Exam 4

hallmarks of chemotherapy in terms of side effects and treatment regimen

DNA damaging agents, non selective, administered in "rounds"; treat with multiple agents; dosed to kill off rapidly dividing cells; side effects include hair loss, oral ulcers, neutropenia/immunocompromised

invariant chain

(Ii) nonpolymorphic protein taht binds to newly synthesized class II MHC molecules in teh ER. Prevents loading of the class II MHC peptide-binding cleft with peptides presetn in the ER and such peptides are left to associate with class I mol the invariant chain also promotes folding and assembly of class II molecules and directs newly formed class II molecules to the specialized endosomal MIIC compartment where peptide loading takes place

examples of targeted therapies?

-BCR/Abl inhibitors: inhibit kinase activity -Anti-VEGF: inhibit angiogenesis -Hormone therapies for breast cancer -PARP inhibitors: induce lethality by blocking ss DNA break repair in cells alreadly lacking the ability to perform homologous recombination due to BRCA mutations -the ss will become ds but no BRCA to save them -EGFR inhibitors: block dimerization and inhibit downstream signaling - not applicable for Kras -imatinib (Gleevec)-

Bortezomib inhibits what step in 26S proteasome function?

-act primary on the chymotrypsin-like site in the beta subunit -it mimics the transition state of peptide cleavage thus stopping up the active site of the beta-subunit

Ig light chain

1 of 2 types of polypeptide chains in an antibody molecule The basic structural unit of an antibody includes 2 identical light chains, each disulfide linked ot one of two identical heavy chains each composed of a variable (V) ig domain an done constant ig domain there are two light chain isotypes called k and lambda both functionally identical about 60% of human anitbodies have k light chains and 40% have lambda light chains

What are the major mechanisms of disease caused by gram positive cocci?

1) direct damage to tissues -S. Aureas: staphyloanthene that cause impetigo (golden crust skin infection) 2) toxin-mediated pathophysiology 3) triggering immune-mediated disease -S. aureas: leukocidins (AB exotoxins) that burst neutrophils and cause release of local inflammatory mediators; hemolysins

How do normal cells obtain cholesterol?

1) endogenous synthesis (HMG CoA reductae) 2) receptor-mediated uptake and lysosomal hydrolysis of LDL (BUT NOT FROM CHYLOMICRONS)

How is the urea cycle regulated

1) feed forward (substrate availability, including arginine) 2) allosteric regulation of first step by arginine

How do gram positive cocci evade host immune responses

1) resisting phagocytosis-mediated by mutliple different cell surface proteins and/or capsule -S. aureas: catalase (converts H2O2 to water preventing ROS destruction) and coagulase (fibrin which walls off infection) positive; fibronectin binding proteins; protein A (binds Fc receptors of immunoglobilin) 2) production of toxins that destroy immune cells -S.Aureas leukocidins and hemolysins and Tss-1 steph enterotoxins B and C (superantigens)

2 hypotheses for why myeloma cells are particularly sensitive to proteasome inhibitors?

1. Block degradation of abdnomal immunoglobins (which is most of what MM cells are producing) - ERAD pathway is unusually active (cell can sense that it is making bad proteins) inhibit proteasome --> can't do ERAD, which typically eliminates misfolded or unassembled proteins from the ER --> immunoglobulins are being made at a high rate in myeloma cells and misfolded ones are supposed to be destroyed by ERAD (via UPR pathway) --> since no ERAD available (bc you are blocking the proteasome) misfolded IgGs accumulate in the cytosol --> activation of APOPTOSIS via the JNK pathway. -> causes ER stress (unfolded protein response) and Heat Shock Response (misfolded proteins accumulate) 2. inhibiting the proteasome turns off the NFkappaB pathway by allowing IkappaBalpha (NFkappaB's antagonist) to hang around longer in the cell IkBa is the inhibitor of NFkB -NFkB is strongly antiapoptotic in all cells (survival factor) -NFkB causes production of critical growth factors for the MM cells (dependent on IL6 and VEGF) (also stabilizes cell0cycle reg proteins p27, p53, induction of apoptosis)

What are the inactivated and oral poliovirus vaccines composed of?

1. Inactivated poliovirus vaccine (IPV). Developed by Jonas Salk. Virus is grown in monkey kidney cell lines, and infectivity is inactivated by formaldehyde treatment. Vaccine is trivalent (viruses of all three serotypes). Multiple inoculations plus boosters are needed. 2. Oral polio vaccine (OPV). Developed by Albert Sabin. This vaccine is a live, attenuated virus, which was attenuated by passage in cell culture until it lost neurovirulence for monkeys. This is a trivalent vaccine also requiring multiple doses. - leads to local immunity mediated by IgA

consequences of P450 enzyme induction

1. drug can increase its own metabolism (ex. Carbamazepine, antiepileptic drug increases expression of certain P450s) 2. drug can increase the metabolism of a co-adminstered drug

How do the two amino groups that are present in urea enter the urea cycle?

1. glutaminase can make free ammonia from glutaminase, glutamate dehydrogenase can make free ammonia from oxidative deamination of glutamate and bacterial oxidation of AA in the gut can all lead to free ammonia which combines with bicarb in the mito -> highly reactive so gives carbaoyl group to ornithine to form citrulline (release of Pi - so lower energy) will cross mito membrane in exchange for ornithine and enter the urea cycle 2. aspartate (comes from diet or breakdown of muscle protein) that enters by a condensation rxn with teh carbonyl group of citrulline to form arginnosuccinate (requires ATP) The enzyme argininosuccinate lyase cleaves this molecule to form arginine and fumarate. The fumarate then enters the TCA cycle to be converted to oxaloacetate, which can then accept an amino group from glutamate to yield aspartate again Finally, the arginine is cleaved by arginase to form urea and ornithine

Why are aspects of physical appearance not as good a proxy for ancestry as being able to guess assignment racial labels would suggest (being able to guess someone's "race")?

1. labels imply definiteness and categorical nature of identity that is not supported by the strength of the correlations with physcial features and/or genetic ancestry (evidence does not match definitiveness with which we treat it) 2. we could be way off- some racial albels correspond to populations whose members are typically admixtures of diff continential genetic ancestries 3 some obvious and hertible physical traits such as height cannot be used to guess racial labels (vary more within pop) 4. existence of group diff for heritable traists doesn't mean that the group diff have a genetic or even bio basis to define racial labels, we often use visual cues that have been under diff environmental selective pressures and are best correlated with pop that have been separated by geo or culture but this does not confer a bio basis for racial labels doesn't mean that the racial labels are not correlated with biological variation but the correlations provided basis for ascribing other traits as being inherent to racial groups (which was wrong) - they were used to extrapolate

Isotype

1/5 types of antibodies determined by which of 5 diff forms of heavy chain is present antibody isotypes include IgM, IgG, IgA, and IgE - each performs a diff set of effector functions Additional structural variations characterize distinct subtypes of IgG and IgA

Advantages and disadvantages for using race/ethnicities in med?

Disadvantages on slide -imperfect proxies for underlying risk factors that are causign disease -prone to misinterp. ex. hypertension correlates with AA but only because of socioeconomics not genetics advantages: some labels are correlated with exposures and outcomes (and can be collected quickly) - do capture info and are easy to collect ex. melanoma related to physical diff that are most strongly correlated with racial labels (pigment in darker skin is protective)

The part labeled 1 in the diagram of an IgG molecule above is which of the following? Light chain variable domain Heavy chain variable domain Antigen binding site Fc region

A 1 points to N-terminal (V domain) of the shorter (light chain), so B is wrong. It is only part of antigen binding site, which also has heavy chain V domain-so C is wrong. The Fc region is made up of heavy chain constant regions--so D is wrong.

In a cell deprived of oxygen, which of the following is likely to occur? The mitochondrial proton gradient will dissipate. The NADH/NAD+ ratio will decrease. The rate of electron transport will increase. The rate of glycolysis will decrease.

A Because there is no oxygen available, the rate of electron transport slows, and thus the rate of proton pumping decreases. The cell will continue to use complex V to make ATP, thereby dissipating the proton gradient. When the cell is deprived of oxygen, the NADH/NAD+ ratio increases. The rate of glycolysis will increase to compensate for the loss of ATP production by mitochondria.

Peptides bound to which of the following are recognized by human CD8+ T cells? HLA-B HLA-D HLA-DR HLA-DP

A CD8+ T cells see peptide bound to class I MHC. Human class I MHC molecules are HLA-A, B, and C

Which of the four different antibodies shown in the figure above is an IgA? 1 2 3 4

A IgA is only Ig that forms dimer (secreted form, not membrane form).

Immature dendritic cells in tissues are activated by microbial molecules, such as LPS, which bind to TLRs and other innate receptors. In response, which of the following happens to the dendritic cells? The dendritic cells up-regulate CCR7 and migrate into the lymph node The dendritic cells turns off expression of costimulatory molecules The dendritic cells secrete IL-2 and proliferate The dendritic cells die by apoptosis

A Innate stimulation upregulates CCR7, a chemokine receptor which guides the DC to enter lymphatics and then to enter the T cell zone of the node to meet up with naïve T cells. Costimulatory molecules also up-regulated in response to innate signals ( b is wrong). DCs do not proliferate in response to innate signals and IL-2 is an autocrine growth factor for T cells (c is wrong).

