that has not (or can not) be removed from the path of the replication fork. One example is human DNA polymerase eta (η), associated with the XP variant disease. Damaged nucleotide was not repaired before DNA replication Translesion DNA polymerases allow for DNA replication to continue but damage is still not corrected High error prone ( mutations)

What are the function of phosphoacylglycerols?

Key components of cell membranes The major component of lung surfactants Playing a pivotal role in signal transduction and metabolism Required for certain enzyme activities

Where does cholesterol synthesis occur?

In the cytosol, particularly on the cytoplasmic face of the endoplasmic reticulum (ER), of liver and intestinal cells.

How does jaundice occur?

In the liver, bilirubin is conjugated to glucuronate (makes more water soluble). When the liver is failing, bilirubin will NOT be glucuronated, so it will not be soluble, and instead deposits in tissues (jaundice). So jaundice reflects an INCREASE in INDIRECT bilirubin

What are the types of liver damage?

In the liver, four types of conditions can develop: Steatosis Steatohepatitis Fibrosis Cirrhosis

Where does beta oxidation occur?

In the mitochondria of mainly the liver and kidney

What areas does acetylcholine target?

In the periphery, it is the neurotransmitter at all autonomic ganglia, the postganglianic parasympathetic fibers and all neuromuscular junctions It is also a neurotransmitter in the CNS

What is prokaryotic mRNA transcribed?

In the promoter region, about 10 base pairs "upstream" from the point at which the transcription of mRNA begins is the sequence TATAAT, known as a Pribnow or TATA box. RNA polymerase binds in this region of the promoter, but only if a repressor protein is not bound to the operator region. The operator is located between the promoter and the mRNA start point. The sigma factor is released when the transcript is about 10 nucleotides long Elongation continues until there is a transcription termination signal One type of signal is the formation of a hairpin loop in the transcript, preceding a number of U residues. The second is the binding of a protein, the rho factor, which causes release of the RNA polymerase. In many instances polycistronic mRNA is produced, and each cistron is translated into its cognate protein.

Where does cholesterol go from the diet?

In the small intestine, dietary cholesterol can be taken up via mixed micelles.

What is the function of lipoprotein lipase?

LPL Involved in processing of chylomicrons and VLDL

What is lipid malabsorption?

Inability to digest triacylglycerols (TGs) due to pancreatic lipase or bile acid deficiencies Lipid (TG) accumulations in the feces, a condition known as steatorrhea Leading to a loss of important energy fuels, severe weight loss, and a loss of vitamins (fat-soluble vitamins, A, D, E, and K) as well as essential fatty acids, and caloric deficiencies

What are the antidotes for organophosphates?

Include artificial respiration/oxygen, atropine (to block the muscarinic effects) and pralidoxime. Pralidoxime is a cholinesterase reactivator. It has strong affinity for the phosphorylated enzyme; the oxime gets phosphorylated, thus regenerating free enzyme. It is not effective once aging has taken place, and is not effective vs carbamate-type inhibitors. Benzodiazepines (lorazepam) are useful to reduce or prevent seizure activity.

What toxicities occur with cholinesterase inhibitors?

Include muscarinic, nicotinic and CNS effects. These include bronchoconstriction, miosis, excessive secretions, diarrhea, urinary incontinence, alterations in heart rate and blood pressure, tremors, and convulsions. Death is due to respiratory depression and circulatory collapse. Exposure to organophosphates can cause a delayed neuropathy and allergic reactions (unrelated to ChE-inhibitor potency).

What is LPS composed of?

LPS is composed of: · lipid A · core glycolipid · O-specific oligosaccharide subunit composed of repeating sugar subunits Carbohydrate composition can vary even within the same species to avoid the immune system

What do trans fatty acids do?

Increase serum LDL cholesterol (bad cholesterol) triacylglycerols platelet aggregation Decrease HDL cholesterol (good cholesterol) Lead to growth retardation in newborns

What changes the alpha level when sample size is unchanged?

Increase in power level increase alpha level Decrease in detectable increases alpha level

What is the purpose of drug metabolism?

Increase water solubility Decrease lipid solubility Increase excretion Most drugs are lipid soluble, remain mostly non-ionized at physiological pH, and are at least partially bound to plasma proteins. Metabolism makes the drug less lipid soluble, more water soluble, and therefore more readily excreted in the body's aqueous excretions (such as in the urine).

What happens to lipid metabolism in a hypercatabolic state?

Increases Lipolysis - breakdown of triglycerides (adipose), fatty acids for muscle cells, glycerol, Enhanced by glucagon Β-oxidation - acetyl CoA, NADH, FADH2 Ketogenesis - produced in liver, function to spare glucose need for fuel.

How do sensors work?

Individual BH3 only proteins are recruited for their death duties in different ways. 1. Mammalian BH3 only proteins regulated transcriptionally include Hrk/DP5, Noxa & Puma/Bbc3. ● 2. BH3-only proteins that are produced constitutively are maintained in a latent form and activated by diverse mechanisms, post translationally. a. Bad is sequestered by 14-3-3 scaffold proteins after phosphorylation by kinases such as Akt/PKB and protein kinase A. Activation requires dephosphorylation. b. Bid undergoes cleavage by caspases or granzyme B, perhaps regulated by phosphorylation, to expose its buried BH3. The pro-apoptotic role of Bid is still unclear. It binds to both Bcl-2- and Bax-like proteins in vitro; mutagenesis studies suggest that the latter are the functionally relevant targets. 3. Extrinsic pathway can recruit intrinsic pathway to amplify caspase cascade. Bid is the link. Individual BH3 only proteins expressed only in certain cell types Some appear to monitor particular subcellular compartments for stress or damage, and/or to respond to specific sets of cytotoxic signals Affinity of activated BH3-only proteins for prosurvival proteins varies Bim, Puma and tBid bind strongly to all the pro-survival proteins. Other BH3-only proteins associate only with subsets. (see Fig2A)

What is triploidy?

Inheritance of an extra copy of every chromosome 69 chromosomes per cell instead of 46 Usually lethal -lost as spontaneous miscarriages, stillborn or die within the first few days after birth Commonly fertilization of one ovum by two sperm

What is I-cell disease?

Inherited lysosomal storage disease (mucolipidosis type II) - defect in enzyme that adds phosphate to mannose, resulting in failure to traffic lysosomal hydrolases to the lysosome. These enzymes are instead secreted, but the cell cannot break down unwanted material and so forms giant inclusion bodies.

What happens in a myophosphorylase (PYGM) enzyme mutation?

Inherited mutation This protein is a muscle tissue specific isoform of glycogen phosphorylase class of enzymes. This enzyme phosphorylates glycogen to break it down into the simpler sugar glucose-6-phosphate.

What do statins do?

Inhibit cholesterol synthesis which then causes the down-regulation of intracellular cholesterol. This causes up regulation of LDL receptors which in turn causes down-regulation of serum cholesterol

What does acetyl CoA inhibit and stimulate?

Inhibits pyruvate dehydorgenase in the mitochondria Stimulates pyruvate carboxylase in the mitochondria

What is the max therapeutic concentration?

Initial peak = 100mg/L (Recall: C0 = D/Vd) fraction remaining (f)= ¼ Max therapeutic concentration = (first peak) / (1 -f ) = 100 / (0.75) = 133.3mg/L

What are the steps of translation?

Initiation: Formation of an initiation complex Elongation: Synthesis of polypeptide occurs by series of elongation steps; repeated as each amino acid is added to the growing polypeptide chain Termination: Occurs where the mRNA contains an in-frame stop codon; completed polypeptide chain is released.

What is inside and on the surface of an emulsion droplet?

Inside: TG Diacylglycerols Cholesterol esters Surface: Fatty acid soaps Cholesterol Bile salts? Monoacylglycerols Lysolecithins

What does the G-beta and gamma dimer do?

Interact with many different effector molecules by protein-protein interactions. Different combinations of the Gβ and Gγ subtypes can influence different effectors and work alone or synergistically with the Gα subunit. Some examples: Gβγ regulates ion channels, such as G protein-gated inward rectifier channels and calcium channels. Gβγ activate or inhibit adenylyl cyclase.

What are the two steps of osteogenesis?

Intramembranous - Bone tissue is formed directly in primitive connective tissue (mesencyhme). Endochondral - Bone tissue replaces a hyaline cartilage template.

How it methionine metabolized?

Involves adenosylation / donation of methyl group / removal of adenosine / methylation of homocysteine by B12-CH3

What are some function of leukotrienes?

LTB4 increases vascular permeability T-cell proliferation leukocyte aggregation interferon-g, interleukin-1, interleukin-2 LTB4 is a potent chemotactic factor LTC4, LTD4 & LTE4 increase bronchoconstriction vascular permeability gastrointestinal smooth muscle contraction interferon-g (the order of potency: LTD4 > LTC4 > LTE4) Has been linked to asthma

How are single carbons metabolized?

Involves three methyl group carriers: Folic acid (FH4 is active form) Vitamin B12 S-adenosyl methionine (SAM)

What is a homeobox?

Is a DNA sequence found within genes that are involved in the regulation of development (morphogenesis) of animals, fungi and plants. Genes that have a homeobox are called homeobox genes and form the homeobox gene family. A particular subgroup of homeobox genes are the Hox genes, which are found in a special gene cluster, the Hox cluster (also called Hox complex). Role: regional pattering information is provided, at least in part, by the master developmental regulators, the Hox genes

What is a southern blot?

Isolation of DNA (10 ugs) and restriction enzyme digestion. Gel electrophoresis. Transfer to nitrocellulose. Generation of a gene specific probe and hybridization. Washing, and exposure to film. Applications: Restriction Fragment Length Polymoriphism (RFLP) Analysis: Identify individuals harboring disease genes that have polymorphic restriction site. Variable Number Tandem Repeat (VNTR) Analysis: Identify individuals based on differing size of DNA repeats (forensics, paternity).

What happens to glucose as it enters the cell?

It is converted to glucose-6-phosphate which can: - be isomerized to glucose-1-phosphate then converted to UDP-glucose for glycogen and proteoglycan synthesis. - enter the pentose phosphate pathway to produce NADPH and ribose for nucleotide synthesis. - enter glycolysis and used as a source of energy and metabolic substrates.

What happens after a high carb meal?

It takes around an hour for glucose and then insulin levels to increase and glucagon to decrease

What are the functions of sphingolipids?

Key components of cell membranes (particularly abundant in nerve cell membranes) Regulators in cell death/survival, toxin binding, and cell-cell recognition Sphingosine 1-phosphate (S1P): an intracellular second messenger and an extracellular mediator. It plays an important role in signaling pathways. It stimulates cell proliferation and survival, and regulates cell motility and cytoskeletal reorganization. Ceraminde: a regulator in programmed cell death (apoptosis)

What is the function of Lecithin-Cholesterol Acyltransferase?

LCAT Catalyzes transfer of long chain fatty acids to cholesterol, forming cholesterol esters Extracellular in HDL- In the blood

What are the end products in aerobic and anaerobic glycolysis?

Lactate and NAD

What is the role of lactic acid in muscle fatigue?

Lactic acid accumulation -Decreases myoplasmic pH (~7 to ~6.2) •Inhibits actin-myosin interactions by altering Ca2+ binding to TnC and decreasing max crossbridges formed Pi accumulation -Inhibition of Ca2+ release from SR -Decrease in Ca2+ sensitivity Alteration in actin-myosin binding

What are the three layers of the basement membrane?

Lamina lucida - electron lucent (very little staining in the EM). (Extracellular portion of Fibronectin and Laminin receptors) Lamina densa - electron dense. (Collagen (IV) Laminin Proteoglycans Entactin) Lamina reticularis - can be associated with reticular fibers of the underlying connective tissue. Type 3 cartilage

What are pathogenicity islands?

Large mobile genetic elements encoding virulence factors Present in pathogenic strains and absent in commensal strains of the same species Related to transposons in that they sometimes, but not always, have IS elements and integrase Tend to be found in tRNA genes

What are the three branched amino acids?

Leucine, isoleucine, valine They are glucogenic and ketogenic Val and Ile are glucogenic through succinyl CoA Ile are ketogenic through acetyl CoA Leucine is ketogenic through HMG-COA/Acetoacetate

What amino acids form ketone bodies?

Leucine- HMG CoA Phenylalanine and Tyrosine can be converted to acetoacetate Threonine, Lysine, Isoleucine and Tryptophan can be converted to acetyl CoA

What are the different types of regulated genes?

Levels rise and fall in response to molecular signals Inducible genes - gene products that increase in concentration under specific circumstances (positive) Repressible genes - gene products that decrease in concentration under specific circumstances (negative)

What is endocytosis?

Ligands bind to receptors on the cell membrane , located in special regions called coated pits, which pinch off and carry the ligand and receptor into the cell. Major protein in coated vesicles is clathrin. Coated vesicles loose their clathrin coat and fuse with endosomes which are small vesicles in the cytosol. All endosomes contain ATP-driven H+ pumps that acidify their interior. Clathrin molecules move back to the cell membrane. (example: transferrin, iron transporting protein).

Where along the axis do limb buds/limbs form?

Limbs develop across from each other. The somite level at which limbs develop vary in different species. Fore and hind limbs always develop at a specific level along the central axis. Their position is dependent on the level of Hox and other signaling molecule gradients (e.g. retinoic acid) along the A/P axis. e.g. forelimb bud are located at the anterior margin of Hoxc6, the position of the first thoracic vertebrae.

Describe stereocilia

Limited to specific regions of the body Long non-motile processes Structurally similar to microvilli Facilitate absorption In the ear, fastidiously sensitive to mechanical vibration

Describe ependymal Cells

Line the ventricles of the brain and the central canal of the spinal cord. The ventricular system is involved in production and circulation of Cerebrospinal Fluid (CSF), which acts as a buffer and cushion for the brain and spinal cord. Ependymal cells form a simple cuboidal epithelium between the CSF and the Interstitial fluid (ISF) of the CNS. They have microvilli (not visible here) and cilia on their apical surface. The ISF-CSF barrier is distinct from, and much looser than, the Blood Brain Barrier.

What are the symptoms of insufficient essential fatty acid intake?

Linoleic acid alpha-linolenic acid Arachidonic acid Skin and kidney damage, cataracts, increased membrane permeability to water

How is Lipoprotein lipase stimulated from adipose cells?

Lipoprotein lipase (LPL) from adipose cells is stimulated by CII and insulin Note that insulin stimulates both the transport of glucose into adipose cells and the synthesis and secretion of lipoprotein lipase (LPL) from the cells. Glucose provides the glycerol 3-phosphate for TG synthesis. Apoprotein CII activates LPL

Where are primary bile salts made?

Liver

What is Zellweger's syndrome?

Liver and kidney lack peroxisomes; accumulation of C26-C38 fatty acids in brain tissue

What are reticular cells?