What signaling role does the cytoplasmic portion of CD4 play in T cell activation? Brings tyrosine kinases into vicinity of the TCR complex at the time peptide-MHC is being recognized Brings tyrosine phosphatases into vicinity of the TCR complex at the time peptide-MHC is being recognized Is as a substrate of tyrosine kinases, which phosphorylate ITAMs in its cytoplasmic tail Serves as docking site for adaptor molecules and tyrosine kinases Acts as GTP-GDP exchange factor initiating MAP-kinase pathways

A Lck, a PTK is associated with cytoplasmic tail of CD4 and CD8. Not B, PTK is not phosphatase. Not C, there are no ITAMs in CD4 protein. Not D, CD4 is not an adaptor protein. Not E, CD4 is not a GEF.

Which of the following would be most effective in preventing Lyme disease? Using an insect repellent Avoiding close contact with people who have Lyme disease Using screens in windows left open at night Avoiding contact with wild rodents

A Lyme disease is transmitted to humans by the bite of a tick. An effective insect repellent will reduce tick bites and reduce the chance of contracting disease. Lyme does not spread person-to-person and ticks do not fly or even jump (screens protect against flying insects such as mosquitos). Wild rodents are important in the life cycle of the pathogen that causes Lyme disease, but rodents do not transmit the infection to humans.

How are the ABO antigens determined and how are they inherited?

ABO antigens are determined by what sugar is going to be added to the glycolipid. a. A antigen has an N-acetyl-galactosamine added to the H antigen. b. B antigen has galactose added to the H antigen. c. O antigen is neither and expresses the H antigen. d. Each person inherits 1 allele from his or her parent, so everyone has 2 ABO alleles resulting in 4 possible ABO blood types: A blood type (AA, AO), B blood type (BB, BO), AB, OO.

antibody-dependent cellular cytotoxicity

ADCC process by which NK cells are targeted to IgG-coated cells, resulting in lysis of the antibody-coated cells. A specific receptor for the constant region of IgG called Fc gamma III (CD16) is expressed on the NK cell membrane and mediates binding to the IgG ADCC is also one of the mechanisms by which therapeutic antibodies used to treat cancers eliminate tumor cells.

What is the difference between the distribution and elimination phases of drugs?

Distribution phase: (i.e. rapid early decrease in drug concentration) is due to drug distributing into highly perfused extravascular tissues (heart, brain, kidney, viscera) and moderately perfused tissues (muscle). Elimination phase (slow, later decrease in drug concentration) is due primarily to drug metabolism and excretion. A. shows distribution but no elimination- the initial rise in drug conc is followed by a rapid decline to a new plateau as teh drug equilibrates/ distributes B shows elimination but no distribution (as if drug was confined to the blood). plasma conc declines in proportion to the rate at which it is eliminated from teh body (one compartment model)

Match the genotype at the ABO locus with the blood type of the individual with that genotype. A. AO B. BB C. AB D. OO

AO - A BB - B AB - AB OO - O Each copy of a gene is expressed. If one has at least one copy of the A gene, then the cells will express A antigen. If a person has at least one copy of the B gene, then the cells will express the B antigen. AB individuals express both. People lacking both A and B genes express neither A nor B antigens and are blood type O.

What step in the function of the 26S proteasome is inhibited by bortezomib?

ATPase component of proteasome (20S subunit) is conserved across archael and mammalian 26S (extracellular ubiquitin components are what change) - so ATPase activity is important the inhibitors really only target the chymotrypsin-like (hydrophobic cutting) sites so at the doses given, you aren't really blocking the proteasome, you are slowing it down (only 20-30% affected) but the cells that are totally overwhelmed with misfolded proteins (like MM cells) will still trigger the jnk pathway- regular cells will compensate and make more proteasomes

How is acetyl CoA transported out of the mitochondrion during fatty acid synthesis?

Acteyl coa in the mito reacts with OAA to form citrate (just like the TCA) in the mito matrix. 1. Citrate crosses the mito membrane thru a transporter 2. enzyme ATP citrate lyase cleaves acetyl coa in the cytosol to form OAA which will back into the mito (after conversion back to pyruvate in 2 step process that produces a molecule of NADPH that will be required for fatty acid synthesis, also given by hte PPP) circuitious because acetyl coa cannot cross the mito membrane and bc pyruvate dehydrogenase is only present in the mito matrix - efficient synthesis of fatty acids from glucose requires the mito (adipose cells don't really have mito so cannot really break done fatty acids)

LDL receptor

All cells express the LDL receptor (which is why you could use fibroblasts in the experiment in class)

IgG

Also plays important role in neonate immunity 1) thru FcRn receptors in the placenta 2) neonate intestinal cells express FcRn which binds to ingested IgG from milk and carries it across teh epithelium

Essential amino acids

Amino acids essential in the diet - carbon skeleton cannot be synthesized by the body histidine, isoleucine, leucine, lysine, methionine, phenylalanine (which then makes tyrosine) , threonine, tryptophan, valine, arginine

Which of the following is the source for the amino group in urea that is added in the cytosol: Ammonium Glutamine Aspartate Glutamate

Aspartate

If you have a graph of log drug conc vs. time: -How do you determine Vd? -How do you measure clearance? -Hod could you calculate the half life?

Assuming that we are using a single compartment model (one line): --The Y intercept is C0 and this is divided into the Dose to get Vd --The slope of the line is kel and this is multiplied x Vd to get clearance --Alternatively you can infer the half-life from the plot and use the relationship Cl=0.693*Vd/t1/2

Gram-positive cocci in clusters are identified on a Gram stain of a blood culture. The identified bacteria are positive by testing for both catalase and coagulase. Which bacteria most likely caused this bloodstream infection? Streptococcus pneumoniae Staphylococcus aureus Group A streptococcus Staphylococcus epidermidis

B

What are the genes expressed in MHC Class I and MHC Class II?

Because there are three polymorphic class I genes, called HLA-A, HLA-B, and HLA-C in humans, and each person inherits one set of these genes from each parent, any cell can express six different class I molecules. In the class II locus, every individual inherits one pair of HLA-DP genes (called DPA1 and DPB1, encoding the α and β chains), one pair of HLA-DQ genes (DQA1 and DQB1, encoding the α and β chains), one HLA-DRα gene from each parent (DRA1), and one or two HLA-DRβ genes from each parent (DRB1 and DRB 3, 4, or 5). The polymorphism resides in the β chains. Thus, a heterozygous individual can inherit six to eight class II MHC alleles, three or four from each parent (one set each of DP and DQ, and one or two of DR, β alleles). Because of the extra DRβ genes, and because some DQα molecules encoded on one chromosome can associate with DQβ molecules encoded from the other chromosome, the total number of expressed class II molecules may be considerably more than six.

blood group

Blood group antigens are polymorphic molecules expressed on red blood cells, such that one individual may express different antigens than another individual. Therefore, transfusions between individuals may result in an immune response to the transfused blood cells. Some blood groups antigens may also be expressed on other cell types, which is important in solid tissue or organ transplantation.

What basic structural features are common to class I and class II MHC molecules?

Both types of MHC molecules contain peptide-binding clefts and invariant portions that bind CD8 (the α3 domain of class I) or CD4 (the β2 domain of class II) they are both co-dominant in their gene expression and polymorphic

What are class II antigen processing/presentation pathways - in general terms- and what T cell types is each one important for?

Class II source of peptides are mainly outside cell-internalized by endocytosis or phagocytosis that fuse with a lysosome The site of enzyme proteolysis is the endo-lysosome qhere proteases such as capthepsins break down the protein site of peptide loading is the specialized vesicle with HLA-DM that will fuse with the endosome once the MHC has joined it. HLA-DM will "bump" the MHC to shake out the invariant chain invariant chain is resposinsible for getting the MHC molecule and the peptide in the same place

CLIP peptide

Class II-associated invariant chain peptide Peptide remnant of the invariant chain that site in the class II MHC peptide-binding cleft and is removed by the action of the HLA-DM molecule before the flect becomes accessible to peptides produced from extracellulat protein antigens. derived from teh invariant chain and binds to class II MHC molecules

Which of the following is typically the latest manifestation of Lyme disease (meaning, which one occurs the longest time after a person gets Lyme disease)? A target-shaped rash Nervous system manifestations (e.g. paralysis of one side of the face) Heart rhythm abnormalities Arthritis

D All of these occur with Lyme disease, but arthritis occurs last in the typical pathogenesis of the disease. Nervous system abnormalities can occur late in disease, but this is uncommon. Usually nervous system abnormalities occur during early disseminated disease.

How do you calculate the dose of a drug required to maintain a par6cular plasma concentra6on? How quickly is steady-‐‐state achieved?

Dosing rate=Target Concentra5on x clearance/F, where F=bioavailability.

Where is the fat in the VLDL coming from in the fasted state?

FFA released from adipocytes by HSL (phosphorylated and activated in presence of glucagon) VLDL levels GO UP in the fasted state

How does the activation of PDH differ in the fed and fasted states in the liver? What is the relevance of this regulation in promoting glucose production during fasting? How is the rate of beta oxidation relevant to this regulation?

Fed state: low rates of B ox and high rates of fat syn. keep acetyl coa low, favoring PDH activation. Favors the conversion of pyrucate to acteyl coa, which support the conversion of glucose to fat. Fasting state: insulin levels drop. high rates of B ox and low rates of fat syn. keep acetyl coa high, inhibiting PDH. Increased acteyl coa levels (and NADH levels as B ox also yields NADH) inhibit PDG. Point: liver conserves pyruvate (low PDH activity) for use by gluconeogeneis. RECALL: elevated levels of acteyl coa stimulate pyruvate carboxylas to favor gluconeogenesis.