Located in the lymph nodes This reticular cell network distributes key molecules and provides a structure for immune cells to move around on. Some cytokines and chemokines that are vital for effective T cell migration—and the nitric oxide that inhibits T cell proliferation are produced by the RCs. The network is thought of as a "road system" for lymphocyte migration.

What is genetic heterogeneity?

Locus (i.e., gene) heterogeneity -A single phenotype is caused by mutation in multiple distinct genes (e.g., Ehrlers-Danlos Syndrome) Allelic heterogeneity -Different mutations in the same gene cause variable phenotypes or even completely different disorders

What are the different classifications of connective tissue?

Loose CT Dense CT: Regular Irregular

What is a 'hit'?

Loss through non-disjunction Mitotic recombination/gene conversion Deletion Point mutation

What is leukopenia?

Low WBC Causes: Marrow failure - due to toxins.

What is an SSRI?

Low serotonin levels: linked to depression, anxiety/panic attacks, obsessive/compulsive disorder. Drugs that inhibit the transporters that mediate reuptake of serotonin into neurons, called selective serotonin reuptake Can sometimes alleviate anxiety, depression Potential side effects (including suicidal thoughts) are widely reported, problematic Fluoxetine (Prozac), Sertraline (Zoloft) are examples of SSRI's

How does phosphorylation regulate enzymes and other proteins?

Lowers Km of enzymes or raises Vmax Raises Km of enzymes or lowers Vmax Changes affinity of an enzyme for a protein cofactor Alters the rate of phosphorylation at another site Alters the rate of protein degradation Alters protein-protein interactions

What are the accessory cells of the lymphatic system?

Macrophages Dendritic cells Follicular dendritic cells Reticular cells Granulocytes

What is KLINEFELTER SYNDROME?

Male with extra X chromosome (47,XXY karyotype) 1/500-1000 male births (not identified at birth) Boys taller than average In late puberty testosterone levels decline -micro-orchidism (small testes) -Oligospermia/azoospermia -Gynecomastia Reduced fertility

What is hematocrit?

Measure of the percentage of total blood volume that is made up by red blood cells The hematocrit can be determined directly by centrifugation ("spun hematocrit") -The height of the red blood cell column is measured and compared to the column of the whole blood

How are vesicles targeted to the lysosome?

Materials are delivered to lysosomes via multiple pathways: i)Endocytic pathway - materials taken up from the extracellular space are delivered to endosomes, and from there to late endosomes, which mature into lysosomes ii)Autophagic pathway - cytoplasmic materials are targeted for degradation by incorporation into lysosomes (or late endosomes). iii)Biosynthetic pathway - lysosomal enzymes that degrade unwanted material are synthesized and then targeted to the lysosome (via the early &/or late endosomal compartments).

What is mitochondrial inheritance?

Maternally derived At fertilization, sperm head with nucleus and no mitochondria enters mature ovum to form zygote Diploid mature ovum has approximately 100,000 maternal mitochondria, each containing many of copies of mtDNA Homoplasmy -All mitochondrial DNA have identical sequences -All cells will have same mitochondrial population after cell division Heteroplasmy -Mitochondria DNA a mix of usually 2 main sequences -Because of random segregation, heteroplasmy will be different after cell division

What is mean cell hemoglobin?

Mean cell hemoglobin (MCH) refers to the amount of hemoglobin per RBC Calculated as HGB/RBC count Reference range -26 - 32 pg (pg=picogram=10-12 grams) Of little clinical or diagnostic use

What is CO2 tested?

Measures the H2CO3 (carbonic acid), dissolved CO2, and bicarbonate ion (HCO3-) Because the amounts of H2CO3 and dissolved CO2 are so small, the CO2 content is an indirect measure of the HCO3- anion -Therefore, clinicians most often refer to the CO2 measurement in the BMP as the "bicarbonate level" or "bicarb level" •CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-

How does smooth muscle contract?

Mechanical impulses (passive stretch) Electrical depolarization (neural stimulation) Chemical stimuli (hormones ...use second messenger pathways)

Describe Co-transport (symport)

Mechanisms: (a)A carrier protein has binding sites for two or more solutes. These sites are alternately exposed to both surfaces of the membrane. (b)Both solutes have to be present for the process to work (c)The empty carrier can reorient to the other side, i.e., it can "come back empty". (d)Co-transport can be electrogenic or electroneutral Example: Na+ and glucose cross the apical surface of the kidney proximal tubule cells by a cotransport mechanism. •This reabsorbs glucose from the tubular fluid so it is not lost in the urine. •This mechanism also results in the reabsorption of Na+. •There is a similar mechanism for Na+ and amino acids.

What is the lateral organization of cholesterol at the cellular level?

Membrane rafts are rich in cholesterol, saturated sphingolipids, and saturated phosphoacylglycerols. Certain proteins like to reside in membrane rafts, rather than non-raft regions. Functional Membrane Rafts Lipid and protein trafficking (sorting) in cells Signal transduction Toxin binding Virus budding and binding (HIV, Ebola) Membrane lateral organization affects membrane dynamics/packing Because of the presence of microdomains, membrane fluidity is not uniform throughout the entire membrane.

What are the functions and localizations of beta 3 receptors?

Metabolic effects; lipolysis, gluconeogenesis, glycogenolysis adipose, GI tract, heart

When are chromosomes the most condensed?

Metaphase

What type of amino acid is methionine and what are its abbreviations?

Methionine, Met, M

What is DNA methylation?

Methylation of cytosine residues in CpG islands in the promoter of a gene results in long term repression of transcription. Important mechanism of epigenetic control of gene expression. Hypermethylation = transcriptionally inactive genes Hypomethylation = transcriptionally active genes

What is the role of the MTHFR enzyme and its tetrahydrofolate-containing substrate and product in metabolism?

Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle that catalyzes the conversion of 5,10-MTHF to 5-MTHF. 5,10-methylene tetrahydrofolate (substrate) is used to convert dUMP to dTMP for de novo thymidine synthesis. 5-Methyltetrahydrofolate (product) is used to convert homocysteine (a potentially toxic amino acid) to methionine by the enzyme methionine synthase. Individuals of 677TT (homozygous; two copies of the allele) are predisposed to mild hyperhomocysteinemia (high blood homocysteine levels), because they have less active MTHFR available to produce 5-methyltetrahydrofolate (which is used to decrease homocysteine)

What is diapedesis?

Migration of inflammatory cells from the circulation to sites of action in the connective tissue. Lifespan: Circulation 6-7 hours In tissues ~1-4 days

What is lipemia?

Milky serum or plasma after a patient has eaten a fatty meal Lipemia affects most chemistry analyses Blood must be recollected when the patient is fasting

What is the core promoter?

Minimal DNA sequence (cis-acting factors) required for accurate transcription initiation, typically 40 to 60 bp located near start site of transcription. Most common cis-acting element is INR. About 15-20% of genes will have a TATA box located around -25 to -30. A mixture of the other cis-acting elements are found however not all of them are found in one particular core promoter. Transcription is initiated in eukaryotic cells by the binding of general transcription factors (trans-acting factors) to the core promoter DNA sequences that aid in the recruitment of RNA polymerase to form the pre-initiation complex and the initiation of transcription.

What are the direct acting selective adrenergic beta 3 agonists?

Mirabegron

What are the selective adrenergic alpha 2 antagonists?

Mirtazapine Yohimbine

Where does ketone body formation occur?

Mitochondria Most commonly in the liver

What do mitogens do?

Mitogens bind to tyrosine receptor kinases, causing the monomers to dimerize and transphosphorylate each other. Mitogens promote cell division by stimulating cell-surface receptors that activate mitogenic signaling (e.g., Ras/MAP Kinase pathway), which triggers the expression of master transcription factors (Myc) that stimulate the expression of cell cycle machinery components

Describe Celiprolol

Mixed Beta adrenergic antagonist/agonists Pharmacotherapeutics **Hypertension and angina **Glaucoma β1-selective antagonist β2-agonist properties Weak 𝞪2 antagonist ⬆NO production

Describe Carteolol

Mixed Beta adrenergic antagonist/agonists Pharmacotherapeutics **Hypertension and angina **Glaucoma (carteolol) less adverse bronchoconstrictor effect Nonselective antagonist β2-agonist properties ⬆ NO production

Describe Ephedrine and Pseudoephedrine

Mixed action sympathomimetic First oral sympathomimetic agent Crosses CNS readily Mild stimulant **Appetite suppressant ** Decongestant and bronchodilator Enhances NE release Directly activates α and β receptors Enantiomer of ephedrine Precursor to methamphetamine - no longer OTC ➯ BTC

What does epinephrine do?

Mobilizes fuels from acute stress; stimulates glucose production from glycogen (muscle and liver); stimulates fatty acid release from adipose tissue

Why do phenotypes show differences in penetrance and expressivity?

Modifier genes Environmental factors Allelic variation Complex genetic and environmental interactions

Describe signaling proteins?

Modular proteins that share highly conserved catalytic and noncatalytic domains

What are the origins or monocytes/macrophages?

Monocytes are derived from the GM-CFU under the influence of M-CSF. Monoblasts are morphologically similar to myeloblasts. Promonocytes have a large, slightly indented nucleus, uncondensed chromatin and may have nucleoli. They have lysosomes (primary granules) with proteases and hydrolases. Both monoblasts and promonocytes are mitotic. Monocytes (12-20 μm) have a large indented nucleus, primary granules (lysosomes) and vacuoles. They circulate in the blood and then enter tissues where they become macrophages under local regulatory influences.w

How is hematocrit calculated?

More commonly the HCT is calculated directly from the RBC and MCV Hematocrit % = RBC (cells/liter) x MCV (liter/cell) Because the HCT is a derived value, errors in the RBC or MCV determination can lead to spurious results

How are mortality and incidence related?

Mortality rate is a good reflection of incidence rate under two conditions When case-fatality rate is high (or survival is low) When duration of disease is short Mortality rate is not a good index of incidence rate when a disease is mild and non-life threatening.

What does it mean that the genetic code is degenerate?

Most amino acids are represented by more than one codon

What are repeat disorders?

Most are di-, tri-, or tetranucleotide sequences. ACGTACGTCGGCGGCGGCGGCGGCGGCGGACTGACG Number of repeats variable Most mutations cause neuromuscular disorders Ex: Fragile X syndrome

Describe hyaline cartilage

Most common of the three cartilage types Locations: articular surfaces of movable joints, walls of larger respiratory passages (nose, larynx, trachea, bronchi), costal cartilages, and epiphyseal (growth) plates Fibers: type II collagen Growth: appositional and interstitial

What are the microtubule associated proteins?

Motor Proteins: Dynein -end directed Kinesin +end directed Non-Motor: Examples = Tau; MAP1A, B, C, D, MAP-1B, MAP-2, MAP4 Functions: organize MTs, regulate MTs stability, Regulate MT dynamics

What are red flags of genetic disease?

Multiple affecteds in multiple generations Extreme or exceptional presentation of common conditions Bilateral primary cancers in paired organs Multiple primary cancers of different tissues Neurodevelopmental delay or degeneration Extreme or exceptional pathology - pheochromocytoma, acoustic neuroma, medullary thyroid cancer, multiple colon polyps, plexiform neurofibromas, multiple exostoses, most pediatric malignancies Unexpected laboratory values -Potassium >5.5 mmol/L, sodium <128 mmol/L, phosphate>2 mg/dL and glucose <35 mg/dL in an infant Cholesterol >500 mg/dL

What is a basic metabolic panel?

Multiple chemistry tests are grouped and reported as a single profile for ease of ordering Includes electrolytes and tests of kidney function: -Sodium (Na) -Potassium (K) -Chloride (Cl) -Carbon Dioxide Content (CO2) -Blood Urea Nitrogen (BUN) -Serum Creatinine (Cr) Serum Glucose (Glu)

What happens to amino acids during a fast?

Muscle protein degraded, muscle uses BCAA's, releases Ala, Gln. Glutamine taken up by gut (for fuel); kidney (fuel, acid-base balance) Glutamine to liver (NOT fuel; mainly gluconeogenesis, urea output)

What is bioequivalence?

Must demonstrate: same peak height concentration, same time to peak height, same area under the blood concentration curve

Describe the Fragile X gene (FMR1) repeat. What disorders are caused by repeat lengths of the Fragile X gene?

Mutations in the FMR1 gene cause fragile X syndrome. The FMR1 gene provides instructions for making a protein called FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are specialized connections between nerve cells. Synapses are critical for relaying nerve impulses. Nearly all cases of fragile X syndrome are caused by a mutation in which a DNA segment, known as the CGG triplet repeat, is expanded within the FMR1 gene. Normally, this DNA segment is repeated from 5 to about 40 times. In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times.

What is an important organism that does not stain well with gram reagents?

Mycoplasma lacks a cell wall and therefore does not stain

What is genome sequencing Human Genome Project (NIH) vs. Celera Genomics?

NIH-Hierarchical shotgun: The chromosomes, each treated separately, are broken into well defined segments by enzymes called restriction endonucleases. The individual pieces are sequenced and since the source of the restriction fragments of DNA are known, the sequence of the entire chromosome is established by reassembling individual segments. Celera-Whole genome shotgun: The chromosomes are fragmented into random sized pieces. Because the fragments are generated randomly, there is overlap at the ends of the pieces. Each piece is sequenced. Powerful computers look for overlaps on the 5' end of one segment and the 3' end of another and then align these segments into contiguous arrays ("contigs").

What type of amino acid is aspartic acid and what are its abbreviations?

Negatively charged, Asp, D (aspar-Dic)

What type of amino acid is glutamic acid and what are its abbreviations?

Negatively charged, Glu, E (glu-E)

How do voltage-gated ion channels work?

Nerve impulses, channels open & close in response to change in electrical voltage affected by change in electrical charge at rest The charge difference inside & outside is maintained by sodium & potassium ions drug therapy Manipulate the degree and speed of sending a message on a nerve Voltage-gated sodium, calcium, potassium, proton channels Hyperpolarization-activated cyclic nucleotide-gated channels

How do neuron cell bodies stain?

Neuron cell bodies stain positively with basic dyes that recognize acidic 'Nissl' material (mainly components of protein synthesis machinery). Nissl material is far less detectable in dendrites and (especially) axons. This suggests that proteins are mainly made in the neuronal cell body and trafficked to distal locations.

What is the function of dopamine?

Neurotransmitter in CNS Inhibit prolactin secretion Splanchnic & renal vasculature vasodilator

What is the function of norepinephrine?