Why did the surgeon request the three frozen sections in the order that she did (first the lymph node, then the nodule itself, and finally the bronchial resection margin)?

Finding out if there is involvement in the lymph node and the degree of dysplasia of the nodule will help determine the stage of the tumor (TMN). The size of the tumor and degree of dysplasia will determine the "T," lymph node involvement will determine the "N," and presence of mets will determine the "M." The involvement of regional lymph nodes will determine the "N." The pathologist will look at the nodule slice and determine its grade by the degree of dysplasia. The bronchial resection will tell the surgeon if she got "clear margins." This will let her know whether all of the cancer has been removed with the excision of the nodule or whether she has to leave some abnormal cells that will continue to proliferate and create a new tumor. The lymph nodes and nodule were requested first because they will determine how advanced the cancer is and will help the surgeon determine how to proceed in surgery (while the patient is open on the table). The bronchila resection of the margin was last because the surgeon has almost completed the case and now wants to see if she has been successful. If her margins are clear, her patient has a better prognosis.

blood components

Following collection from a blood donor, blood is almost always separated into components by various centrifugation steps. Whole blood can be separated into Red Blood Cells units (RBCs), Plasma, and platelets. RBC units contain very little plasma. Plasma units, commonly referred to as fresh frozen plasma (FFP), contain no red blood cells. Platelet units contain plasma and may contain a few contaminating red blood cells.

S. pyrogenes non-suppurative sequelae

GAS!

How are drugs typically absorbed from the GI tract? What factors can influence the amount of drug that is absorbed?

GI epithelial cell junctions make paracellular transport across an intact epithelium difficult so ingested substances must traverse the cell membrane at apical and basal surfaces before entering the blood. Efficiency of this is determined by drug size, hydrophobicity and by the presence of carriers thru which the drug may enter or exit teh ell IN GENERAL, hydrophobic and neutral drugs cross cell membranes more efficiently than hydrophilic or charged drugs, unless the membrane contains a carrier molecule that facillitates the passage of hydrophilic substances all orally administered drugs are subjected to first pass metabolism in teh liver (which may inactivate a fraction of teh ingested drug)

Please match the following enzymes with their proper localization: A. Glutamate dehydrogenase B. Glutaminase C. Glutamine synthase D. Transaminase

Glutamate dehydrogenase - liver (mitochondria) Glutaminase - liver (mitochondria) Glutamine synthase - peripheral tissue e.g. muscle Transaminase - liver (cytosol)

Please match each substrate/product pair with the respective enzyme: A. Glutamate/alpha-ketoglutarate B. Glutamine/glutamate C. Glutamate/glutamine D. Alanine/pyruvate

Glutamate/alpha-ketoglutarate - Glutamate dehydrogenase Glutamine/glutamate - Glutaminase Glutamate/glutamine - Glutamine synthase Alanine/pyruvate - Transaminase Note that glutamate can also be converted to alpha-ketoglutarate by a transamination reaction, so if you picked transaminase, that would be correct, but that would leave you without an answer for alanine/pyruvate.

What gets phosphorylated (and deactivated) by PKA?

Glycolysis: Pyruvate Kinase (last regulated step), PFK2 Fat Synthesis: ACC (RLS)

What are the morphology and Gram stain of Neisseria?

Gonorrhea is gram negative diplococci.

Red cells from a donor with which ABO blood type carry the least risk causing a transfusion reaction and why?

Group O red blood cells lack both the A and B antigens and are least likely to cause a transfusion reaction.

What is the rate limiting-step in cholesterol production and how is it regulated?

HMG-CoA reductase is RLS, converst hydroxy methyl glutaryl CoA to mevalonic acid (MEVALONATE) - makes cholesterol which in turn acts as a substrate for the enzymes tha tmake vitamin D, Bile acids, steroid hormones, and CEs. A few proteins are modified by cholesterol (such as hedgehog) HMG CoA reductase is regulated at the level of its expression. High levels of cholesterol in the cell will sequester its TF (SREBP) in the ER. Low levels of cellular cholesterol will release SREBP (cleaving it to its basic domain) for entry into the nucleus and increased expression of HMG CoA reductase and the LDL receptor

why is low insulin signaling important in the adipose tissue in the fasted state

HSL is very sensitive to insulin except in T2DM when your receptors are no longer receptive to insulin so you get high VLDL with endogenous FA from the adipose

What is affinity maturation?

Heavy-chain isotype (class) switching and affinity maturation enhance the protective functions of antibodies. Affinity maturation is induced by prolonged or repeated stimulation with protein antigens, and it leads to the production of antibodies with higher and higher affinities for the antigen. This change increases the ability of antibodies to bind to and neutralize or eliminate microbes, especially if the microbes are persistent or capable of recurrent infections. This is one of the reasons for the recommended practice of giving multiple rounds of immunizations with the same antigen for generating protective immunity.

heavy chain class switching

Heavy-chain isotype (class) switching and affinity maturation enhance the protective functions of antibodies. Isotype switching and affinity maturation are two changes that occur in the antibodies produced by antigen-stimulated B lymphocytes, especially during responses to protein antigens (see Chapter 7 ). Heavy-chain isotype switching results in the production of antibodies with distinct Fc regions, capable of different effector functions. By switching to different antibody isotypes in response to various microbes, the humoral immune system is able to engage host mechanisms that are optimal for combating these microbes.

HDL

High density lipoprotein important in reverse cholesterol transport (LCAT) and exchange of cholesterol and apolipopretins with LDL, IDL, and VLDL APoA

How can alterations in the diet affect the rate of ketone generation in the body?

High levels of fat and low levels of protein and carbohydrates will keep insulin levels low and therefore facilitate high rates of fat release and oxidation by the liver, promoting generation of ketone bodies. -what our patient has to do to prevent seizures (without glucose hte brain seems to do ok on ketone bodies and seems to manage the epilepsy)

How can first-‐‐pass metabolism affect the pharmacokine6c behavior of a drug?

High first pass effect will decrease peak concentra5on as well as area under the curve if you compare oral to IV administra5on.

How do liver glycogen levels change during the fed and fasted states?

How do liver glycogen levels change during the fed and fasted states? insulin favors glycogen synthesis Glucagon and epinephrine favor glycogenolsys

What happens to the rate of electron transport if ADP is fully converted to ATP? What happens to the magnitude of the proton gradient? What happens to the NADH/NAD ratio?

If ATP levels are very very high, complex V will go its other direction and start pumping protons out of the matrix (conc. dependent). This will inc

Where mainly does IgA perform its function and how does it get there?

IgA is a secreted dimer

IL-13

In addition, some of the cytokines produced by T H 2 cells, such as IL-4 and IL-13, promote the expulsion of parasites from mucosal organs and inhibit the entry of microbes by stimulating mucus secretion. The cytokines of T H 2 cells also activate macrophages. Unlike T H 1-mediated activation, which enhances the ability of macrophages to kill microbes, T H 2-mediated macrophage activation enhances other functions, such as synthesis of extracellular matrix proteins involved in tissue repair. This type of response is called alternative macrophage activation (see Fig. 2-10 ). Some of the cytokines produced by T H 2 cells, such as IL-4, IL-10, and IL-13, inhibit the microbicidal activities of macrophages and thus suppress T H 1 cell-mediated immunity. Therefore, the efficacy of cell-mediated immune responses against a microbe may be determined by a balance between the activation of T H 1 and T H 2 cells in response to that microbe.

What factors predict whether a patient's lung tumor will respond to EGFR inhibition?

In general, EGFR mutations are only found in adenocarcinomas and rarely (if ever) in squamous cell carcinomas. In addition, Asian ethnicity, female sex, and lack of smoking history correlate with clinical benefit of EGFR inhibitors.

Different subsets of CD4+ helper T cells arise where and when? In the thymus during positive selection In secondary lymphoid organs after naïve T cell activation by microbial antigens In the liver prior to infection In the bone marrow during T cell development

In secondary lymphoid organs after naïve T cell activation by microbial antigens

agglutination

In the Blood Bank, red blood cells are "typed" using reagent antibodies (usually mouse monoclonal antibodies nowadays) against A and B. Red cells with these antigens are agglutinated by the appropriate anti-A or anti-B antibodies.

What methods does the blood bank use to test for antibodies to red blood cell antigens?

In the blood bank, red blood cells are typed using reagent antibodies against A and B. Red blood cells with these antigens are agglutinated by the appropriate anti-A or anti-B antibodies.

Where and in which forms is energy stored in our body?

In the fed state, acetyl-CoA is used to synthesize faTy acids, which can then be stored as triglycerides in adipocytes Amino acids are stored as proteins in muscle cells glucose is stored as glycogen in muscle and liver cells

How do the kinetic and regulatory properties of hexokinase and glucokinase differ? In what tissues are these proteins expressed?

In what tissues are these proteins expressed? * Hexokinase: expressed in most tissues, low Km for glucose o G6P product inhibition will prevent this -THIS IS THE HEX * Glucokinase: liver and pancreatic beta cells, higher Km (10 mM) o Rate of P will be proportionate to blood glucose levels o Liver will process blood glucose faster after a meal important because pancreas will make insulin according to amount of glucose conc and liver rate will depend on glucose concentration

What are the basic mechanisms by which viruses damage the host?

Infection of a host organism can be acute, chronic or latent. The host adaptive immune responses can target either virions, e.g., antibody-mediated neutralization, or infected cells, e.g., cytolytic T lymphocytes. cytotoxic effect is the result of the damage

How common is N. meningitidis as microbiota in healthy people?