Neurotransmitter in CNS Similar, not as prominent as EPI in periphery Skeletal muscle vessel dilation (β2) Smooth muscle, relax &/or contract (β2/α) Urinary retention (mixed α/β) Metabolic ⬆ plasma glucose (α2) ⬆ glycogenolysis (β) ⬇ insulin secretion (α2); ⬆ (β2)

Describe neutrophils

Neutral in color The neutrophil nucleus has 3-5 lobes and its cytoplasm stains a light pink Neutrophils are active phagocytes. Recognize foreign substances, e.g., bacteria and get rid of them. "First line" of defense. Specific (secondary) granules: gelatinase, alkaline phosphatase, collagenase, lactoferrin, lysozyme, antibacterial basic proteins, other proteases... Azure (primary) granules: are lysosomes with a few differences, elastase, defensins, myeloperoxidase, etc. In blood vessels 50% of the neutrophils are circulating; the rest are marginated, i.e., resting near the endothelium of small vessels. Motile in tissues and do NOT re-enter blood.

What is the name for vitamin B3 and what does it do?

Niacin A component of NAD+ and NADP+ which are involved in many oxido-reductase reactions. Key co-factor in many metabolic pathways affecting carbohydrate, lipid and amino acid metabolism and DNA repair.

Are all drugs inactivated by metabolism?

No drugs can become inactive, they can turn from inactive to active, they can stay active or they can become more toxic

Is dietary galactose essential?

No it can be made from glucose

Describe Labetalol

Non-selective adrenergic antagonist (S,R)-isomer, potent α1 blocker (R,R)-isomer, potent β blocker ** Vasodilation, decreased peripheral resistance **Used in pregnancy **Used in acute aortic dissection **Useful IV med for hypertensive emergencies Local Na+ channel blocking activity

What type of amino acid is glycine and what are its abbreviations?

Nonpolar, Gly, G

How does splicing occur?

Nuclear ribonucleoproteins (snurps U1 to U6) bind to the intron, causing it to form a loop. The complex is called a spliceosome. The U1 snurp binds near the first exon/intron junction, and U2 binds within the intron in a region containing an adenine nucleotide residue. Another group of snurp—U4, U5, and U6—binds to the complex, and the loop is formed. The phosphate attached to the G residue at the 5'-end of the intron forms a 2'-to-5' linkage with the 2'-hydroxyl group of the adenine nucleotide residue. Cleavage occurs at the end of the first exon, between the AG residues at the 3'-end of the exon and the GU residues at the 5'-end of the intron. The complex continues to be held in place by the spliceosome. A second cleavage occurs at the 3'-end of the intron after the AG sequence. The exons are joined together. The intron, shaped like a lariat, is released and degraded to nucleotides

How are microtubules organized?

Nucleation - the genesis of a cytoskeletal polymer Polymerization - the elongation of a cytoskeletal polymer following the initial nucleation Nucleation occurs at the centrosome

What are nucleosomes?

Nucleosomes are a stretch of 147 nt wrapped around octamers of four different histone proteins. Another histone (H1) binds in the linker region between nucleosomes Protein-protein interactions between nucleosomes further compact chromatin Chromatin is made up of DNA and five types of protein molecules called histones. In a nucleosome core there are two copies each of histone H2A, H2B, H3, and H4 The linker region between nucleosome cores includes histone H1

What is the function of exonucleases?

Nucleotide misincorporation occurs (1 in 105 times) 3' exonuclease activity sits in a different active site within the same enzyme (DNA polymerase) This activity has strong preference for mismatched nucleotides. Misincorporation also reduces catalysis of the next nucleotide. Destabilization and unpairing increases exo activity Eliminates the last rNTP from the 5' end of RNA primer

Where are TGs stored?

Oily droplets in adipose tissue

How does protein modification occur within the golgi network?

On the cis facing side of the Golgi proteins come to the ER On the trans facing side vesicles are formed into secretory vesicles or transported to other membranes Details are not important, but appreciate that within the Golgi, proteins are modified to generate signals that determine their final destination. We will focus on one of the best understood of these signals, which targets acid hydrolases to lysosomes. Ex. phosphorylation of oligaosacchariades on lysosomal proteins, removal of MAN, addition of Gal, GlcNAc, NANA, sulfation of tyrosines and carbohydrates

Describe RecA-mediated homologous recombination

Once inside the cell the DNA is protected by ssDNA binding proteins RecA recombinase binds to the ssDNA and mediates homologous recombination The ssDNA must have regions of homology to DNA already in the chromosome In these stretches the DNA will bind and RecA will mediate strand exchange As long as the DNA is not cleaved by restriction enzymes (enzymes that cleave DNA), it will be incorporated into the genome Numerous additional genes can be introduced into the chromosome as long as they are flanked by regions of homology

How do you extract DNA from specimens?

Once the specimen is obtained the DNA can be characterized Depending on the type of specimen, PCR reactions can be performed directly on the sample or purified DNA DNA has to be extracted for whole genome sequencing (WGS) Processing of DNA includes · disrupted the tissue · lysing the bacterial cells · removing cellular debri - lipids and proteins · removing proteins from the DNA (protease) concentration of the DNA by precipitation or using affinity chromatography

What does acrocentric mean?

One chromosomal arm is much shorter than the other

What is a type strain?

One strain of a species is designated as the type strain. It is usually one of the first strains studied and is often more fully characterized than other strains; however, it does not have to be the most representative member.

Describe lipid gated ion channels

Open in response to specific lipid molecules binding to the channel's transmembrane domain membrane. Phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid (PA) are the best-characterized lipids to gate these channels Many potassium channels are gated by lipids, including the inward-rectifier potassium channels and two pore domain potassium channels TREK-1 and TRAAK. KCNQ potassium channel family are gated by PIP2. The voltage activated potassium channel (Kv) is also regulated by PA. This suggests Kv could be opened by lipid hydrolysis independent of voltage and may qualify this channel as dual lipid and voltage gated channel.

Describe voltage gated proton channels

Open with depolarization, but in a strongly pH-sensitive manner. Open only when the electrochemical gradient is outward, such that their opening will only allow protons to leave cells. Their function thus appears to be acid extrusion from cells.

What are OTUs?

Operational taxonomic units Often organisms are identified that have not been studied. They are assigned OTU numbers. The OTUs are often unidentified bacterial species.

What are components of an expression vector that allows for production and purification of proteins from bacteria?

Origin of replication LacI repressor Bacterial promoter that is under the control of the lacI repressor. Poly-linker sequence that allows for cloning of desired sequences in-frame with GST. GST (Glutathione-S transferase) sequences that encode a protein that binds glutathione. Used for purification of the recombinant fusion protein). Ampicillin resistance gene

What are Tandem repeats: Satellite, minisatellite and microsatellite DNA?

Originally identified as distinct secondary bands in density gradient centrifugation (different density is due to base composition) Tandem repeats: Often at subchromosomal regions. Large arrays form heterochromatin, which is kept condensed through the cell cycle. Satellite DNA its is found at centromeres (poorly conserved between species). The centromere domain establishes a chromatin structure independent of its sequence. However, it contains some sequences that are important for recruiting centromeric proteins. Mini satellite DNA includes telomeric DNA that is highly conserved through evolution. It also includes Variable Number Tandem Repeats (VNTRs). The number of these repeats varies within individuals and is the basis for forensic fingerprinting and diagnosis. Microsatellite widely dispersed. Some may include also VNTRs, but are now referred as Simple sequence repeats (SSR) or short Tandem Repeats (STR).

Where does the urine odor come from?

Ornithine decarboxylation to diamine putrescine Putrescine can be used to form longer compounds with three (spermine) or four (spermidine) amines. These polyamines bind to the phosphate groups of DNA and may be important in stabilizing nucleic acids. They also control the function of potassium channels, modulate the cardiac action potential

What is the epimysium?

Outer layer layer of connective tissue in skeletal muscle. Located beneath the fascia

What is the rate limiting step in purine synthesis?

PRPP is the universal ribose-5-P donor in de novo and salvage pathways. PRPP synthase is rate limiting and controlling step for purine synthesis. Also the first step and requires ATP Converts Ribose 5-Phosphate to PRPP

What are the symptoms of niacin deficiency?

Pellagra In times of poverty (war, depression) a deficiency disorder is seen Characterized by the four D's: Dermatitis Diarrhea Dementia (irritability, insomnia, loss of memory) Death "Casal necklace", a clinical sign of pellagra

What is the function of glucose-6-phosphate dehydrogenase

Pentose Phosphate Pathway G-6-P to 6-Phosphogluconolactone Creates NADPH Inhibited by beta-oxidation Active when fatty acid synthesis is active

What is the difference between trypsin vs pepsin

Pepsin is located in the stomach while trypsin is located in the intestine They are both endoproteases Pepsin is activated by acid and trypsin is activated by enteropeptidase The key role of pepsin is that it is the first protease The key role of trypsin is that it activates other zymogens

What is a white blood cell differential?

Percentage of each type of leukocyte -Neutrophils (includes bands) -Lymphocytes -Monocytes -Eosinophils -Basophils Performed either manually or by an automated instrument

How does a bone grow in width?How does the cortex increase in thickness as the bone grows in length and width?

Periosteal bone formation increases the outer (periosteal) circumference. Endosteal bone resorption increases the inner (endosteal) circumference, which in turn increases the size of the bone marrow cavity. Net periosteal formation exceeds net endosteal resorption over time, resulting in a gradual increase in thickness of the cortical bone.

What are the functions of peroxisomes?

Peroxisomal function in Mammals •Fatty acid ß-oxidation •Metabolism of reactive oxygen and nitrogen species (detoxification - the former process involves generation of hydrogen peroxide) •Early steps in Plasmalogen synthesis (specific subtypes of phospholipid) •Bile acid synthesis •Glyoxylate metabolism (converts glyoxylate generated in peroxisomes to glycine - this prevents conversion of glyoxylate to oxalate, which is highly toxic)

Describe peroxisomes

Peroxisomes are NOT made in association with the Golgi Complex. Peroxisomes contain oxidative enzymes and catalase. Function in lipid metabolism (beta oxidation of long chain fatty acids, etc.) Also synthesize cholesterol, plasmalogens, etc. Degrade hydrogen peroxide, a product of oxidative reactions. Granule like spots in TEM

What are persisters?

Persisters are dormant bacterial cells that can occur in any population because persistence is regulated by a biphasic switch These persisters are completely antibiotic resistant After antibiotic treatment, these bacteria can regrow forming a new biofilm

What are pharmacokinetics and pharmacodynamics?

Pharmacokinetics: How the body handles a drug (absorption, distribution, metabolism, excretion) Pharmacodynamics Interactions between drug and biological system leading to a series of events resulting in a pharmacological response (therapeutic; adverse reactions include side effects, toxicity, idiosyncratic, hypersensitivity, lethal; and placebo)

What are the categories of metabolic reactions?

Phase 1 Oxidation Reduction Hydrolysis Phase 2 Conjugation/synthetic Glucuronidation Acetylation Methylation

What are the non-selective alpha adrenergic antagonists?

Phentolamine Phenoxybenzamine

What amino acids are ketogenic?

Phenylalanine, Tyrosine, Leucine form Acetoacetate Threonine, Tryptophan, Lysine, Leucine and Isoleucine form Acetyl CoA

What are the adrenergic alpha 1 agonists?

Phenylephrine Midodrine Metaraminol (Direct and indirect agonist)

What do you use to treat antimuscarinic Drug Intoxication?

Physostigmine has been used to treat intoxication by drugs with antimuscarinic action (e.g., atropine, tricyclic antidepressants). It can reverse central and peripheral signs. Only used in extreme intoxication.

What are filmbriae/pili and flagella?

Pili/Fimbriae: Composed of protein Involved in attachment, adherence, conjugation, Motility - gliding/twitching motility Flagella: Composed of flagellin Uses the proton motive force to power bacterial motility Sometimes used for attachement

What is the non-selective Beta adrenergic antagonist/partial agonist?

Pindolol

What is located within diffuse lymphatic tissue?

Plasma cells Eosinophils

What is the difference between serum vs plasma?

Plasma is collected in the presence of an anticoagulant Serum lacks fibrinogen as it stays in the clot

What are thrombocytes?

Platelets FUNCTIONS: 1)Continuous surveillance of blood vessels for breaks. 2)Clot formation / plug wounded vessels. 3)Secrete factors to stimulate other cells, e.g., serotonin = vasoconstrictor. Produced in bone marrow. Life span ~10 days in circulation. Alpha granules - store proteins involved in hemostatic functions, including adhesion e.g. fibrinogen, coagulation e.g. plasminogen, endothelial cell repair e.g. platelet-derived growth factor, etc. Dense granules - store mediators of vascular tone, e.g. phosphate, ADP, serotonin

What type of amino acid is asparagine and what are its abbreviations?

Polar, Asn, N (asparagiNe)

What type of amino acid is glutamine and what are its abbreviations?

Polar, Gln, Q (glutamine-the-Qtamine

What type of amino acid is serine and what are its abbreviations?

Polar, Ser, S

What type of amino acid is threonine and what are its abbreviations?

Polar, Thr, T

What type of amino acid is tryptophan and what are its abbreviations?

Polar/Aromatic, Trp, W

What type of amino acid is tyrosine and what are its abbreviations?

Polar/Aromatic, Tyr, Y (t-Y-rosine)

What are the types of error-prone polymerases in E.coli?

Poly V- Replicates past pyrimidine dimers caused by UV light Pol IV- Replicates past various other lesions in DNA Error prone polymerases lack proofreading capabilities, allowing them to read past lesions by randomly inserting nucleotides · important under conditions of stress o increased mutation rates under stress such as oxidative damage (e.g. oxidative burst by immune cells) o starvation (in deep layers of a biofilm)

When does mitosis end in erythrocyte maturation?

Polychromatophilic erythroblast

How are carbohydrates digested?

Polysaccharide digestion begins with chewing and salivary amylase Disaccharides are not hydrolyzed by amylase Low pH inhibits CHO digestion in stomach Pancreatic amylase resumes hydrolysis in lumen of the duodenum Enzymes on enterocyte brush borders hydrolyze disaccharides to monosaccharides.

What is scurvy?

Poor nutrition leading to Vitamin C deficiency causes the failure to form hydroxyproline and hydroxylysine (Post-translational modification via hydroxylase) Results in unstable triple helix Characteristics of the disease include capillary fragility (bruising, bleeding gums), poor wound healing, poor bone growth in children

What happens in porphyria?

Porphyrin synthesis is the process that produces heme, ALA synthase is the rate limiting enzyme. Porphyrin synthesis is important because it is the key factor in hemoglobin production. If heme isn't functional then oxygen cannot be carried around for the ETC. These attacks are typically triggered by prescription drugs (including oral contraceptives), alcohol, and other factors such as fasting, infections, or stress.

Where does the positional information for limb formation come from?