It colonizes the oropharynx in 10% of population or 25% of adolescents and young adults.

Why is fatty acid oxidation important for glucose production by the liver in the fasted state? What is the role of carnitine in this process?

It supports energy needs and allows the TCA cycle components to be used for glucose production (OAA). Carnitine supports fatty acid transport into mitochondria for oxidation. remember the patient without carnitine (seizure meds): symptoms: easily fatigued, esp after waking and after mild exertion with leg cramps in fasting state, can't draw on stores of fatty acids (no carnitine) and cannot go thru gluconeo (no excess acetyl coa to drive pyruvate carboxylase) cramping because T1 muscle fibers lose all their glycogen/glucose quickly and don't have enough ATP

Alanine levels in the blood are higher than other amino acids because: It transports amino groups from muscle to the liver It has a higher solubility It is needed for the urea cycle in the liver It fuels metabolism in the fed state

It transports amino groups from muscle to the liver

Why can ketone bodies be used by the brain whereas fatty acids cannot? Why doesn't the liver consume the ketone bodies that it makes?

Ketones can be used if the enzyme thiophorase, which converts ketone bodies back to acetyl CoA, is present. Thiophorase is present in the brain and muscle but not in the liver. The brain and muscle convert the ketone bodies to acetyl CoA and then use the TCA cycle to generate energy.

What are the general components of lipoproteins?

Lipoproteins consist of the following components: 1. Proteins. These help provide a scaffold to the particle, and also interact with receptors on the cell surface, or activate enzymes. The isolated proteins are referred to as "apolipoproteins". 2. Lipids. Each lipoprotein has a distinct composition of lipids, including cholesterol, cholesterol esters, and triglycerides. All of them have a phospholipid coat so that they are soluble in the blood. HDL= High Density Lipoprotein IDL= Intermediate Density Lipoprotein LDL=Low Density Lipoprotein VLDL=Very Low Density Lipoprotein Chylomicrons: Have the least density Particles containing a high amount of triglyceride have the lowest density

How can the pH affect the rate of absorption of weak acids or weak bases?

Lower pH protonates acids and bases, so acids are more non-ionized and bases are more ionized. Acids are better absorbed and bases less absorbed at low pH. remember henderson hasselbach pH =pKa + log(A/HA)

What are the class I antigen processing/presentation pathways - in general terms- and what T cell types is each one important for?

Main source of proteins are those made in the cell, located in the cytosol (ex. iral protein that has been translated by the host's macinery). OR internalized and transported into the cytosol via cross presentation in the DCs The site of proteolysis/enzymes is the immunoproteasome (protein gets ubiquitinated) site of peptide loading is the ER (bridge between MHC and TAP) Molecule responsible for getting peptide and MHC in same place is the TAP protein transporter (ATP dependent)

What is the significance of the multiple serogroups of N. meningitidis?

Meningitidis has 13 known serogroups with capsules composed of different polysaccharides. This leaves the host vulnerable since hosts lack protective antibody or complement.

How is infection with N. meningitidis prevented and treated?

Meningitidis is prevented by vaccination and antibiotic prophylaxis of those who have close contact with individuals who are infected. Meningitidis is treated with cephalosporin.

How is N. meningitis transmitted?

Meningitidis is spread by close contact (living together, kissing, medical exposure to respiratory secretions).

By what general mechanisms do antibodies protect against intracellular pathogens?

Microbes that are able to enter host cells may be released from these infected cells and go on to infect other neighboring cells. Antibodies can neutralize the microbes during their transit from cell to cell and thus limit the spread of infection. antibody-dependent cellular cytotoxicity (ADCC). Cells infected with enveloped viruses typically express viral glycoproteins on their surface that can be recognized by specific antibodies and this may facilitate ADCC-mediated destruction of the infected cells.

Glucogenic or ketogenic refers to the pathways that metabolize carbon skeletons of amino acids. Which of the following statements is true: Strictly ketogenic amino acids can fuel gluconeogensis Purely glucogenic amino acids are essential An amino acid can be both glucogenic and ketogenic Branched amino acids are ketogenic and therefore degraded by muscle

Most amino acids can enter both pathways. Whether an amino acid is essential is not linked to their glucogenic or ketogenic nature. The only exceptions are Leucine and Lysine, which happen to be strictly ketogenic and also are essential. Branched amino acids are degraded in the muscle because the liver lacks the appropriate transaminase. An amino acid can be both glucogenic and ketogenic

First order kinetics

Most drugs show so-called first-order kinetics, meaning that the plot of this type shows a straight line during the elimination phase. The line is used to calculate the half-life, the amount of time that it takes to reduce the plasma concentration by half. In most clinical situations, the concentration of the drug is much lower than the Km so equation reduces to equation B- means that the rate of METABOLISM and ELIMINATION are directly proportional to the concentration of free drug (first order kinetics observed) means that a constant fraction of drug is metabolized per unit of time (with every half-life the concentration reduces by 50%) AKA LINEAR kinetics bc when the drug concentration versus time is plotted on a semi-log scale, the plot is linear

A person with a defect in IL-17 production would be most susceptible to which type of infection? Mucosal fungal (candida) infections Pulmonary tuberculosis Viral hepatitis Malaria

Mucosal fungal (candida) infections

What is the difference btween muscle and adipose tissue in terms of LPL expression?

Muscle will upregulate LPL in fasting state while adipose will decrease expression. - allows each tissue to regulate how much fat it needs in different situations Type 1 muscle fibers will be taking up and using fatty acids- need a way to upregulate uptake of FA during fasting for muscles so that AA can go to liver for glucose for brain - therefore you NEED VLDL in teh fasted state taking up of FFA is not regulated (operates at the same level across cells)

How can triglyceride breakdown contribute to glucose production?

NO NET SYNTHESIS OF GLUCOSE FROM ACETYL COA When insulin levels fall and glucagon/epi levels rise, the rate of fatty acid release by the adipcytes increases. This causes a rise in acetyl coa levels which activates pyruvate carboxylase (in the mitochondrion) which promotes the gluconeogenesis pathway (pyruvate to oxaloacetate is first step of gluconeogenesis) but more importantly the glycerol backbone can be converted into glucose

What are the major transcription factors that are induced upon TCR signaling? The activation of which one is blocked by cyclosporine?

NFAT present in an inactive phosphorylated form in the cytoplasm of resting T cells. -This signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of an enzyme called phospholipase Cγ (PLCγ), which catalyzes the hydrolysis of a plasma membrane inositol phospholipid (PIP 2 ). One byproduct of PLCγ-mediated PIP 2 breakdown, (IP 3 ), binds to IP 3 receptors on the endoplasmic reticulum (ER) membrane and stimulates release of Ca 2+ from the ER, thereby raising the cytosolic Ca 2+ concentration. In response to the loss of calcium from intracellular stores, a plasma membrane calcium channel (CRAC) is opened, leading to the influx of extracellular Ca 2+ into the cell, which sustains the elevated Ca 2+ concentration for hours. Cytoplasmic Ca 2+ binds a protein called calmodulin, and the Ca 2+ -calmodulin complex activates a phosphatase called calcineurin. This enzyme removes phosphates from cytoplasmic NFAT, enabling it to migrate into the nucleus, where it binds to and activates the promoters of several genes, including the genes encoding the T cell growth factor interleukin-2 (IL-2) and components of the IL-2 receptor. A drug called cyclosporine binds to and inhibits the phosphatase activity of calcineurin and thus inhibits the NFAT-dependent production of cytokines by T cells. This agent is widely used as an immunosuppressive drug to prevent graft rejection; its introduction was one of the major factors in the success of organ transplantation Ras/Rac-MAP kinase pathways include the guanosine triphosphate (GTP)-binding Ras and Rac proteins, several adaptor proteins, and a cascade of enzymes that eventually activate one of a family of mitogen-activated protein (MAP) kinases. These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane, leading to the recruitment of Ras or Rac, and their activation by exchange of bound guanosine diphosphate (GDP) with GTP - ultimately lead to transcription factor activating protein 1 (AP-1), which enhances the transcription of several T cell genes. Another major pathway involved in TCR signaling consists of activation of the θ isoform of the serine-threonine kinase called protein kinase C (PKCθ) and activation of the transcription factor nuclear factor κB (NF-κB). PKC is activated by diacylglycerol, which, like IP 3 , is generated by PLC-mediated hydrolysis of membrane inositol lipids. NF-κB exists in the cytoplasm of resting T cells in an inactive form, bound to an inhibitor called IκB. TCR-induced signals, downstream of PKCθ, activate a kinase that phosphorylates IκB and targets it for destruction. T cell receptor signal transduction also involves a lipid kinase called phosphatidylinositol-3 (PI-3) kinase, which phosphorylates membrane PIP 2 to generate PIP 3 . The phospholipid PIP 3 is required for the activation of a number of crucial targets including a serine-threonine kinase called protein kinase B, or Akt, which has many roles, including stimulating expression of anti-apoptotic proteins and thus promoting survival of antigen-stimulated T cells The various transcription factors, including NFAT, AP-1, and NF-κB, stimulate transcription and subsequent production of cytokines, cytokine receptors, cell cycle inducers, and effector molecules such as CD40L

What is the importance of elevated glucagon following a protein-‐‐only meal?

Need to increase amino acid catabolism in the liver to increase glucose output protect against hypoglycemia induced by insulin which also rises after a protein only meal, insulin rises just a little bit while glucagon rises a lot. Insulin rises because the pancreatic beta cells will digest some of the AA and will create ATP, allowing for release of insulin vesicles. But only a little bit. This insulin targets the muscle to prevent protein breakdown (via AKT). There are no glucagon in teh muscle. The glucagon will promote gluconeogenesis to prevent hypoglycemia - in the liver, AA are catabolized for glucose AS IF THE CELLS WERE IN A FASTING STATE (high glucagon)

How will the metabolic fate of pyruvate change if oxygen is not available or in the fed versus fasting states?

No oxygen, will convert to lactate (NADH goes up because electrons cannot be given to O2 so PDH goes down and pyruvate gets shuttled off to makte lactate) . Fed state favors conversion to acetyl CoA (PDH) for fat production or thru TCA for energy needs for the liver cells, fasting to OAA (pyruvate carboxylase) for gluconeogenesis (or to replenish the TCA if energy needs are not met thru beta ox) but high levels of beta ox will produce a lot of NADH that will inhibit PDH, allowing for conversion to OAA for gluconeo

Rh antigens Are they naturally occuring?

No response unless exposed via transfusion or pregnancy (which is why they aren't usually tested for in typing because we don't make the antibodies for them even if they are Rh-

Can the liver make VLDL only in the fasting state?

No, VLDL is produced both in the fasting an dfed states. In the fed state, the lipid source is endogenous synthesis (exogenous goes into chylomicrons); whereas in the fasting state, it is recycled fatty caids

Do MHC only present foreign peptides?

No, majority are actually self peptides (not a specific pathway) but the specificity comes from T cell activation in that the T cells that were specific to self were already killed T cells need less than .05% of MHC complexes on surface are necessary to initiate the T cell

What distinguishes the two major cellular pathways that degrade cellular proteins?

One major difference is structural: The core particle of a proteasome is a hollow 28-subunit tube. The 19 subunit cap (which contains a ubiquitin-recognizing lid and ATPases that function to unfold the tagged protein) traps the tagged the protein before it can gain access to the barrell of the core. Once in the core, the unfolded protein binds to the active sites and is degraded. Lysosomes on the other hand, fuse with autophages full of cytoplasmic contents which then get degraded or with endosomes that come from invagination of the cell wall (or the lysosome itself). There is no regulation system for what the lysosome puts in its mouth. There is a lot of regulation for the proteasome core (picky eater). Another is the specificity: Although there is some specificity within the autophagy pathway, the lysosome has to be prepared to degrade all different types of cell components and even organelles so it has a large number of degradation enzymes. Proteasomes only degrade proteins so their proteases within the cap are specific to breaking down peptide bonds that bind to aspartic acid active sites within the core. Only proteins properly targeted by ubiquitin gain access Lysosomal - less specific? Proteasomal - more specific? mechanism of degradation (M6P vs. ubiquitin tagging pattern)

How does a decrease in insulin signaling and an increase in glucagon/epinephrine signaling favor the production of glucose by the liver in the fasting state

Overall - activation of PKA leads to phosphoylation: 1. PFK2 becomes inhibited -> low levels of F26BP 2. PKA phosphorylates phosphorylase which activates glycogen phosphorylase leading to glycogen breakdown 3. pyruvate kinase becomes phosphorylated (and inactivated) In the fasting state, there will be high levels of glucagon and epinephrine and low levels of insulin. This will favor activation of protein kinase A. PFK2 will become phosphorylated, inactivating its ability to generate F-2,6-BP. This will lead to decreased ac-vity of PFK1. Protein kinase A can also directly phosphorylate pyruvate kinase and inactivate it. Together this will slow the rate of glycolysis. The rate of gluconeogenesis will be s-mulated due to rising acetyl CoA levels in the mitochondrion, which are a consequence of elevated release of fatty acids from adipocytes. The increased acetyl CoA s-mulates pyruvate carboxylase and also inhibits pyruvate dehydrogenase. The combined effect is to s-mulate the conversion of pyruvate to oxaloacetate. Later in gluconeogenesis, the the drop in F-2,6-BP levels stimulates the activity of fructose 1,6 bisphosphatase. The fructose 6 phosphate is isomerized to glucose 6 phosphate, which is then dephosphorylated by glucose 6 phosphatase. Remember that Glut2 is not regulated—in the fas-ng state it will help export glucose from the liver into the blood stream.

How can polymorphisms in P450 enzymes affect the metabolism of drugs?

Pa5ents with elevated levels of P450 enzymes may either be more sensi5ve to drugs if the enzyme is required for ac5va5ng the drug (as in the case of codeine), or less sensi5ve to the drug if the enzyme is involved in the inac5va5on of the drug. Polymorphisms may also result in reduced ac5vity or amounts of enzyme, which would have the opposite effect.

How does poliovirus spread in the body?

Pathogenesis: Virus is ingested and replicates in cells of the mucosa of the pharynx and gut, including tonsils and Peyer's patches of ileum. The virus then spreads through the lymphatics to deep lymph nodes followed by a minor viremia to extraneural tissues. There is then a major viremia coincident with prodrome and spread to the CNS via nerve fibers or the blood stream. The virus specifically targets motor neurons, in particular anterior horn cells of spinal cord. This infection leads to motor neuron necrosis and paralysis. The most severe form is bulbar poliomyelitis, in which infection involves the medulla oblangata and respiratory paralysis. Entry into the brain from the blood requires crossing the blood-brain barrier consisting of endothelial cells surrounded by glial cell processes. While it has long been thought that poliovirus enters the brain by growing in these cells to cross this barrier, studies on another enteric virus, reovirus, has raised an alternative pathway for entry into the CNS by entry into the vagus nerve in the intestine. Poliovirus is transmitted by shedding in feces. Fecal-oral spread leads to infection of new individuals.

How are sexually transmitted infections transmitted?

Pathogens spread by sex are transmited in mucosal secretions (genital or oral), from open sores on th eskin or mucosa or in semen. The sit initially infected will depend on behaviors, but the common sites are the genitals, anorectum, or oral mucosa. Most pathogens transmitted by sexual contact can also be transmitted from mother to fetus before or during delivery. They can spread across the placenta or during passage through the birth canal.

What is the genetic basis of pilus variation in Neisseria?

Pili variation is established through recombination.

What is the significance of the poliovirus serotypes in vaccine design?

Poliovirus is a member of Picornaviridae (pico- small; RNA) family. Three serotypes have been defined based on antibody neutralization. The epitopes responsible are on capsid surface proteins. Immunity is serotype-specific. Oral feeding of live vaccine leads to circulating antibody and local immunity mediated by IgA. Parenteral administration of killed virus vaccine leaves the gut susceptible but protects against viremia. Neutralizing IgG antibodies persist for life. Both vaccines are trivalent

What are typical manifestations of primary and secondary tuberculosis?

Primary: Cellular immunity and tissue hypersensitivity usually appear 3 to 8 weeks after infection and are marked by a positive tuberculin skin test. In most affected individuals, this response controls infection (although viable organisms may persist in the tissues), no symptoms develop, and the only evidence of infection is a positive tuberculin skin test. However, in some cases, the immune response does not control the primary infection (no positive tuberculin test), and progressive primary TB develops.In such individuals, the primary focus directly progresses to worsening pneumonia, and the very young may develop tuberculous meningitis. The most important consequence of lymphohematogenous dissemination (the organisms preferentially localize in certain tissues, including lymph nodes, vertebral bodies, and meninges but most importantly the apices of the lungs) is seeding of the lung apices, where either progressive primary or secondary disease can occur.Immunocompromised persons may not contain the primary infection, and organisms may invade the bloodstream and disseminate to cause a lifethreatening infection known as miliary tuberculosis. The term miliary is derived from the resemblance of the tubercles to millet seeds (bird seed). Characteristic of the disease are tubercles found in many organs, including the liver, spleen, kidneys, brain, and meninges. Caseation and cavitation are less frequent than in secondary TB. Secondary: The most common site of reactivation is the apex of the lung. - think Victorian England; the contained bacteria then explode... Lesions slowly become necrotic, undergo caseous necrosis (named for its cheesy appearance), and eventually merge into larger lesions. With time, the caseous lesions liquefy and discharge their contents into bronchi. This event has several major consequences. It creates a well aerated cavity in which the organisms proliferate. The discharge of caseous material also distributes the organisms to other sites in the lung, which can lead to a rapidly progressive tuberculous pneumonia. In addition, the bacterialaden contents of caseous lesions are coughed up and become infectious droplet nuclei. Although the reason for the apical pulmonary localization is not known with certainty, it is likely that deficient lymphatic flow at the apices, where the pumping effect of respiratory motion is minimal, favors retention of organisms. When hypersensitivity develops, tissue damage creates apical cavities characteristic of pulmonary TB in adults. The pathologic features of TB are the result of hypersensitivity to mycobacterial antigens. The classic tissue response involves organization of macrophages, Langhans giant cells, and lymphocytes resulting in formation of granulomas (sometimes called tubercles). This pattern constitutes a successful tissue reaction with containment of infection, healing with eventual fibrosis, encapsulation, and scar formation. However, with time, the centers of the tubercles may become necrotic

indirect coombs test

Prior to a transfusion, the patient's blood is typed, meaning the ABO and Rh type is determined and an antibody screen is performed to test for the presence of antibodies to Rh or other blood group systems. The antibody screen is performed by determining whether the patient's serum contains antibodies that agglutinate red blood cells expressing a variety of antigens. The test method is called the indirect antibody test, or indirect Coombs test (figure below). The indirect antibody test can also used to "cross match" a sample of the recipient's serum against a sample of the blood donor's RBCs.