Positional information is located in signaling centers that promote growth and control patterning along the three axes. The apical ectodermal ridge at the distal end of the limb bud ectoderm produces WNT and FGF and promotes limb bud growth and distalization. The zone of polarizing activity located in the posterior-dorsal mesenchyme of the limb bud produce Sonic Hedgehog, which organize the anterior-posterior axis. Dorsal and ventral ectoderm produces WNT7A and BMPs, respectively, which organizes the dorsal-ventral axis. Transplantation and ablation studies showed that cells in a limb field, at early stages of development, are pluripotent and regulate their fate based on their position within the field. Organizing centers arise at the posterior margin and the distal AP margin that regulate limb pattern formation along the three body axis. The organizing centers establish morphogen gradients that specify the proximal-distal, anterior-posterior, and dorsal-ventral positional values of cells in the limb.

What type of amino acid is arginine and what are its abbreviations?

Positively charged, Arg, R, R-ginine

What type of amino acid is histidine and what are its abbreviations?

Positively charged, His, H

What type of amino acid is lysine and what are its abbreviations?

Positively charged, Lys, K

Why is potassium tested?

Potassium is the major intracellular cation -90% intracellular Elevated serum potassium level -Hyperkalemia -Renal insufficiency or failure, certain drugs -Can be associated with life-threatening cardiac conduction abnormalities -Very common is artifact from poor phlebotomy or prolonged storage Decreased serum potassium level -Hypokalemia -Diarrhea, diuretics

What are the selective adrenergic alpha 1 antagonists?

Prazosin Tamsulosin Terazosin Doxazosin

How are DA, NE, and E actions terminated?

Primarily by re-uptake by dopamine and norepinephrine transporters into pre-synaptic terminals Amenable to pharmacological intervention. Inhibitors prolong actions of neurotransmitters.

What are the functions and localizations of alpha 1 receptors?

Primarily for vasoconstriction of arteries and veins particularly in vascular smooth muscle **Leads to an increase in blood pressure **Venous pressure increase leads to increased venous return which is useful for shock **Pupil dilation (mydraisis) and urinary retention because of urethral sphincter contraction ⬇GI smooth muscle motility, constinpation **Can be used for decongestion Gq pathway that activates IP3-DAG cascade causing the increase in intracellular calcium that activates smooth muscles cells. heart, liver, smooth muscle, blood vessels, platelets, lung, eyes, blood vessels, bladder, vas deferens, prostate, kidney, spleen, brain; postsynaptic

What cells are located in the primary follices of lymph nodes?

Primary follicles: B cells and B memory cells (lacks mantle and GC), secondary follicle (mantle and GC), exposure to Ag results in development of a mantle and GC (B cells and plasma cells).

What are the components of the lymphatic system?

Primary lymphoid organs: produce the cell components of the immune system 1.Bone Marrow 2.Thymus Secondary lymphoid organs: are sites in which immune responses are initiated and maintained in order to generate protective immunity against exogenous pathogens and tolerance to self-antigens and commensal organisms. 1.Lymph nodes: contain specialized compartments where immune cells congregate, and where they can encounter antigens 2.Spleen: specialized compartments where immune cells gather and work, and serves as a meeting ground where immune defenses confront antigens 3.Tonsils/Peyers Patches/Appendix 4.Aggregates of lymphocytes: BALT/GALT

Describe the structure of collagen

Pro-α collagen chains are the starting material in the synthesis of mature collagen These chains are woven into long rigid right-turned triple helices which form the base unit for all collagens Different pro-α collagen chains can be "mixed and matched" to form the different types of collagen A defining feature of collagen is that it is 33% glycine, 13% proline and 9% hydroxyproline (unique AA), organized in a repeating tripeptide (Gly-X-Y) Glycine and proline/hydroxyproline each have unique properties critical for the stability of the collagen triple helix Glycine is small (R-group is a proton) and flexible, forming tightly packed turns Proline/hydroxyproline are rigid, providing strength Collagen is stabilized by both hydrogen bonds (yellow) and covalent bonds (red) Procollagen-Procollagen peptidases hydrolyze extension peptides-Tropocollagen Collagen is a glycoprotein Covalent attachment of disacharides to hydroxylysine on collagen Most glycoproteins are N-linked (Asparagine) or O-linked (Serine or Threonine) - in collagen, this also includes hydroxylysine Occurs in 2 steps - first galactose and then glucose No physiological role has been identified for this glycosylation Glycosylation does affect immunogenicity - implications to autoimmune diseases

What is processivity?

Processivity is defined as the average number of nucleotides added every time the polymerase engages Processivity is facilitated by the sliding capacity of the polymerase along the DS portion of the template in a sequence independent manner Additional processivity is mediated by a protein complex designated "sliding clamp" (see below)

How is the beta oxidation of odd-chain fatty acids different?

Produces a propionyl CoA as well as Acetyl CoA

What tissues do prostacyclin and thromboxane and PGF2 target?

Prostacyclin PGI2- Vascular endothelial cells (Decreases platelet aggregation and increases vasodilation) Thromboxane TXA2- Platelets (Increases platelet aggregation, vasoconstriction and bronchoconstriction) PGF2 increases vasoconstriction and bronchoconstriction

What is FAD and where does it come from?

Prosthetic group that comes from riboflavin (B2)

What is a strain?

Pure culture isolate or mutant generated in the lab that differs from other members of the species in a number of definable consistent ways

What is an isolate?

Pure culture obtained from a heterogenous wild population of microorganisms e.g. disease isolate

What do you use for the treatment of myasthenia gravis?

Pyridostigmine or neostigmine for chronic therapy: May combine with antimuscarinic agents to reduce side effects. Edrophonium is used to confirm diagnosis of myasthenia or access therapy. (Cholinergic crises vs Myasthenic crises)

What G protein subtypes is each adrenergic receptor?

Qiss aka Kiss Gq,Gi,Gs,Gs Alpha-1, Alpha-2, Beta-1, and Beta-2

How is vitamin B12 absorbed?

R-binders (haptocorrins): produced in gastric mucosa, destroyed by proteases in duodenum. Intrinsic factor: produced by parietal cells Intrinsic factor-B12 complex attached to specific receptors in the ileum and internalized In the enterocyte, B12 binds to transcobalmin II and is released into the circulation 50% deposited in the liver What could go wrong? Loss of parietal cells (autoimmune, as with pernicious anemia) or gastric mucosa (stomach surgery) could decrease R-binders/Intrinsic factor, Pancreatitis could cause decreased protease activity, interfere w/intrinsic factor, Liver damage could decrease storage of B12,

What is red blood cell distribution width?

RDW is an indication of the variation in the RBC size (anisocytosis) It is derived from the red blood cell volume distribution Represents the coefficient of variation of the curve An elevated RDW (indicating more variation in the size of RBCs) is associated with anemias from various deficiencies, e.g. iron, B12, or folate

What is Real time PCR or qPCR?

Real-time PCR is a machine based quantitative PCR that measures the amount of PCR product after each cycle. Real-time PCR can be used to compare normal (control) samples to disease samples, giving an idea as to expression changes which occur with pathogenesis. Real-time PCR due to its sensitivity is also used in the detection of pathogens in the blood such as viruses and oncogenic fusion mRNAs as markers for relapse. Real time PCR relies on specialized probes that bind sequence between the PCR primers Molecular beacons primers are designed to have a stem loop structure that brings a fluorophore at the 5' end in very close proximity to a quencher at the 3' end. However, in the presence of complementary target (correlates to the amount of generated PCR product in a reaction) the probe unfolds and hybridizes to the target. As a result, the quencher no longer absorbs the photons emitted by the fluorophore and the probe starts to fluoresce. Taq man double dye probes. Similar principal, but the ability of the quencher to suppress flourophore signal is not dependent on any secondary structure and signal is released as polymerase move through the amplified region.

How are 7TMR regulated?

Receptor phosphorylation and uncoupling from G proteins Receptor internalization: Important for reduced response and re-sensitization The major pathway involved: Agonist-promoted phosphorylation of the receptor by G protein-coupled receptor kinases (GRKs), Binding of arrestins, Binding of the phosphorylated receptor-arrestin complex to adaptor proteins and clathrin Endocytosed by clathrin-coated vesicles in a dynamin-dependent manner. Receptor down-regulation: More prolonged exposure leads to reduction in the number of receptors, known as down-regulation. Enhanced receptor degradation Following prolonged agonist stimulation, GPCRs are trafficked from endosomes to lysosomes and degraded by lysosomal enzymes. Decreased receptor synthesis

How does information flow in a signaling cascade?

Receptor-Intracellular signaling machinery-Transcription factors-Gene expression One ligand-receptor interaction can result in diverse cellular effects

What are the different molecules used for signaling?

Receptors and their specific ligands initiate the signaling process Scaffold molecules bring specific proteins together in proximity G proteins and GTPases regulate a wide diversity of processes Second messengers are soluble, low molecular weight regulators of signaling proteins Protein kinases hydrolyze ATP and add a phosphate group to a substrate Protein phosphatases remove a phosphate group from a substrate

What are MHCs?

Receptors on Macrophage (APC) 1. The surface of antigen-presenting cells house proteins encoded by the MHC. 2. Presentation of Ags to T cells is carried out by these proteins Major histocompatibility complex (MHC) is a set of genes that code for cell surface proteins essential for the acquired immune system to recognize foreign molecules MHC molecules are proteins recognized by T cells when distinguishing between self and nonself. A self MHC molecule provides a recognizable scaffolding to present a foreign antigen to the T cell.

What is recombinant DNA technology?

Recombinant DNA technology refers to methodology used to isolate and "clone" (amplifying from a single source) genes and gene products (I.e. cDNAs) AND using the cloned material for further study of the DNA sequence and functional properties of the encoded products. This field has revolutionized modern medicine, diagnostics, and food production.

How is hemoglobin degraded?

Red blood cells are destroyed in liver/spleen/bone marrow (reticuloendothelial system, also called mononuclear phagocyte system- MPS) by phagocytes (hemolytic anemia occurs when destruction is more rapid than replacement, as in sickle cell disease) Globin, the protein part, is degraded to amino acids (not directly reused); the amino acids are reutilized. Iron is removed, captured and recycled by transferrin in blood. The porphyrin ring (heme) is partially oxidized to form product bilirubin, which is conjugated (attached) to glucuronate to make it more water-soluble, and then excreted in urine and feces Heme degrades to unconjugated (indirect) bilirubin, and initially is transported in blood bound to albumin; this is how it arrives to the liver

What are some examples of acidic dyes?

Red/Pink Eosin Fuchsin

What are the steps of acetylcholine release?

Release of acetylcholine Binds to receptors on the muscle cell membrane Membrane becomes permeable to sodium ions Depolarization of muscle cell membrane Depolarization (action potential) transmitted throughout the muscle Via the T-tubule system Acetylcholine degraded

What is drug excretion?

Removal of a drug or its metabolites from the body to the external environment. This is important in preventing or minimizing toxic effects of drugs. Drugs can be excreted by several routes. Volatile drugs (e.g., inhalational general anesthetics) may be eliminated largely via the lungs (exhaled air). Non-volatile, relatively water soluble agents, or their metabolites, may be eliminated via any of the bodily secretions, but principally in the urine or bile.

What components control initiation of DNA replication?

Replicator: Set of cis-acting DNA sequences sufficient to initiate DNA replication. Initiator: Protein(s) that recognizes specific DNA sequences within the replicator and activates initiation of replication (nucleates the assembly of the initiation machinery).

How is fuel utilized during longer duration exercise?

Requires aerobic oxidation -Muscle glycogen -Glycogen from plasma •Uptake increases dramatically after a few minutes •Rising AMP levels stimulates glucose transport (AMP kinase) •Normal plasma glucose maintained by dramatic (up to 5x) increase of hepatic glucose production by glycogenolysis, gluconeogenesis Eventually fatty acids released from triglycerides in adipose tissue are predominant energy source •Increased AMP levels activates AMP kinase, which phosphorylates and reduces activity of acetyl-CoA carboxylase. Releases inhibition of CPT by malonyl CoA, promoting entry of fatty acids into the mitochondria

What are the different types of microbiota?

Resident Microbiota •life long members of an individual's microbiota •composition can be influenced by early events (e.g. breast milk vs. formula) Transient Microbiota •competition from resident flora •immune system elimination •nutrient availability (e.g. changes in diet)

What metabolic process could nitrate and nitrate reductases be used for that would give Salmonella a metabolic advantage over other bacteria in the intestinal tract, which are gaining energy predominantly by fermentation?

Respiration Nitrate is an electron acceptor that Salmonella (which encodes nitrate reductases) can use for respiration. Since concentration of nitrate rises during inflammatory response, under these conditions Salmonella would have a metabolic advantage over other bacteria in the intestinal tract that are gaining energy predominantly by fermentation. (Salmonella out-competes the fermenting microbes in gut)

What do osteoblasts do?

Responsible for the synthesis and mineralization of bone ECM Protein producing cells are cuboidal or columnar and lining active bone-forming surfaces Osteoid versus mineralized matrix Actively synthesizing proteins: well-developed Rough ER and Golgi network

Describe reticular fibers

Reticular cell of Fibroblast Very fine type III collagen fibers form a three dimensional network rather than a thick bundle for support Support hemaotpoietic and lymphoid organs (except thymus) Stained with silver salts due to high content of sugar chains

What is the name for vitamin B2 and what does it do?

Riboflavin Modified with a phosphate group (FMN) or an adenine (FAD). Integral part of coenzymes in a variety of oxido-reductases including a-amino acid oxidase, aldehyde dehydrogenase, and succinate dehydrogenase. Each can undergo reversible reduction (to FMNH2 and FADH2). Required for metabolism of both sugars and lipids to derive energy.

How does and NDP form a dNDP?

Ribonucelotide reductase In humans, only the NDP forms can be used to make deoxynucleotides Uses NADPH

How is rRNA synthesized in eukaryotes?

Ribosomal RNA is transcribed as a large precursor molecule that is then modified and trimmed to form the mature species that participates in protein synthesis. RNA polymerase I transcribes the 45S ribosomal RNA precursor which is cleaved to produce the 18S, 28S and 5.8S rRNAs. The promoter consists of two sequences in the 5'-flanking region of the gene that differ from the promoters for RNA polymerases II and III. The 45S precursor is methylated by S-adenosyl methionine (SAM) and cleaved to produce a 41S precursor, which undergoes further processing. (A small number of the nucleotides [1 to 2% of total] are methylated, usually on the 2'-hydroxyl of the ribose moieties. During processing the rRNA precursors are associated with proteins. The genes for the 45S rRNA precursor are found in the nucleolar region of the nucleus. About 1,000 of these genes are present in the human genome and are linked in tandem. The 5S rRNA, produced by RNA polymerase III from genes located outside the nucleolus, migrates into the nucleolus and joins the ribonucleoprotein particles. The nucleolus consists of a fibrous region in which the genes for rRNA are being transcribed and a granular region in which the precursors of rRNA, complexed with proteins, are being modified and trimmed. Ultimately, the 40S and 60S ribosomal subunits are produced, which migrate through the nuclear pores to the cytoplasm where they combine, forming the 80S ribosomes which, complexed with mRNA, serve as the sites of protein synthesis

What is osteomalacia?