Where and how are chylomicrons produced? How are they metabolized?

Production (similar to VLDL): 1. apoB48 translated by ribosomes and enters lumen of ER 2. If TAG available, apoB48 lipidated by action of microsomal triglyceride transfer protein (MTP) in 2 steps (accumulating TAG and CEs). 3. resulting VLDL secreted by exocytosis (vesicle secretion pathway) into the blood stream by hepatocytes. In the absence of TAG, the apoB protein is degraded in the hepatocyte one ApoB protein for each lipoprotein particle produced so measurement of ApoB100 can give a measurement of amount of VLDL+LDL+IDL Ezetimibe is a drug that reduces cholesterol absorption by inhibiting the intentinal NPC1L1

Where and how is VLDL produced?

Production (similar to chylomicron): 1. apoB100 translated by ribosomes and enters lumen of ER 2. If TAG available ( from FA or monoacylglycerol MAG produced from pancreated lipases), apoB lipidated by action of microsomal triglyceride transfer protein (MTP) in 2 steps (accumulating TAG and CEs). The CEs get into teh cell thru Niemann Pick C1-like 1 (NPC1L1) transporters that take the cholesterol from micelles. THe c is then esterified into CE by ACAT2. All this forms prechylomicrons. 3. Precylmoicrons packaged into prechylomicron transport vesciles (PCTV) that bud off the ER membrane to fuse with the cis-Golgi (in the absence of COPII proteins, unlike protein vesicles that require this COPII- think of SREBP) 4. resulting chylomicron secreted by exoctyosis into lymphatics by enterocytes

In the figure below, Lck and the protein labelled D are the same general type of enzymes. What type is this? Protein Serine/threonine kinase Protein tyrosine kinase Serine/threonine phosphatase Tyrosine phosphatase Protease

Protein tyrosine kinase

Rh antigens What types of antigens are they?

Protein- T cell response!

What cells express ABO antigens?

RBCs, platelets, lymphocytes, endothelial cells and epithelial cells.

What are the steps in poliovirus RNA metabolism?

Replication in host cells: Poliovirus enters cells by endocytosis or delivery of genome across the plasma membrane. Following uncoating, the positive (+) strand genomic RNA is translated to yield one "polyprotein" which is cleaved by viral-encoded proteases to give 7 viral proteins that are involved in viral RNA replication and protein cleavage and 3 proteins that serve as capsid proteins for assembly of the protein shell. The viral replicase copies the (+) strand genomic RNA into complementary negative (-) strands and then into progeny + strands. These progeny (+) strands are encapsidated into virus particles. The strong inhibition of host cell macromolecular synthesis leads to cell death and lysis.

Rh antigens consist of what type of moiety (chemical structure)?

Rh antigens consists of transmembrane proteins.

Which cells express Rh antigens?

Rh system antigens are only present on some proteins of the red blood cell membrane, and are not present on other blood cells or cells of other tissues.

What is the cholesterol scensing protein in cholesterol synthesis?

SCAP (presence of cholesterol recruits Insig)

What are frozen sections, and why do we do them? Why would a surgeon want to know the histopathologic classification, grade, and stage of a lung tumor in real time (while the patient is still under anesthesia)?

See slide 4. An intraoperative consultation or "frozen section" is done to evaluate a specimen while the patient is still in the operating room under anesthesia, when the results of the biopsy will dictate the course of the surgery or how the remainder of the tissue is processed. Reasons for this include assessing margins, histologic type (small cell is not amenable to surgery), and stage (if there are already metastases, there is no benefit to removal of the primary tumor, and the surgeon might as well close up and spare the patient the risk). - this is why they did lymph, tumor, margin

What factors regulate the activity of pyruvate dehydrogenase?

Substrates of PDH tend to ativate the enzyme, products inhibit. If you know the substrates and products you can infer the regulation. Products: NADH, ATP (by way of NADH), and acetyl coA -NADH and acetyl coa are both indirect (activates the kinase) and direct inhibitors substrates: pyruvate, NAD+, ADP (indirect activators that inhibit the kinase that inactives PDH)

Rh antigens What types of antibodues are formed and why?

T cell DEPENDENT B cell response -> igG

What methods are used to detect M. tuberculosis in patient samples?

TB is usually diagnosed by microscopy and culture of sputum. tuberculin skin test (PPD) acid fast staining microscopy culture (gold standard) -3-6 weeks (slow growing) radiometric techniques speed this up to 1-2 weeks nucleic acid amplification

Il-5

TH2 cytokine T H 2 cells produce interleukin-4, which stimulates the production of IgE antibodies, and interleukin-5, which activates eosinophils. IgE activates mast cells and binds to eosinophils. These IgE-dependent, mast cell- and eosinophil-mediated reactions are important in killing helminthic parasites. IgE coats the heminths, eosinophils bind to the IgE, eosinophils are activated to release their granule contents, and granule enzymes kill the parasites.

Why does the host fail to make a strong antibody response against the capsule of group A streptococcus?

The HA capsule Hyaluronic acid is found in great abundance in human connective tissue. Therefore, streptococci enveloped in an HA capsule have camouflaged themselves in a host antigen that does not elicit an immune response.

Which of the following best describes Rh antigens? RBC membrane lipids RBC membrane proteins RBC membrane oligosaccahrides RBC cytosol proteins RBC cytosol sugars

The Rh antigens are encoded by two membrane proteins that are expressed exclusively on red blood cells.

direct coombs test

The direct Coombs test, also known as the direct antiglobulin test, is a commonly used laboratory test to determine if a patent has anti-RBC antibodies bound to his/her RBCs. This is done when a patient has a hemolytic anemia, and an immune cause is suspected.

immunodominant epitope

The epitope of a protein antigen that elicits most of the response in an individaul immunized with the native protein. Correspond to the peptides of the protein that are proteolytically generated within APCs and bind most avidly to MHC moleucles and are most likely to stimulate T cells

B7-1 (CD80) and B7-2 (CD86)

The full activation of T cells depends on the recognition of costimulators on APCs in addition to antigen (signal 2). Microbes, as well as cytokines produced during innate immune responses to microbes, induce the expression of costimulators, such as B7 molecules, on the APCs. The B7 costimulators are recognized by the CD28 receptor on naive T cells, providing signal 2. In conjunction with antigen recognition (signal 1), this recognition initiates T cell responses. The best-defined costimulators for T cells are two related proteins called B7-1 (CD80) and B7-2 (CD86), both of which are expressed on APCs and whose expression is increased when the APCs encounter microbes. These B7 proteins are recognized by a receptor called CD28, which is expressed on virtually all T cells.

Mycobacteria

The genus Mycobacterium includes closely related species of obligate aerobes (Table 231). Species other than M. tuberculosis are often called atypical mycobacteria. These organisms are usually acquired from the environment rather than from persontoperson spread and tend to cause diseases distinct from TB. Many mycobacteria are harmless, and some live on the human body without causing disease (e.g., M. smegmatis), while others are found in soil and other niches in the environment. Mycobacteria are acid fast, are unusually resistant to drying, and grow slowly compared with most other bacteria.

TCR recognition

The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on APCs. The T cell receptor (TCR) recognizes MHC-associated peptide antigens, CD4 or CD8 coreceptors recognize the MHC molecules, adhesion molecules strengthen the binding of T cells to APCs, and receptors for costimulators recognize second signals provided by the APCs These biochemical pathways are initiated when the TCR complexes and the appropriate coreceptor are brought together by binding to MHC-peptide complexes on the surface of APCs. In addition, there is an orderly redistribution of other proteins in both the APC and T cell membranes at the point of cell-to-cell contact, such that the TCR complex, CD4/CD8 coreceptors, and CD28 coalesce to the center and the integrins move to form a peripheral ring. This redistribution of signaling and adhesion molecules is thought to be responsible for optimal induction of activating signals in the T cell. The region of contact between the APC and T cell, including the redistributed membrane proteins, is called the immunologic synapse.

What regulates the rate of lipolysis from adipose cells?

The level of cAMP and protein kinase A activity, which regulates hormone sensitive lipase. Insulin suppresses this pathway while glucagon and epinephrine activate it. likely that niacin, used for pts with elevated blood levels, inhibits a Gi GPCR because it inhibits adenylate cyclase production of cAMP, acting similarly to insulin (which will shut off HSL)

What are the manifestations of gonorrhea?

The organism can spread within the urogenital tract to cause pelvic inflammatory disease in women, and epididymitis and prostatitis in men. Anorectal infection is usually asymptomatic but can cause proctitis. Pharyngeal infection can be asymptomatic or cause mild pharyngitis. Ocular infection can be mild or severe. Disseminated gonococcal infection (DGI) occurs in less than 1% of patients with genital infection. The bacteria spread from the genital subepithelium to the blood, and then to the skin (papules that form pustules) and joints (septic arthritis). Neonatal infection causes "opthalmia neonatorum," a progressive and severe conjunctivitis.

How does N. meningitidis escape from phagocytosis?

The organism produces an anti-phagocytic capsule.

What are the products of the pentose phosphate pathway?