Rickets Inadequate Mineralization * Defective vitamin D intake or metabolism. * Defective mineralization of osteoid. * Increased osteoid thickness. * Increased fracture risk. * Treatment by vitamin D supplementation Bowing of lower limb long bones

What is SAM?

S-adenosylmethionine that donates its methyl group to other compounds

What is the SOS response?

SOS response · LexA is a global repressor (negative regulator) · LexA represses genes involved in recombination, repair and error prone polymerases and cell division · DNA damage, fork stalling during chromosome replication, ssDNA (brought in by conjugative plasmids and transposons) activates the RecA · RecA can interact with other proteins as a recombinase AND other proteins to act as a protease cleaving LexA · RecA cleaves LexA and relieves repression · DNA recombination and repair and error prone polymerases are activated and cell division pauses

What is PRADER-WILLI SYNDROME?

Same deletion (15q11 to 15q13) as in Angelman Syndrome except of PATERNAL chromosome 15 1 out of 10,000 to 30,000 live births No obvious birth defects Short stature with disproportionately small hands and feet Developmental delay Insatiable appetite that usually manifests by age 3 years leading to obesity When obesity and its associated health problems are controlled, life expectancy normal

How do you determine nucleic acid sequence of identified clone?

Sanger DNA sequencing involves enzymatic DNA synthesis using base specific chain terminators- Concept is the same except the 4 reactions contain the same primer with a different fluorescent label. Reactions are then combined prior to separation and signal is detected by a laser. Size DNA products on large denaturing polyacrylamide gels that can resolve sizes of products by one nucleotide.

How do you conduct a case control study?

Select subjects with outcome/disease of interest (Cases) Select similar group of individuals without disease/outcome of interest (Controls) Determine exposure status of all subjects Quick and easy Able to study multiple risk factors simultaneously Efficient for rare diseases Requires 'small-ish' sample sizes Assumptions: 1.Cases are representative of all persons who develop the disease. 2.Controls are representative of the healthy population from which the cases were drawn. 3.Information on exposure is collected equally in cases and controls.

Describe Terbutaline

Selective Beta 2 adrenergic agonist **Management of chronic airway diseases **Prevents premature labor by relaxing the uterus Pharmacodynamics Bronchial and arteriole dilation (↓PR) Slows GI motility Inhibits mast cell histamine release

Describe Albuterol

Selective Beta 2 adrenergic agonist **Management of chronic airway diseases Pharmacodynamics Bronchial and arteriole dilation (↓PR) Slows GI motility Inhibits mast cell histamine release

Describe Salmeterol

Selective Beta 2 adrenergic agonist **Management of chronic airway diseases Pharmacodynamics Bronchial and arteriole dilation (↓PR) Slows GI motility Inhibits mast cell histamine release

Is DNA conservative, semi conservative, or non-conservative?

Semi conservative

What do perinuclear cisterna do?

Separates the inner nuclear envelop from the outer nuclear envelop, which bears ribosomes.

What is eukaryotic mRNA transcribed?

Sequences in the 5'-flanking region of a gene are involved in controlling its transcription. Other DNA elements (enhancers and silencers) regulate the frequency of transcription of genes; they are position independent Enhancers Variety of consensus sequences: •In -25 region TATA box (12.5% of genes); •other consensus sequences farther upstream or downstream after transcriptional start signal.

What are promoters?

Sequences on DNA determine where RNA polymerase binds, and where to begin transcribing Promoters are usually composed of smaller sequences called "boxes" or "elements". RNA polymerase must recognize which genes to §Because promoters are on the same molecule of DNA and near the gene being regulated they are referred to as "cis acting". Proteins that bind to DNA and influence RNA polymerase are referred to as "trans acting"

Describe stratified epithelium

Shape based on Top-Most layer Stratified squamous epithelium non-keratinized/non-cornified Cells at the surface are nucleated Typical Location: Oral cavity, esophagus, Vagina

Describe a Simple Columnar Epithelium

Shaped like a column Nuclei are lined up in the basal portion of the cells Typical Location: Small Intestine, Stomach Lining etc. Sometimes apical domain contain specializations Cells are frequently of the same type, but sometimes a "special" cell is found among these cells, e.g. goblet cell Goblet cell it is a secretory cell or "unicellular gland" which secretes mucus

What is the perichondrium?

Sheath of dense connective tissue surrounding most cartilage Contains vasculature, nerves, and lymphatic vessels Outer layer of fibroblasts Inner layer of chondroblast precursors

What is the definition of lamellar?

Sheets stacked adjacent to each other with fluid or matrix in between

Why do artifacts arise?

Shrinkage because of fixation, dehydration and embedding Loss of molecules that were not retained after fixation or removed during dehydration (glycogen and lipids) Other Artifacts: wrinkles in tissue, precipitate of stains.

Describe cholinesterase inhibitors

Simple quaternary alcohol - edrophonium Carbamic acid esters (carbamates) - physostigmine, pyridostigmine, neostigmine, carbaryl Organophosphates - malathion, sarin, soman All of these agents act to inhibit AChE and pChE, thus preventing the destruction of ACh. Molecular details vary among the three groups.

How are smooth muscles organized?

Single unit: A unit or group of cells work together, are connected by gap junctions that allow ions and small molecules to pass between cells and thereby regulate contaction of the sheet or bundle of cells. Multiunit: Individual smooth muscle cells are independently innervated fibers. They are controlled by signals from nerves.

What is hereditary elliptocytosis and sphereocytosis?

Smears from an individual who has hereditary spherocytosis or elliptocytosis (autosomal dominant inheritance) contain a mix of RBC morphologies. Some have the typical biconcave RBCs with a pale center. Others will be ellipses or spheres and lack the pale center. Gene defects in the RBC lattice network cause hereditary elliptocytosis and spherocytosis. Spherocytosis is a defect in spectrin Ellipotcytosis is a defect in either Band 4.1 or spectrin

Why is sodium tested?

Sodium is the main determinant of plasma osmolality Increased serum sodium level -Hypernatremia -Dehydration, i.e., diarrhea Decreased serum sodium level -Hyponatremia -Increased fluid volume, e.g., congestive heart failure

What are some inhibitors of RNA synthesis?

Some bind to DNA -Actinomycin D intercalates DNA, blocks replication and transcription. Very toxic for both prokaryotic and eukaryotic cells. Some bind to RNA polymerase -rifampicin binds to bacterial RNA pol, prevents initiation of RNA synthesis, does not block elongation. Used as antibiotic. -Streptolydigin binds to bacterial RNA polymerase and prevents elongation of RNA chains. Used as antibiotic. -a-Amanitin inhibits eukaryotic RNA polymerase (Pol II readily inhibited, Pol I is insensitive). Found in poisonous mushrooms

What is Hfr?

Some conjugative plasmids can integrate into the bacterial chromosome forming Hfrs (high frequency recombination)

Describe tyrosine kinases

Some receptors have kinase activities Some receptors do not, but are associated with tyrosine kinases when activated. Most receptors are involved in growth and differentiation of various types of cells Insulin receptor is involved in glucose regulation Mutations of receptors may lead to cancers Approximately 20 different RTK classes have been identified Growth factor receptors regulate phospholipase c-gamma

What happens during undershoot

Some voltage dependent K+ remains open even the membrane potential returns RMP because K+ channels close slowly (Figure 9-5):

What is specialized transduction?

Specialized transduction depends on phage integration into the chromosome (lysogeny) When the phage switches to lytic cycle, DNA around the integration site is picked up and packaged The DNA is inserted into the recipient cell when the virus reintegrates (lysogeny) Phage encode their own integrase and excisase, do integration is directed by the phage and does not require homologous recombination (non-homologous recombination) Only genes immediately adjacent to the virus are transferred

Describe the path of trabecular arteries through the spleen

Splenic artery enters hilum Gives rise to trabecular arteries Trabecular arteries (TA) in trabeculae of splenic pulp TA leaves trabeculae and becomes the central artery (CA) as it becomes surrounded by T cells (periarteriolar lymphoid sheath (PALS) and travels through a lymphatic nodule (white pulp). As the CA leaves the white pulp it branches into penicillar arteries, ending in macrophage sheathed capillaries, which drain into sinusoids (closed circulation) or into the red pulp (open circulation). Sinusoids drain into pulp veins, trabecular veins or splenic veins.

What is located in red pulp?

Splenic cords (Cords of Billroth): plasma cells, macrophage and blood cells, supported by reticular fibers. Splenic sinusoids = discontinuous capillary. Plasma cells and macrophages take up and destroy particles and cellular debris in blood

What are the steps of cholesterol synthesis?

Stage I: synthesis of mevalonate from acetyl CoA Stage II: Formation of activated isoprene units and condensation of six 5-carbon isoprenes to from the 30-carbon squalene. Condensation reactions From C5 to C30 Stage III: Conversion of squalene to cholesterol Cyclization Epoxide formation (oxygen is needed) Reduction by NADPH

What does sudan black stain for?

Stains lipids Myelinated axons stain heavily

What is variance?

Standard deviation squared

What are the principles and applications of Cell Therapy?

Stem cells are cells that can both cell renew and also give rise to differentiated progeny. Present in all stages of development and in all tissues. Pluripotent embryonic stem cells are derived from the early embryo (ethical issues?), can be isolated and cultured to generate embryonic stem cell lines. Can be manipulated to induce differentiation into a number of cell types. Tissue stem cells are derived from adult tissues and cord blood. Likely to have limited plasticity. Still very difficult to control the efficiency of the differentiation process. Concerns about cancer risk as inject a high number of actively proliferating undifferentiated cells.

What are the steps in transfer of ICE?

Steps in transfer of ICE Excision by excisase Circularization (not a plasmid - no replicon) Conjugative transfer of a single strand through at T4SS Reforming of the double stranded (dsDNA) circular form (this is technically a single round of replication but NOT an autonomous replicon like a plasmid) Integration by integrase

What are the steps of a gram stain?

Steps of the Gram stain 1. staining with crystal violet - both Gram positive and Gram negative cells appear purple under oil-immersion light microscopy 2. treatment with iodine aggregates the crystal violet -both Gram positive and Gram negative cells appear purple 3. washing with ethanol collapses peptidoglycan and extracts lipids from the outer membrane - Gram positive cells appear purple; Gram negative cells are colorless 4. counterstaining with safarnin - Gram positive cells appear purple; Gram negative cells appear red

What stimulates and inhibits the formation of oxidized LDL?

Stimulated by superoxide, H2O2 and other ROS Inhibited by Vitamins E,C,A

How is adipose tissue lipolysis inhibited by glucose and insulin?

Stimulation of glucose uptake Inhibition of Hormone sensitive lipase Synthesis of triglycerides in the presence of glucose-derived glycerol 3-phosphate

eIF2B is a main regulator of protein synthesis. Given what you know about protein synthesis regulation during stress, provide an explanation for why individuals with VWM undergo irreversible progression of disease when they develop high fever.

Stress often causes global suppression of protein translation. Protein translation is a very energetically intensive process, and its suppression allows for stress adaptation and recovery. Under normal circumstances of stress (e.g. mild fever) the eIF2a protein will be phosphorylated and binds to eIF2B , effectively inhibiting its activity. This mutation in the epsilon subunit of eIF2B must cause a hyper-suppressive response that cannot be reversed.

What are the different forms of senescence?

Stress-induced senescence Telomere shortening-induced senescence (replicative senescence). Oncogene-induced senescence Normal cells have a finite life span when placed in culture. Cells divide a defined number of times and then enter a senescent stage, at which cells permanently exit the cell cycle. Senescent cells are metabolically active, but do not progress through the cell cycle despite presence of mitogens (hypermitogenic arrest). These cells will eventually die.

What is the passive length-tension relationship of muscles?

Stretching the muscle requires relatively little force until the preload reaches 3.2 µm. The resistance to stretch depends on the elastic properties of titin and other proteins in parallel with the thick and thin filaments. The increased stiffness at high preloads prevents the muscle from being over stretched.

Describe macrophages

Structural Features: Lysososmes for break down of phagocytic material Numerous phagocytic vesicles for transient storage of ingested material Oval or kidney shaped nucleus FUNCTIONS: Phagocytose large objects, microbes, aged RBCs, dead cells, tumor cells and digest them Antigen-presenting cells Under light microscope macrophages can be identified by the dense pigment - injected vital dye or particulate material Small granules will appear within

What are intermediate filaments?

Structure -Non-polarized -Roughly 10nm in diameter -Comparatively NON-dynamic (much more stable) Functions -Space-filling elements -Give cells tensile strength -Specialized functions depending on cell type -Important at cell junctions Important point: -Much less conserved across cell types than microtubules or microfilaments -Different cell types have different kinds of intermediate filaments (can be used as cell-specific "markers") Intermediate Filaments are expressed in a Cell Type Specific Manner

What is Km?

Substrate concentration required to react at 1/2 Vmax (maximum rate) The value of Cout, that gives half the maximum flux is called KM

What is an example of substrate level phosphorylation?

Succinyl CoA - Succinate by Succinyl CoA Synthetase forming GTP

What does the smooth ER do?

Synthesis of various lipids and steroid hormones; detoxification of drugs and poisons; oxidation of many xenobiotics (cytochrome P450 enzymes)

What is the effect of NO on the cell?

Synthesized by arginine and requires O2 NO is inherently unstable inactivated rapidly (metabolized to NO3). NO can play a key role in vasodilation; drugs like nitroglycerin, sodium nitroprusside work by producing NO (metabolized to NO).

How is acetylcholine synthesized and degraded?

Synthesized by choline acetyltransferase Degraded into acetic acid and choline by acetylcholinesterase Insecticides (Malathion) inhibit insect AChE. Sarin, VX are very potent inhibitors of AChE, used as chemical weapons.

Where are teichoic acids located?

Teichoic acids attached to the wall confer a negative charge The amount of teichoic acid depends on the bacterial spp. and the amount of peptidoglycan The cell wall can have proteins covalently attached to the peptide side chain in place of a peptidoglycan crosslink (predominantly in Gram positive bacteria)

How is DNA synthesized?

The 3'OH attacks the a-phosphoryl of the substrate nucleotide, releasing pyrophosphate, which hydrolyzes into 2 phosphates, providing the energy needed for the reaction.

What are the differences between the two acetyl CoA carboxylases?

The ACC1-generated malonyl-CoA is utilized by fatty acid synthase (FAS) for the synthesis of fatty acids in the cytosol. In contrast, the ACC2-generated malonyl-CoA functions as inhibitor of CPT1 activity and the beta-oxidation.

What is the AER?

The AER is important both for supporting limb development and also in patterning the limb. The apical ectodermal ridge at the distal end of the limb bud ectoderm produces WNT and FGF and promotes limb bud growth and distalization...P/D axis Limb mesoderm supports limb development and specifies the identity of the limb.

How is membrane fluidity determined?

The C-C bonds in the polymethylene segment of a fatty acyl chain can adopt either a trans or a gauche conformation. Lipid hydrocarbon chain can undergo trans and gauche conformational changes. As the number of gauche conformation is increased, the chain length is shortened and the cross sectional area occupied by the hydrocarbon chain is increased. The conformation at a given C-C bond is not fixed; rather, it fluctuates (~ns) from one conformation to another at different instances. Single gauche rotation (B) is not favored. b-coupled rotations (C) are favored because they keep the acyl chain roughly linear, establishing better chain-chain interactions. The b-coupled rotations shorten the acyl chain length by 1.27Å and create a minimum defect volume. Since the b-coupled rotations may occur at many different locations in the acyl chain, the defect volume moves along the chain. This defect volume contributes to the overall membrane free volume (or membrane "fluidity"). Several gauche conformations may be present in a single acyl chain at the same time (2-7 in DPPC at 50oC).

Describe the NF-kB pathway

The NF-kB proteins are latent gene regulatory proteins that regulate many inflammatory responses. NF-kB is a heterodimer of two related proteins of 65 kDa and 50 kDa (p65 and p50). NF-kB is sequestered in an inactive state in the cytoplasm by direct binding to an inhibitor called I-kB. In response to an appropriate signal, I-kB is phosphorylated by I-kB kinase. Phosphorylated I-kB is degraded, which releases the NF-kB heterodimer. Following release from the inhibitor, NF-kB dimers translocate from the cytoplasm to the nucleus, where they bind target sequences and stimulate transcription of specific sets of genes. Many transcription factors transactivate sets of multiple genes related by a common function

How does bacterial RNA compare to eukaryotic RNA?

The RNA polymerase has the same basic function as in eukaryotic cells, but the proteins are different, making it a target for antbiotics

Describe Ras proteins

The Ras family of monomeric GTPases link activated tyrosine kinases receptor complexes to the next series of intracellular protein kinases 1. The Ras proteins belong to the large Ras superfamily of monomeric GTPases, which include two other subfamilies: • the Rho and Rac proteins, involved in relaying signals from cell-surface receptors to the actin cytoskeleton, and • the Rab family, involved in regulating the traffic of intracellular transport vesicles. 2. Ras proteins were first discovered as the hyperactive products of mutant ras genes. About 30% of human cancers have such mutations in a ras gene.

What is the reflection coefficient?

The Reflection coefficient relates to how a semipermeable membrane can reflect solute particles from passing through. A value of zero results in all particles passing through. A value of one means that no particle can pass If the concentration of the solute in the filtrate is called Cf, the reflection coefficient (s) of the membrane for the solute is: Reflection Coefficent= 1-(Cf/Ci) If s = 1 the membrane is absolutely impermeable to the solute If s = 0 the membrane does not act as a barrier to the solute. If s for example, = 0.2 eventually the solute will cross the membrane and come into equilibrium across the membrane. Reflection coefficients are always between 0 and 1.

What is quorum sensing?

The ability of bacteria in a biofilm to communicate with each other and coordinate their activities Quorum sensing occurs when bacteria produce a small diffusible molecule at a consistent rate The bacteria can sense the small molecule o take it up into the cell through transporters and it binds to a regulatory molecule o the use of a histidine kinase sensor in the cellular (plasma) membrane If diffusion is limited (e.g. a group of tightly packed cells) the signal will accumulate in the microenvironment When it surpasses a threshold, a signal is transduced and behavior is changed Some signals are used to detect the same species o homoserine lactones in Gram negatives o oligopeptides in Gram positives · some signals work to sense the general population o autoinducer-2 (AI-2) = S-adensyl-methionine derivative that is a metabolic byproduct of many bacteria

What components are in the fatty acid synthase complex?

The acyl chain elongations and reductions are catalyzed by fatty acid synthase which is a homodimer in which enzyme-bound phosphopantetheine from the acyl carrier protein (ACP) and a unique cysteinyl residue from ketoacyl synthase are the important functional groups for carrying and transferring the acyl groups.' Chain elongates on the phosphopantetheine SH group Contains two SH groups where elongation occurs

What is the basic structure of the bacterial cell wall?

The bacteria cell wall is made up of peptidoglycan Alternating residues of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) Peptide chain - 3 variant amino acids with a terminal D-Ala that can be crosslinked to the 3rd amino acid of a neighboring chain The crosslink between 4th D-Ala and the 3rd amino acid can be direct for gram-negative bacteria or via a multi-amino acid bridge for gram-positive bacteria Cross-linking adds strength to the petidoglycan

How is gene transcription activates by a rise in cAMP concentration?

The binding of an extracellular signal molecule to its G-protein-linked receptor leads to the activation of adenylyl cyclase and a rise in cyclic AMP concentration. The increase in cyclic AMP concentration activates PKA in the cytosol, and the released catalytic subunits move into the nucleus, where they phosphorylate the CREB gene regulatory protein. Once phosphorylated, CREB recruits a coactivator CBP, which stimulates gene transcription. * This signaling pathway controls many processes, ranging from hormone synthesis in endocrine cells to the production of proteins required for long-term memory in the brain.*

How is the half-life of mRNA regulated by RNA binding proteins?

The binding of iron to aconitase causes a conformational change in the protein that greatly reduces the ability of aconitase to bind the iron-response element (step loop structure) Binding of aconitase to the 5' end of the mRNA causes a block in translation. Binding of aconitase to the 3' end of the mRNA causes stabilization of mRNA.

What is the volume of distribution?

The body volume that the drug can distribute within - related to the amount of drug in the body and the concentration of drug in the blood or plasma Apparent plasma and extravascular compartments that the drug may enter Vd = Amount of Drug in the Body (mg)/ Concentrationplasma (mg/L) *Units expressed as: L/70kg Vd may exceed the volume of the body, i.e., chloroquine 13,000 L/70 kg trimethoprim 11 L/70 kg Relationship: the larger the Vd, the longer the t1/2

Why is the parasympathetic division often called the craniosacral part of the ANS?

The cell bodies of preganglionic parasympathetic neurons are found in the brain stem and the lateral intermediate gray column of spinal cord segments S2-S4

What is a polysome?

The complex of mRNA and multiple ribosomes As ribosomes move along the mRNA, a second ribosome can bind to the vacant 5'-end of the mRNA. One ribosome covers about 80 nucleotides of the messenger RNA, so ribosomes can associate with mRNA at about every 100 nucleotides. As each ribosome progresses from the 5' to the 3' end of the mRNA the polypeptide chains attached to the ribosomes become longer

What is the rate limiting step for cholesterol synthesis?

The conversion of HMG-CoA to mevalonate via the enzyme HMG-CoA reductase It is embedded in the ER membrane. However, its N-terminal domain, which contains the enzymatic activity, faces the cytoplasm.

Where does malonyl CoA come from and what does it do?

The conversion of acetyl CoA by biotin and acetyl CoA carboxylase Consumes ATP and CO2 Inhibits CPT1 enzyme preventing B-oxidation

Explain why the RBC cytoskeleton is crucial for RBCs to function optimally.

The cytoskeleton and its associated proteins give RBCs their flexibility and stability. The arrangements of the spectrin protein of the RBC's allows them to change shape which is important during the movement in narrower areas (arteries to capillaries). Ankyrin proteins allow the RBCs to resist forces in circulation. Band 3 links the plasma membrane to the cytoskeleton. Protein 4.2 regulates the connection of Band 3 to ankyrin.

How do you determine the degree of ionization of a drug?

The degree of ionization is based on the pH of the physiological compartment and the pKa of the drug. Based on the Henderson-Hasselbach equation, For weak acids: pKa-pH = log non-ionized/ ionized For weak bases: pKa-pH = log ionized/ non-ionized

What is the end replication problem and what the solution?

The discontinuous synthesis of the lagging strand using RNA primers generates a problem for complete replication of the lagging strand in chromosome ends The ends of human chromosomes have repeated sequences called "telomeres". The telomeres are synthesized by an enzyme called "telomerase"

How do the filaments slide on one another in muscle contraction?

The energy for each cross bridge cycle is derived from the hydrolysis of one ATP molecule. 1. The enzyme catalyzing the hydrolysis of ATP, actin-myosin ATPase, is contained within the cross bridge and is activated when the myosin molecule binds to actin. 2. The ATP is bound to myosin as a high-energy complex referred to as myosin ADP·Pi. 3. When the cross bridge bends, ADP and Pi are released from myosin. 4. The thin filament detaches from myosin when a new molecule of ATP binds to the myosin molecule.

Describe the extracellular matrix

The extracellular matrix includes all proteins found outside of cells Collagens are the most abundant proteins in your body, comprising 25% of all proteins There are at least 28 different types of collagen, each type exhibiting some unique features and some common features The most common by far is fibrillar type I collagen (80 to 90%) - Much of this lecture focuses on this type of collagen Since collagens are located outside of cells, their synthesis and maintenance exhibits several unique and defining features

What is the function of by triacylglycerol synthase?

The fatty acyl CoA derivatives and their 2-monoacylglycerols are converted to triglycerides in intestinal epithelial cells and combine with other lipid-soluble materials and apo-proteins to form chylomicrons, which are secreted into the lymph

What increases the rate of absorption?

The higher the concentration of drug, the faster the rate of absorption The more lipid soluble, the greater the rate of absorption The lower the molecular weight, the greater the rate of absorption The larger the surface area, the faster the rate of absorption The greater the regional blood flow, the faster the rate of absorption

What are the 4 steps of EC coupling?

The initiation of muscle contraction is referred to as excitation-contraction (EC) coupling The four steps of EC coupling - Generation of the muscle action potential and depolarization of the T-tubule -Release of calcium from the sarcoplasmic reticulum -Binding of calcium to troponin and removal of the blocking actions of tropomyosin -Initiation of the cross bridge cycle and contraction

What are the components of the innate immune system?

The innate immune system acts as the first line of defense, so it consists of defense mechanisms located at entry points into the body. Physical barriers_ Epithelia: Junctions and Cilia Chemical barriers (non-specific defenses): Mucosa Acids found in skin and GI tract (lower pH) Lysozyme found in tears and saliva. Complement Non-specific cellular immune responses: Macrophages Neutrophils Natural killer cells Eosinophils

What is the major site of acetoacetate formation? Why?

The liver HMG CoA Synthetase is not abundant in tissues other than the liver

What are sheddases?

The major Sheddase families are the ADAM (A Disintegrin And Metalloproteinase) and BACE (beta-site amyloid precursor protein cleaving enzyme) families Major feature is their ability to shed extracellular portions of transmembrane proteins

What does glucagon do?

The major counter regulatory hormone(s) to insulin Promotes glucose production (glycogenolysis, gluconeogenesis) and glucose release into the blood Stimulates the mobilization of fatty acids from adipose tissue (catecholamines) Decrease in glycolysis Increase in gluconeogenesis Decrease in glycogenesis Increase in glycogenolysis Increase in β-oxidation Decrease in fatty acid synthesis

What does the rough ER do?

The major site of synthesis of secretory proteins, peptide neurotransmitters, and N-linked oligosaccharide addition to proteins

What is an operon?

The majority of genes in prokaryotic cells are organized into operons. An operon is two or more genes whose protein products often have a related function that are located adjacent to each other on the chromosome. These genes are transcribed using a single promoter region and produce one long polycistronic mRNA.

How does the mitochondrial genome differ from the nuclear genome?

The majority of the mitochondrial genome consists of genes encoding either proteins or RNAs Resembles a reduced genome of a bacterial genome. Encodes its own ribosomes and translational machinery (origin from an engulfed prokaryotic cell). No Introns 95% functional

What is Vmax?

The maximum rate of reaction -- when the enzyme is saturated with substrate

What is rheobase?

The minimum current that can cause an action potential If the current is less than the rheobase, it cannot induce an AP no matter how long it stimulates the cell

What DNA repair pathway is defective in Lynch Syndrome and what are the most common mutations often associated with this disorder?

The mismatch repair (MMR) system is defective in Lynch Syndrome. Variations in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes increase the risk of developing Lynch syndrome. MLH1, MSH2, MSH6, and PMS2 are all involved in the mismatch repair pathway. EPCAM is not directly involved, but EPCAM gene lies next to the MSH2 gene on chromosome 2 and certain mutations cause the MSH2 gene to be inactivated, interrupting DNA repair and leading to accumulated DNA errors. About 50 percent of all cases of Lynch syndrome with an identified gene mutation are associated with inherited mutations in the MLH1 gene. Normally, MLH1 protein joins with another protein called PMS2 (produced from the PMS2 gene), to form a protein complex. This complex coordinates the activities of other proteins that repair errors made during DNA replication. The repairs are made by removing a section of DNA that contains errors and replacing the section with a corrected DNA sequence. When the MLH1 protein is absent or nonfunctional, the number of DNA errors that are left unrepaired during cell division increases substantially. The errors accumulate as the cells continue to divide, which may cause the cells to function abnormally, increasing the risk of tumor formation in the colon or another part of the body.

What is redistribution?

The movement of drug away from its active site to other tissues where it can be stored. Factors altering redistribution include physicochemical properties and blood flow. Example - a highly lipid soluble drug can redistribute away from its active site and be stored in adipose tissue.

What are the consequences of the oxidation of ethanol?

The oxidation of ethanol generates an excess of reducing equivalents in the liver, increasing the NADH/NAD+ ratio. This affects metabolic reactions/pathways dependent on sufficient levels of NAD+. Increased NADH/NAD+ ratio in liver result in: Pyruvate reduced to lactate - lactate build-up and decreased gluconeogenesis. Metabolic acidosis: lacticacidemia and ketoacidosis Oxaloacetate reduced to malate - decreased gluconeogenesis. Hypoglycemia: lack of gluconeogenic substrates; ie. pyruvate and oxaloacetate. DHAP reduced to Glyceraldehyde 3-P - increased fatty acid synthesis and triglyceride formation. Acetyl CoA oxidation in TCA is reduced (little available oxaloacetate and NADH inhibits citrate dehydrogenase and α-ketoglutarate dehydrogenase. Acetyl CoA forms ketone bodies Fatty liver: reduced oxidation of fatty acids and increased triglyceride synthesis. (AFLD) Ethanol exposure stabilizes and activates the transcription factor (SREBP1c) that regulates a number of the genes involved in lipogenesis. Hyperuricemia - kidney excretion of uric acid is decreased by the elevated lactic acid. Liver damage/hepatitis: acetaldehyde-induced damage Physiological consequences Facial flushing, tachycardia, nausea Metabolic and molecular consequences Formation of protein/DNA adducts Alterations of cell membrane structure and function Inhibits DNA repair Depletion of glutathione, increasing oxidative stress Mitochondrial dysfunction Increases collagen synthesis (hepatic fibrosis)

What is the effect of cis-double bonds on membrane free volume?