The pentose phosphate pathway represents an alterna-ve route to glycolysis for oxidizing glucose. Importantly, it generates NADPH rather than NADH. It is also generates ribose-5 phosphate, which is important for nucleo-de (RNA and DNA) synthesis. Both glycolysis and the pentose phosphate pathways are cytoplasmic. pathways are cytoplasmic. The pentose phosphate pathway is also referred to as the "hexose monophosphate shunt" because the ribose 5 phosphate that is generated can be converted into glycoly-c intermediates downstream of the rate limi-ng step of glycoslysis (PFK1). A mnemonic for the role of the pentose phosphate pathway (PPP): the PPP makes Pentose (5 carbon sugar) and NADPH.

Why is the NSCLC classification no longer considered adequate to meet the standard of care? What are the two major clinical/pathologic subtypes of lung cancer that were formerly lumped together as "non-small cell"? How do they differ in terms of epidemiology, clinical behavior, and sensitivity to therapy?

The reasons for abandonment of the term "NSCLC" include: • Epidemiologic differences between adenocarcinoma and squamous cell carcinoma. While all forms of lung cancer are more common in smokers, adenocarcinoma is relatively more common in non-smokers. • Chemosensitivity profile. Adenocarcinoma and squamous cell carcinoma respond differently to particular chemotherapeutic agents. In particular, while anti-angiogenic agents are effective against adenocarcinoma, they are associated with a risk of fatal pulmonary hemorrhage in squamous cell carcinoma. • Sensitivity to targeted therapy. Although the above factors were important, what really did in the NSCLC/SCLC paradigm was the advent of targeted therapy for lung cancer. Most adenocarcinomas have a defined oncogenic driver, and are good candidates for targeted therapy. In contrast, squamous cell carcinomas have more complex genomic profiles, and tend to be harder to target. As a result, the new standard of care is to render a specific diagnosis of adenocarcinoma or squamous cell carcinoma, rather than lumping them together as "non-small-cell lung cancer".

How is glucagon production by the alpha cell regulated?

There are mulUple regulatory inputs into glucagon producUon. One input is the level of insulin—if insulin levels are high, then glucagon release by the alpha cells is suppressed. At its most fundamental level then, the regulaUon of glucagon and insulin release is reciprocal: if insulin is high, then glucagon is low, and vice versa. However, there is another important regulator of glucagon producUon, which is the level of circulaUng amino acids. Higher circulaUng amino acids will sUmulate glucagon secreUon. For example, following a meal rich in protein, glucagon levels will tend to rise.

How can lipids affect gene expression at the level of transcription?

There is a family of nuclear hormone receptors called PPARs where fatty acids bind to them and then they mediate the effects of the fatty acids SATURATED fatty acids will bind to the receptors and increase expression of genes involved in cholesterol and fat syn POLYUNSATURATED fatty acids (which can only be gotten from the diet) bind and activate receptors that inhibit hte expression of these genes or stimulate the expression of genes that break down fat SO diets high in saturated and trans fats may promote fat synthesis which can lead to insulin resistance and cardiovascular disease

=What are the unique features of the structure of C. trachomatis?

They are structurally similar to gram negative bacteria because they have an outer membrane and little to no peptidoglycan, and are only a quarter of the size of most bacteria.

What is the tuberculin skin test and how does it work? What other diagnostic tests are available for the same purposes as the TST?

This test involves the intradermal injection of proteins, or tuberculin, from tubercle bacilli. The material used is a poorly defined mixture known as purified protein derivative (PPD). A positive reaction is indicated by thickening (induration) of the skin several days after inoculation, which results from infiltration by mononuclear phagocytes and T cells. This delayed type hypersensitivity reaction recapitulates the local events that take place in the lung and other infected tissue. Depending on the site of the reaction, delayed type hypersensitivity may account for diverse manifestations, such as pleurisy with effusion (the sometimes massive accumulation of exudate in the pleural cavities) or sudden inflammation of the meninges. Surprisingly few tubercle bacilli are present in the pleural fluid or cerebrospinal fluid during these infections, but they are able to cause considerable inflammation. The tuberculin skin test is most useful for diagnosing latent tuberculous infection.The test is much less useful in countries where most of the population is tuberculin positive or has received the bacille Calmette Guérin (BCG) vaccine. A newly positive test after a previous negative test (tuberculin conversion) indicates recent tuberculous infection and is an indication for chemoprophylaxis. newer assays that quantify the immune response to M. tuberculosis have been developed. Interferonγ plays a critical role in regulating the cellular immune response to M. tuberculosis. There are now FDAapproved assays that measure the in vitro production of interferonγ in response to antigens specific for M. tuberculosis. These tests have increased specificity for diagnosing latent TB infection because the antigens used are not present in nontuberculous mycobacteria or BCG vaccine strains. The diagnosis of asymptomatic tuberculous infection is usually based on tuberculin skin test results. In contrast, active disease is usually diagnosed by acidfast staining and culture of sputum or affected tissues.

How does pilus variation allow Neisseria to escape from the immune response?

To escape the host antibody response, N. gonorrhoeae varies the antigen on its surface by shuttling different pilin genes next to the single promoter for pilin expression, creating a variety of pili.

How does poliovirus spread between hosts?

Transmission is predominantly fecal-oral so summer and early autumn were peak seasons.

TAP complex

Transporter-associated with antigen processing Adenosine triphosphate dependent peptide transporter that mediates the active transport of peptides from teh cytosol to the site of assembly of class I MHC mol inside the ER. TAP is a heterodimeric mol composed of TAP-1 and TAP-2 polypeptides that are required for stable assembly of Class I MHC molecules. TAP-deficient animals express few cell surface class I MHC molecules which results in diminished development and activation of CD8 T cells

What are the VLDL levels in a patient with T2DM?

VLDL will be high - normally insulin suprreses rates of adipose FA but now you have insulin resistance.

Virus

Viruses (the word "virus" derives from the Latin word for poison) are obligate intracellular parasites that have a simple "life" cycle. Upon entry into a host cell, they disassemble themselves and undergo replication to make more copies of themselves using the host cell machinery.

How is insulin production by the beta cell regulated?

When blood glucose levels rise aher a meal, this results in more glucose entering the beta cell through a glucose transporter called Glut2. The higher levels of glucose result in higher ATP levels in the cell, following metabolism of the glucose by glycolysis, the TCA cycle, and oxidaUve phosphorylaUon in mitochondria. The increased ATP levels block the acUvity of a potassium channel. Normally these channels must be open to allow cells to maintain a normal resUng negaUve membrane potenUal. However, when the channel closes, the membrane potenUal increases (becomes more posiUve) and this depolarizaUon causes the opening of a voltage-sensiUve calcium channel. The increased cellular calcium triggers the fusion of vesicles that contain insulin with the plasma membrane, causing the insulin to be secreted. Thus increased blood glucose levels trigger the release of more insulin into the circulaUon. Insulin is also regulated by glucagon! The two hormones cross regulate

What is the function of bile acids and how is their production is regulated?

When cholesterol is returned to the cell (reverse transport via HDL), activates a nuclear hormone receptor LXR (ligand-dependent TF) which induces expression of genes that convert cholesterol to bile acids and other genes that enhance biliary cholesterol secretion one of the enzymes is a cytochrome p450 family member (CYP7A1) that converts cholesterol into bile acids which, as they rise, bind and activate ANOTHER nuclear hormone receptor (FXR) which stimulates the expression of a trasnporter that transprots bile acids into the bile duct = liver can deliver excess cholesterol into the bile and convert cholesterol to bile acids function of bile acids are 1) to get rid of excess cholesterol 2) to function as a detergent to solubilize dietery cholesterol into micelles -regulated by excess cholesterol in the liver

PPARs

a family of nuclear hormone receptors that can be modulated by fatty acids.

SREBP

a key TF that mediates the expression of HMG COA reductase and the LDL receptor (increases expression of both of these) when sequestered, it is a transmembrane protein in the ER

arachodonic acid

a polyunsaturated fatty acid that is the precursor for the eicosanoids, which include hormones such as protaglandins, thrombaxanes, and leukotrienes, which participate in diverse signaling pathways such as the inflammatory response and smooth muscle contraction

How might Th2 responses impair Th1 reponses, with respect to macrophage activation

activation of Th2 cells causes alternative macrophage acitvation, there macrophages which do not produce Il-12 to induce Th1 cells Th2 also produce Il-4 which feeds back to cause more Th2 cells and inhibits Th1 cell development kids with leishmania got sick bc couldn't activate T cells - macrophages had the leishmania stuck in their phagolysosomes with high levels of IgE (suggesting Th2)

reactive oxygen species -superoxid -hydrogen peroxide -hydroxyl radical

all modify/damage DNA, lipids, proteins about 85% of the ROS in our bodies come from the mitochondrial electron transport chain (mostly from complexes I and III) -superoxide of special itnerest bc it is the initla ROS mad eform tehe ETC -> can eventually lead to hydroxyl radicals which are the most reactive ROS by reacting with bases -when electrons build up in the cain because the rate of NADH proudction is higher than necessary to meet the needs of ATP production (associated with an increase int he protn gradient across the mito membrane which slows the rate of electron transport) ,the liklehood of E- reacing with O2 at complex I or III is increased in DNA to create a variety of molecular lesions - WHY NAHD inhibits PDH, the TCA (at alpha-ketoglutarate dehydrgenase, and beta ox) when there is enough ATP presnt -normally O2 only reacts with complex IV to make water

Why shouldnt we just kill off all of hte homozygotes?

allele frequencies are essentially stable in our pop (low incidence of homozyg cuz neg selcetion already acting) most severe dom disease is very recent or de novo so in every gen there is an influx this would have little impact bc you still have carriers (ex. Thalassemia screening carrier rate not affected - goal to reduce disease frequency not carrier frequency)