The presence of a cis double bond reduces the energy barrier to gauche-trans conformational change for the adjacent C-C bond. A cis double bond creates a 120o bend (A, the figure below) or a small defect volume due to the Dtg kink (B, the figure below). In addition, the saturated segments of the acyl chain can adopt various gauche conformations including the b-coupled g+tg- configuration. Thus, unsaturated acyl chains containing cis double bonds have more membrane free volume (or membrane fluidity) than saturated acyl chains

What is the clearance?

The rate at which the body eliminates the drug - related to the functional capability of the liver and kidney Ck + CL + Cother The amount of drug removed or "cleared" per unit time predicts the rate of elimination in relation to drug concentration CL = Rate of Elimination (mg/h/70 kg) Plasma Concentration (mg/L)

What is the function of programmed cell death?

The processes of cell division and cell death interact to generate the proper numbers and types of cells during development and to maintain this balance in the mature animal. -development -homeostasis -elimination of defective or potentially dangerous cells Dysregulation can lead to disastrous consequences; involved in cancer, autoimmunity and neurodegeneration.

Describe the progress zone model

The progress zone model postulates that each mesoderm cell is specified by the amount of time it spends dividing in the progress zone. Experiments have lead to this model where Fgf supplied by the AER specifies proximal distal fate in PZ cells. The longer cells remain in the PZ exposed to Fgf, the more distal their identity. When cells leave the PZ their proximal-distal positional value is fixed and they differentiate appropriately. So, the first mesodermal cells derived from the lateral plate mesoderm that exit the progress zone would condense to form the humerus, the most proximal bone in the limb. The last to exit give rise to the cartilage of the digits, the most distal bones. First cells leaving become the stylopod. Exposure to Fgf from the AER is the morphogen gradient. The longer cells stay in the PZ the higher the exposure to Fgf. When cells leave the PZ their proxmal-distal positional value is fixed and they differentiate appropriately. So, the first mesodermal cells derived from the lateral plate mesoderm that exit the progress zone would condense to form the humerus, the most proximal bone in the limb. The last to exit give rise to the cartilage of the digits, the most distal bones.

What is the biochemical effect of a defect in the Galactose-1-phosphate-uridyl transferase enzyme?

The reaction of galactose-1-phosphate -> glucose-1-phosphate can't happens so galactose can't be metabolized. This pushes Galactose in the aldolase direction, turning it into galactitol. You will also have a deficiency of UDP-galactose because the transferase turns Gal-1-P and UDP glucose into UDP galactose and G-1-P Since the patient has high amounts of galactose in the body because it can't be converted to glucose, some of it will be converted to galactitol via aldose reductase.

Describe a refractory period

The refractory period of a nerve or muscle is a time in which it is more difficult to cause another action potential. The hyperbolic shape of the strength-duration curve Absolute refractory period: A second AP cannot be generated no matter how strong a stimulus is used. Not enough Na+ channels available to trigger another AP. They are either all already in use, or have been inactivated. Relative refractory period - a second AP can be generated but a stronger stimulus (greater voltage) must be used. There are not as many Na+ channels available as normal to trigger another AP because many are inactivated. Also, many more K+ channels are open, so it is more difficult to depolarize the membrane to threshold.

What are the steps of transcription in bacteria?

The sigma factor directs the RNA polymerase to the promoter - assembly in bacteria does not happen without the sigma factor The RNA polymerase assembles at the promoter forming the closed complex DNA is melted forming an open complex The core transcribes mRNA and the sigma factor disassociates In prokaryotes there is no nuclear membrane so transcription and translation is coupled Sigma factors bind the promoter at conserved sequences around -35 and -10 bp upstream of the ATG start codon

What is the therapeutic drug effect?

The stead state 4-5 half lives Half life= t 1/2 = (0.7 )( Vd)/CL Vd= Volume of distribution CL=Clearance Aging decreases Vd Pathology and obesity increases Vd P 450 inhibition, cardiac failure, hepatic failure and renal failure decreases clearance

What is the mechanism of homologous recombination during meiosis?

The steps are again similar to those seen earlier, but specialized proteins direct the programed cuts and recombination in cells of the germ line. Branch migration determines, in part, the lenth of the strands interganged In meiosis a specialized protein, Spo11 in yeast, catalyzes the double strand break in one pair of replicated non-sister homologs. This is followed by resection of the 5' end by a nuclease complex. A RecA-type protein (RAD51) is then loaded forming the nucleoprotein filament that mediates strand invasion. DNA synthesis and ligation results in the formation of a double Holliday junction, which can be resolved by alternative paths depending whether the cuts are in the same or opposite direction. The final step is resolution. The Holliday junction is cleaved at the junction point where the DNA molecules cross one another and recombining DNA strands are joined to one another. This step that separated the two recombining DNA molecules is called resolution. It is accomplished by a protein called a resolvase, which has properties similar to a topoisomerase. If the crossed strands are cut and rejoined with different partners a patch is formed in the recombinant. If the flanking strands are cut and joined to different partners a splice is formed between the two duplex DNA molecules that are engaging in recombination. If maternal and paternal sequences at the heteroduplex are not identical, the mismatch will be corrected by the mismatch repair machinery, which does not distinguish between paternal maternal strands. This will lead to gene conversion (one allele is lost and the other is duplicated).

Describe ubiquitin mediated protein degradation by the 26S proteasome

The substrate-linked polyubiquitin chain is recognized by proteins in the base 19S subcomplex of the 26S proteasome. An engagement site (red) is recognized by one or more of the ATPase subunits. Translocation through the poor is driven by ATP hydrolysis and denatures the substrate. The substrate polypeptide transits through the axial pore of the 20S complex. The substrate is hydrolysed. The peptides exit the catalytic chamber through the axial pore. A deubiquitinating enzyme present on the lid hydrolyses the isopeptide bond that links the polyubiquitin chain to the substrate.

What is an isometric contraction?

The total length of the muscle does not change. 1.The initial length of the muscle prior to contraction is called the preload. 2.The force produced during an isometric contraction depends on: •The preload (i.e., the overlap between thick and thin filaments). •The number of muscle fibers activated. •The frequency of action potentials generated by the muscle.

Why is total calcium tested?

The total serum calcium is a measure of both -Free (ionized) calcium -Protein bound (usually to albumin) calcium Therefore, the total serum calcium level is affected by changes in serum albumin -As a rule of thumb, the total serum calcium level decreases by approximately 0.8 mg/dL for every 1 gram/dL decrease in the serum albumin level.

What is transference?

The transference of an ion is the fraction of the total membrane conductance that is due to the specific conductance of that ion For a typical cell at rest, the K+ conductance is about 9 times greater than the Na+ conductance, so the transference for K+ is 0.9 and the transference for Na+ is 0.1.

What is the synthesis and fate of chylomicrons?

The triacylglycerol is produced in the smooth endoplasmic reticulum (SER) of intestinal epithelial cells from the digestive products, fatty acids, and 2-monoacylglycerols. The major apoprotein in chylomicrons is B-48. The protein is synthesized in the rough endoplasmic reticulum (RER). Assembly of the lipoproteins occurs in both the ER and the Golgi complex. Exocytosed to lymph and then to blood where it irecieves lipoprotein E and C2 from HDL and then is degraded by LPL into FA, glycerol and chylomicron remnants. FA go to muscle for use and adipose for storage Glycerol goes back to the liver Chylomicron remnants attach to receptors on the liver and are endocytosed where they are mixed with lysosomes and broken down into FA, cholesterol, amino acids and glycerol

What determines the velocity of shortening?

The velocity of shortening at any given afterload depends on the preload. The maximum velocity of shortening occurs at zero afterload Vmax Vmax is not affected by changes in initial muscle length or preload. Vmax is determined by molecular properties of the contractile proteins (eg. The ATPase activity of myosin).

What does triclosan do?

Triclosan kills a broad spectrum of bacteria and yeasts by inhibiting enoyl-acyl carrier-protein reductase, which is necessary for fatty acid synthesis in germs. Humans do not have this enzyme, so Triclosan is often thought to be "harmless".

What are different families of heterotrimeric G proteins?

There are at least 16 different a subunits, 5, b subunits, and 11 g subunits. Because of the potential for several hundred combinations of the known subunits, G proteins are ideally suited to link a diversity of receptors to a diversity of effectors. Examples include: • Adenylyl cyclase •Phosphatidylinositol 3 kinase • Phospholipase C • Ion channels Based on their effects on these effectors, the a subunits of G proteins are classified into Gs for stimulatory, or Gi for inhibitory.

Describe non-receptor tyrosine kinases?

There are at least eight members of the Src family of nonreceptor protein tyrosine kinases in mammals: (Src, Yes, Fgr, Fyn, Lck, Lyn, Hck, and Blk). They contain SH2 and SH3 domains and are all located on the cytoplasmic side of the plasma membrane, held there partly by their interaction with transmembrane receptor proteins and partly by covalently attached lipid chains. In each case the Src-family tyrosine kinase is activated when an extracellular ligand binds to the appropriate receptor protein.

How does red cell development occur?

There are three important phases that take place in the development of a mature RBC. 1. Ribosome synthesis 2. Hemoglobin accumulation 3. Ejection of nucleus

Why not just myelinate the entire axon?

There is a limit on how much Rm can be increased by myelin while still allowing space for enough axons, and Ri is also significant, so any membrane potential change will always decay over distance (in reality, after about 1-2mm). Many axons are much longer than this, so sodium channels clustered at gaps in the myelin (Nodes of Ranvier) re-boost the action potential.

Is there a flow of ions when Em=Eion?

There is no effective voltage difference for that ion across the membrane and there is no flow of that ion even though: The channels for that ion are open, and There is a voltage difference across the membrane.

What is the name for vitamin B1 and what does it do?

Thiamine Coenzyme for transketolase, pyruvate dehydrogenase (PDH), alpha-ketoglutarate dehydrogenase, decarboxylation of branched chain amino acids. Involved in energy release from metabolic substrates. Beri-beri is a classic dietary thiamine deficiency disorder.

Why is this patient getting recurrent bouts of septicemia even though each bout of septicemia is cleared by antibiotics?

There were dormant (antibiotic resistant persisiters) cells that are on the knee implant structure (S. aureus does not form spores but that is another possibility for infections by other organisms) that were unaffected by the antibiotic, so they survived to reproduce and pass on their resistance to the next generation. Nutrient and oxygen gradients could create a niche in the biofilm produced by the infection that induce a biphasic switch for certain cells to become dormant, and those dormant cells are the ones that survive and begin the next round of infection. Two-component regulators can sense these changes in the environment and regulate gene expression and the biphasic switching. SOS response when cells are under stress from starvation - leads to increased RecA, degrading LexA repressor, leading to mutation-prone DNA receptors. Quorum sensing. Slow growers can get killed with long courses of antibiotic treatment (quorum sensing is important with these)

What is the role of eIF2B in protein synthesis?

This protein complex consists of five different subunits; it activates the protein initiation factor eIF2 by exchanging eIF2-bound GDP for GTP. eIF2 functions in the transport of the initiator tRNA to the ribosomal 40S subunit. The enzyme eIF2 mediates the binding the met-tRNA to the 40S ribosomal subunit in a GTP dependent manner. This initiates protein synthesis for all proteins as methionine is the initiator amino acid.

Describe antimuscarinic agents

Though there are various subtypes of muscarinic receptors, many current therapeutic agents are relatively non-selective. Dicyclomine has some M1 selectivity. Newer bladder antispasmotics (Darifenacin) are M3 selective. Competitive, reversible antagonists of ACh at muscarinic receptor sites. These agents have marked affinity for muscarinic receptors, but no intrinsic activity. (cholinolytics, parasympatholytics, anticholinergics, atropine-like agents) Natural alkaloids - atropine, found in Atropa belladonna and Datura stramonium and scopolamine, found in Hyoscyamus niger. Semi-synthetic analogs - homatropine, benztropine and ipratropium Synthetic compounds - glycopyrrolate, dicyclomine and tropicamide

How do proteins enter and exit the nucleus?

Through nuclear pores Nuclear Pore Complex is 70-80nm wide, with 5-10nm central channel Small molecules (<9 nm) can diffuse freely through Nuclear Pores Larger molecules (most proteins, RNA) must be actively transported through Nuclear Pores. Transport is mediated by receptor proteins in the NPC and requires energy.

How is the pentose phosphate pathway regulated?

Through the rate limiting enzyme glucose-6-P dehydrogenase Inhibited by high NADPH Induced by Insulin

Describe positive and negative selection in the thymus

To ensure that T cells are able to bind MHC complexes, T cells undergo positive selection. •Epithelial cells in the cortex of the thymus (CTEC) synthesize MHC I and MHC II. cTECs present these peptides to the T cells . •If T cells are incapable of binding they undergo apoptosis. Positive Selection=only T cells that recognize MHC survive and this is where CD4+ and CD8+ cells are differentiated. Essential that these T cells do not recognize and attack our own, i.e. negative selection. •In the medulla, CD4 or CD8 T cells interact with antigen presenting cells, such as mTECs and dendritic cells, and these interactions normally result in the deletion of autoreactive T cells. Negative Selection=Removes strongly reactive T cells. T cells expressing a functional TCR without significant reactivity to self-antigens then migrate to secondary lymphoid organs such as the spleen and lymph nodes, and circulate throughout the body.

How do you alter Na+/K+ pump activity?

To inhibit Na+/K+ pump: ①Low sodium inside ②Low potassium outside ③Ouabain, digitalis and other drugs ④Cooling or anoxia limit ATP supply so they slow the pump-ischemia. To stimulate Na+/K+ pump: ① Increasing the intracellular Na+ concentration

What are amino acids used for?

To make protein To make nitrogenous compounds (nucleotides, neurotransmitters, other stuff) To make energy (from carbon skeletons; requires removal of amine group) To make glucose / ketone bodies (also from carbon skeletons, also requires removal of amine group) In western diet the bulk of dietary amino acids are used as fuel and nitrogen is excreted as urea

What is a lipid panel composed of?

Total cholesterol -Cholesterol in all the lipoprotein particles High-density lipoprotein cholesterol (HDL-C) -Cholesterol in HDL particles - "good cholesterol" because it removes excess cholesterol and carries it to the liver for removal Low-density lipoprotein cholesterol (LDL-C) -Cholesterol in LDL particles that is ESTIMATED by subtracting HDL-C and triglycerides from total cholesterol - LDL = Total cholesterol - (triglycerides/5) - HDL -"bad cholesterol" because it deposits excess cholesterol in walls of blood vessels, which can contribute to atherosclerosis Triglycerides -Triglycerides in all the lipoprotein particles -Most is in the very low-density lipoproteins (VLDL)

What does botulinum toxin do?

Toxin blocks ACh release Small doses are used for muscle spasticity, wrinkle reduction

What is linkage analysis?

Traces disease or trait through a family Traces chromosomal differences through a family Statistically correlates disease/trait with variants across chromosomes Genes on different chromosomes independently inherited. Genes that are close to each other on the same chromosome are "linked" and tend to be inherited together. Association is shared across families

Describe the mitochondria

Transform chemical energy into high energy phosphate bonds in ATP Stain intensely with acidophilic dyes Located in part of the cell where energy requirement is high! Lamellar Cristae Increase surface area Both mitochondria and the endoplasmic reticulum are involved in the uptake, storage and release of calcium. DNA is synthesized in mitochondrion, independent of the nuclear DNA. Mitochondria also have a key role in steroid hormone synthesis - they are the site at which the side chain on cholesterol is removed. This is termed "side chain cleavage". The enzyme system (desmolase/CYP11A1/P450 11A1) involved in side chain cleavage is located on the inner mitochondrial membrane. The conversion of cholesterol to pregnenolone is the rate-limiting step. However, the enzyme activity is not rate-limiting, rather substrate availability in the mitochondria is limiting. StAR is required for cholesterol import into mitochondria (except placenta) and in all tissues except placenta, StaR is what regulates the rate of conversion to pregnenolone. Inner Mitochondrial Membrane (impermeable to most molecules) Bears enzymes/cofactors of electron transport chain, transporters Site of side chain cleavage enzyme (converts cholesterol to pregnenolone) Regulates apoptosis Amino & organic acid metabolism Heme synthesis Hepatic ammonia detoxification Neurotransmitter metabolism

What are the types of horizontal gene transfer?

Transformation Conjugation Transduction

What is a transition vs a transversion mutation?

Transition: purine to purine (A->G) or pyrimidine to pyrimidine (C->T) Transversion: purine to pyrimidine (A->T) or pyrimidine to purine (C->G)

What happens in tryptophan degradation?

Tryptophan is the least abundant amino acid in protein. Its major fates are to produce alanine (glucogenic) and acetyl CoA (ketogenic) Some niacin can be made from tryptophan Niacin (as nicotinamide) is part of the cofactor NAD+ Formed from the six-membered ring of tryptophan, but synthesis is weak, and inhibited by leucine

What is a retinoblastoma?

Tumor of the developing retina due to loss of expression of Rb gene product Can happen by multiple somatic mutations (Single Tumors, Unilateral, later-onset) or by genetic mutation and then somatic mutation (Multiple tumors, bilateral, early-onset) Loss of function mutation in retinoblastomas Interstitial chromosome 13 deletion in Retinoblastoma patient

What is the function of the malic enzyme?

Turn cytosolic malate into pyruvate and generate NAPDH for fatty acid synthesis

What does the glutamate dehydrogenase reaction do?

Turns glutamate into alpha-ketoglutarate and vise versa Does NOT require PLP NADP+-NADPH and NH4+ or NAD+-NADH

How is pyruvate carboxylase regulated?

Turns pyruvate into OAA Present in the mitochondria and expressed in most cells. Activation of PC requires allosteric binding of acetyl-CoA Acetyl CoA is product of fatty acid oxidation levels rise with low insulin and high glucagon/catecholamines Insulin indirectly inhibits by stimulating PDH decreasing pyruvate and inhibiting lipolysis Requires the vitamin biotin, CO2 and ATP

What are the three stop codons?

UAG, UGA, UAA

How is Fructose-1,6-bisphosphatase regulated?

Two genes, liver isoform FBPase1 and a muscle isozyme FBPase2. FBPase1 expressed in gluconeogenic tissues. FBPase2 expressed in most other tissues. Both isozymes are inhibited by F-2,6-bP and AMP. FBPase2 also inhibited by Ca (muscle contraction). FBPase2 is 100x more sensitive to inhibitors than FBPase1. The absence of insulin and the increased PKA signaling increases PFK2 phosphatase activity and F-2,6-bP levels fall. Decrease in F-2,6-bP and increase in AMP prevent futile cycle of F-6-P phosphorylation by PFK1. F-6-P levels rise leading to increased isomerization to G-6-P by phosphoglucoisomerase.

Describe Stratified cuboidal epithelium

Typical Location: Sweat gland ducts, Large ducts of exocrine glands Still can appear circular but have multiple layers

Describe a Pseudostratified Epithelium

Typical Location: Trachea All cells touch the base, only some reach the surface.

Describe a Stratified columnar epithelium

Typical Location: largest ducts of exocrine glands, Rectum, Anus Can draw a line between the sections

Describe the ubiquitin conjugation pathway

Ubiquitin is a highly conserved 76 amino acid protein in eukaryotic cells. Synthesized as fusion with ribosomal subunits or with self. Converted to free ubiquitin by de-ubiquitinating enzymes. Is covalently conjugated to lysine residues on proteins and itself (has 7 lysine residues) to form chains on substrates. The type of chains formed on the substrate dictate its fate.

How does cell based cloning work?

Unlike proteins, the chemical make-up of genes are VERY similar and can't be easily separated. The identification of restriction enzymes or endonucleases (cut in the middle of DNA) that digest DNA at specific sites provided a means of cutting DNA up in multiple pieces. There are a lot of Restriction Enzymes: they recognize different sequence and generate different types of cuts Once DNA is broken up into individual units by restriction endonuclease digestion, the pieces are moved into a plasmid or vector that allows for replication and amplification. The restriction enzyme generates ends on the to be cloned DNA and vector that are complementary to one another and this allows them to anneal to one another. A DNA ligase is then use to ligate (create a stable phosphodiester bond) the DNA fragments into a vector. This allows for production of the cloned product in E. Coli. Next step is to introduce (a process called transformation) into host E. coli that contains all factors needed for amplification of the vector that contains the DNA insert. Remember that the vector contains an antibiotic resistance gene so only those bacteria that take up the plasmid can survive when platted on antibiotic containing media. Each colony is derived from a single transformation event and now contains a billion or so bacteria that harbor the same vector-insert DNA. Identifying the cloned gene product of interest in DNA library-Use of radiolabeled probes and nucleic acid hybridization. Probes can bind complementary DNA in solution as well as when present on a solid support such as nitrocellulose

What does the helicase enzyme do?

Unwind DNA at the origins of replication ATP-dependent Donut structure Movement of DNA helicases unwinding the DNA duplex creates positive supercoilds (plectomenic structures).

What are the major metabolic routes for long-chain fatty acyl CoAs?

Used as energy in beta oxidation or ketogenesis Become membrane lipids such as phospholipids or sphingolipids Storage of fatty acids through triacylglycerols

What is the Warburg effect?

Utilization of aerobic glycolysis as the major source of ATP-Goes to lactate instead of the normal path Activates pentose phosphate pathway Produces NADPH, Protects cells against ROS Involves massive increase in glucose uptake, reliance on glycolysis, and inhibition of oxidative phosphorylation Tremendous inefficient use of glucose makes the tumor a parasite on surrounding stroma Excess glycolysis in tumors

Describe the Microsomal Ethanol-Oxidizing System (MEOS)

Utilizes CYP2E1, NADPH and O2 The Km of CYP2E1 is 10 mM, high relative to the ADH system, but still within range obtained by social drinkers. Accounts for 5% of metabolism in normal drinkers. EtOH induces CYP2E1 mRNA and protein levels; transcriptional and preventing proteosomal protein degradation. At higher EtOH concentrations CYP2E1's contribution to oxidation of EtOH becomes more significant. A metabolic adaptation to ethanol, expression of CYP2E1 increase causing an enhanced rate of clearance of ethanol from the blood of alcoholics. In chronic alcoholics, tolerance to different drugs also occurs as their metabolic rate also increases. Acute ethanol consumption may inhibit the metabolism of other drugs in a competitive manner. EtOH inhibits other CYPs such as one metabolizing phenobarbitol. The conversion of xenobiotics into toxic metabolites may also be enhanced (ex. Acetaminophen)

What are the functions of alpha adrenergic receptors?

Vasoconstriction Iris dilation Intestinal relaxation Intestinal sphincter contraction Bladder sphincter contraction

What are the functions of beta adrenergic receptors?

Vasodilation (𝝱2) Cardio-acceleration (𝝱1) Intestinal relaxation (𝝱2) Uterus relaxation (𝝱2) Bronchodilation (𝝱2) Metabolic effects (𝝱3)

What does the vitamin folate do?

Vitamin B9 Involved in nucleotide biosynthesis and conversion of homocysteine to methionine.

What is hematocrit?

Volume of packed RBCs in a centrifuged blood sample

Why is bilirubin tested?

Water-soluble conjugated bilirubin= Direct INsoluble= INdirect= UNconjugated van den Bergh reaction diazo reacts directly with water soluble conjugated form Add alcohol and both conjugated and unconjugated react (Total bilirubin) Indirect (unconjugated) is the difference between total and direct

What are the general rules for oral absorption?

Weak acids - initial absorption may be in stomach; major portion in upper part of small intestine Weak bases - absorbed in upper portion of small intestine Charged molecules - poorly absorbed Neutral molecules - readily absorbed

How do you describe a bacterias taxonomy?

When discussing bacteria involved in disease bacteria are usually referred to by their genus and species (Streptococcus pyogenes). Occasionally pathogens are referred to by subspecies (Salmonella enterica ssp Typhi). Bacterial names should always be in italics. When analyzing the microbiota, bacteria are often grouped by phylum and/or families.

What happens with nitrogen excretion during fasting?

When glucose is low for 12+ hrs, N is released from amino acids to contribute to energy metabolism, gluconeogenesis. Glucose is depleted, muscle proteins are broken down Amino acids used as fuel, NH4 transferred to glutamine, alanine; exported from muscle Glutamine/alanine taken up by liver, NH4 released and pkg into urea

What happens during protein processing?

When polypeptides that are elongating exceed about 30 amino acids, they emerge from ribosome and start to form 3-dimensional conformations. Chaperones are proteins that bind to emerging, nascent polypeptides to mediate appropriate conformation. Disulfide isomerases calalyze the formation of disulfide bonds between cysteine residues, which impacts on 3-D conformation.

Can the body synthesize fatty acids with an odd number of carbons?

When the "primer" is propionyl CoA, a fatty acid with an odd number of carbons is generated.

What is chronaxie?

When the rheobase is determined, the minimum stimulus time that will cause an AP using a current twice the rheobase

What does RNA polymerase do?

When to transcribe a gene Where to initiate transcription Which strand of DNA to use as template Where to stop transcription How fast to transcribe a gene

How does attenuation occur at different tryptophan levels?

When tryptophan levels are high, the ribosome quickly translates sequence 1 and blocks sequence 2 before sequence 3 is transcribed. Continued transcription leads to attenuation at the terminator-like attenuator structure formed by sequences 3 and 4. The leader peptide is completed. When tryptophan levels are low, the ribosome pauses at the Trp codons in sequences 1. Formation of the paired structure between sequences 2 and 3 prevent attenuation, because sequences 3 is no longer available to form the attenuator structure with sequences 4 transcription continues

What is in white matter and gray matter?

White matter: bundles of myelinated axons. Term derives from appearance in fresh (unfixed) material. White matter also contains oligodendrocytes Gray matter: collections of neuron cell bodies, plus large numbers of astrocytes.

Describe a Simple Cuboidal Epithelium

Width of the cell is similar to its height Nuclei of the cell arranged at similar levels and the cell is not much taller than the nuclei Location: Kidney Tubules, Small ducts of exocrine glands etc. Appear circular often in cross section

What is the cellular process that becomes defective in the absence of BRCA2 function? Explain using schemes the mechanistic consequences of the BRCA2 mutation?

With a mutation of the BRCA2 gene, damaged DNA won't be fixed during homologous recombination and this can lead to an increase in mutations. During homologous recombination repair, the RPA protein will initially bind then BRCA2 binds. With BRCA2 binded, RAD51 can bind and then initiate the strand exchange by looking for homology between the base strands in the invading donor and recipient strands. Without BRCA2 this step wouldn't happen since RAD51 wouldn't be able to bind.

Can the body synthesize fatty acids containing double bonds?

Yes with ER bound enzymes that use molecular oxygen. Both the fatty acid and NADH are oxidized. Human desaturases cannot introduce double bonds between carbon 9 and the methyl end. Therefore, m is equal to or less than 7. Creates Fe3+ from Fe2+ Fatty acyl CoA desaturase NADH to NAD+ Poly-unsaturated fatty acids can be synthesized by using various desaturases and elongases.

Could growth in biofilms increase the chance of P. aeruginosa becoming hypermucoid?

Yes, the growth of P. aeruginosa in a biofilm is associated with the development of SNPs in the mucA gene of P. aeruginosa. MucA mutants are typically associated with chronic inflammation in the lungs of Cystic Fibrosis patients, as they begin to constitutively express genes associated with alginate synthesis.

What is a type 2 errror?

You accept the null hypothesis when it is wrong Power (1-type 2 error Beta) Probability of detecting a difference when, in fact, a true difference exists (true positives)

What are the different types of lateral junctional complexes?

Zonula occludens (Tight junction) Zonula adherens (Adhesion belt) Desmosome ("Spot weld")

How do you profile mRNA expression?

•Class discovery -Understanding global view of tumor biology -Distinguishing histopathological subtypes •Class Prediction -Signatures for prognostication •Gene discovery -especially when combined with DNA copy number information -discovery of fusion transcripts •Therapeutic target discovery

What is ORC?

•ORC is an initiator protein that recruits two helicase loaders.

What are the steps of beta-oxidation?

1. Fatty acyl CoA to trans Fatty enoyl CoA vis the enzyme Acyl CoA dehydrogenase Generates FADH2 2. trans enoyl CoA to L-beta-hydroxy acyl CoA via the enzyme Enoyl CoA hydratase 3. L-beta hydroxy acyl CoA to beta-keto acyl CoA via the enzyme beta-hydroxy acyl CoA dehydrogenase Generates NADH 4. beta-Keto acyl CoA to Fatty acyl CoA and Acetyl CoA via the enzyme beta-keto thiolase

What are the 4 major functions of membrane proteins?

1.Recognition / Adhesion Glycophorin Cadherin(s) 2. Structure / Organization Spectrin, Actin, Ankyrin, Band 4.1 3. Signal Transduction β-adrenergic receptor Insulin receptor 4. Transport Na+-K+ ATPase Glucose Transporter (GluT1) Anion transporter (Band 3)

Where are ketone bodies synthesized and where are the utilized?

Ketone bodies are mainly synthesized in the liver. However, ketone bodies cannot be utilized as energy fuels by the liver. Instead, ketone bodies are utilized by the brain, muscle and kidney for ATP production.