Immune defense against helminthic (parasitic worm) infections is mediated by the same helper T cell subset that is strongly associated with which one of the following types of diseases? Autoimmune Cancer Allergic Immunodeficiency Cardiovascular

allergic

What is the difference between a glucogenic and a ketogenic amino acid?

amino acids are called "glucogenic" because their carbon skeletons can be used to generate glucose. Amino acids that are "ketogenic only" can only be used to generate acetyl-coA or ketone bodies and cannot be used to make glucose

poly Ig-receptor

an Fc receptor expressed by mucosal epithelial cells that mediatest eh transport of IgA and IgM thru the epithelial cells into the intestinal lumen

What are biological constructs of genetic differences?

ancestry and allelic differences NOT RACE

serotype

antigenically distinct subset of a species of an infectious organism that is distinguished from other subsets by serologic (ie sreum antibody) tests Humoral responses to one serotype of microbes may not be protective against another serotype

Why would we thinking of elimination as coming from the blood instead of from the liver and kidney

because it has to move from the tissue to the blood to be eliminated "blood" compartment represents plasma drug concentration and all highly perfused tissues like heart brain, viscera, etc. Extravasular volume represents all other tissues

codominant expression

both maternal and paternal MHC gene alleles are expressed

What is the role of carnitine in beta oxidation? What is the key regulated step of beta oxidation?

carnitine receives the FA grou pfrom acyl coAmolecule in a rxn catalyzed by carnitine acyltransferase I. The acyl carnitine molecule can then be moved into the matrix via a specific transporter in exchange for carnitine coming out. movement of hte FA into the mitochondira is the RLS for beta ox

thiamine pyrophosphate (vitamin B1)

cofactor for the massive enzyme complex of pyruvate dehydrogenase along with lipoic acid

ApoA

core protein of HDL that activates LCAT, enzyme that triggers reverse cholesterol transport from cells to HDL

malonyl coa

created from acetyl coa from ACC added to the sulfur chain of the ACP arm of FA synthase every time you add an acetyl group to the FA chain (adding two carbons each time) inhibits CPT1 (CAT1) so that beta ox and FA syn don't happen at the same time

What are the factors that cause genetic variation in populations?

differences in allel frequencies across populations have causes different environment- selective pressured - gets the greatest attention but not the greatest player Chance (genetic drift) -great majority of allele frequency changes in population size (growth/botteneck- type of drift) admixture with other populations (some separation, some mixture) - ex. neanderthals (1-4% of all non-African pops); racism against neanderthals, no evidence that they were less sophisticated

skin manifestations of DGI

disseminated gonoccocal infection

antigen binding site

each antibody has a minimum of two

cytochrome C

electron carrier in the ETC in the inner-membrane space brings electrons from complex III to complex IV where the electrons will reduce O2 to become water

What is the difference between excretion of a drug and the elimination of a drug?

elimination is a more general term and refers to any process that inactivates a drug. It encompasses the idea of drug metabolism (inactivates the drug by modifying its structure so it can no longer affect the target) and the idea of excretion. excretion inactivates the ability of the drug to interact with the target by physically removing teh drug from teh body they are inherently related to each other in many cases, because some drugs need to be metabolized before they can be excreted. Principal site of excretion is the kidney but bile can also be important

MHC polymorphism

existence of two or more altnerative forms or variants of a gene that are present at stable frequencies in a population each common variant of a polymorphic gene is called an allele and one individual may carry 2 diff alleles of a gene, each inherited from a diff parent. The MHC genes are the most polymorphic genes in the mammalian genome

What are the major types of antigen-presenting cells (APCs) and how do they function?

express MHC II and MHC I (all nucleated cells) Naive T cellS (in lymph nodes or other secondary lymphoid organs) talk to dendritic cells -class 1 or 2 Effector T Cells (infection sites in tissues or lymph nodes) talk to macrophages (APCs at infection sites)-class 1 or 2 b cells (lymph nodes)-class 1 or 2 dendritic cells-class 1 or 2 any infected cell (CD8 or CTL) -class 1

coagulase

extracellular enzymes secreted by S. aureus (staphylococcus) that clots plasma and is useful in distinguishing the most pathogenic species of the genus, S. aureus, from others because only S. aureus produces the enzyme. S. aureus is best distinguished from other species of the genus by using the coagulase test. Free coagulase, a secreted enzyme that clots plasma, is made by S. aureus but not by the other staphylococci. Occasional strains fail to produce free coagulase, but S. aureus also makes clumping factor (bound coagulase) that causes plasma to clump around the organisms in a diagnostic slide test. clumping factor (also known as bound coagulase) binds fibrin and helps the organism form walled-off abscesses protected from phagocytes.

Virion

extracellular form of a virus = virus particles or virions

What are some of the func6ons of P-‐‐glycoproteins?

hese proteins pump drugs out of cells, and can be involved in the excre5on of drugs from the liver and the kidney. They may also slow absorp5on of drugs by the GI tract and contribute to the ability of the blood-‐‐ brain barrier to decrease drug distribu5on to the brain.

what is the primary mechanism of virulence of STIs?

host reponse to PAMPS genital mucosa (gono and chlamydia) meninges (meningococcal meningitis)

Eugenics

idea of improving human pop base on breeding genetics rediscovered in early 1900s and usurped to justify social politics (Pearson- dirty Jewish children in IMMIGRANT population living in bad conditions) wrong on human rights, social justice, and genetics (ignorance of evolution and how that affects genetic variation)

Ketone bodies

includes acetoacetate and beta-hydroxybutyrate -synthesized in liver mito with build up after 2 days of fasting -water soluble, unlike FAs and travel thru blood to brain and muscle -circulating Ketone bodies are an important source of fuel bc they reduce the need for AA carbon skeletons for gluconeogenesis and sparing muscle protein (become acetyl coA again thru thioporase enzyme (first one) and 2 molecules of acetyl coa can enter the TCA

Clonal expansion

increase in number of lymphocytes specific for an antigen that results from antigen stimulation and proliferation of naive T cells. occurs in lymphoid tissues and is required to generate enough antigen-specific effector lymphocytes from rare naive precursors to eradicate infections

IDL

intermediate density lipoprotein Has apolipoB100 and apoE ( after VLDL gets rid of TAGs from the tissues, IDL gets directed to the liver by the apoE)

antigen processing

intracellular conversion of protein anitgens derived from the extracellular space or the cytosol into peptides and loading of these peptides onton MHC molecules for display to T cells

branched chain amino acids (don't have to now which ones these are)

leucine, isoleucine and valine pass thru the liver and used primarily as alternative enrg source be peripheral muscle (esp in fasting) or adipose tissue (in the fed state) liver lacks enzyme required for metabolism of branched chain AA uptake of AA into peripheral tissues is stimulated by insulin and in the liver by glucagon (turns it into gluconeo)

glutaminase

liver enzyme that regeneartes ammonia and glutamate from glutamine (which comes in from the bloodstream)

Cross-presentation

mechanism by which a DC activates or primes a naive CD8 CTL specific for the antigens of a 3rd cell (eg a virus infected or tumor cell) AKA cross-priming Occurs when an infected (often apoptotic) cell is ingested by a DC and the microbial antigens ar eprocessed and presented in association with class I MHC mols, unlike the general rule for phagocytosed antigens, which are presented in association with class II MHC mols. The DC also provides costim for the T cells

is most genetic variation within a pop or across pop?

most genetic variation is shared across populations: human pop have not been sufficiently separated for long enuf (relative to size!!!) to lead to large group diff -but some allele frequencies differ across populations more so for pop with diff continental ancestry and mostly due to genetic drift -less common alleles tend to be pop specific

Enteral

oral or sublingual adminstering a drug by mouth safest and most common, convenient, and economical method of drug administration may be swallowed, allowing oral delivery, or placed under the tongue (sublingual), facillitating direct absorption into the bloodstream

What was the basis for the classification of lung cancer as either small cell or non-small cell?

original classificatio based on histology and clinical behavior (doesn't include sarcomas or mets): NSC lumped togehter bc have relatively good prognosis compared to small cell and both tend to mets late in course (surgical resection is initial treatment)

muscoal immunity

part of immune system that responds to and protects against microbes that enter the body thru mucosal surfaces such as the gastrointestinal and respiratory tracts but also maintains tolerance to commensal organisms that live on the outside of the mucosal epithelium mucosal immune system is composed of organized mucosa-associated lymphoid tissues, such as Peyer's patches, as well as diffusely distributed cells within the lamina propria

classical pathway of complement activation

pathway of activation of the complement system that is initiated by binding of antigen-antibody complexes to the C1 molecule and induces a proteolytic cascard involving multiple other complement proteins. Effector arm of the humoral immune system that generates inflammatory mediators, opsonins for phagocytosis of antigens and lytic complexes that destroy cells

HLA-DM

peptide exchange molecule that plays a critical role in the class II MHC pathway of antigen presentation. found in the specialized MIIC endosomal compartment and facillitates teh removal of the invariant chain-derived CLIP peptide and the binding of other peptides to class II MHC molecules encoded by a gene in the MHC and is structurally similar to class II MHC molecules but is not polymorphic

Clearance

pharmacokinetic parameter that most significantly limits the time course of action of the drug at its molecular, cellular, and organ targets can be thought of as the volume of plasma that is completely cleared of active drug in a given amount of time depends onf th erate oe elimination pathways as well as conc of drug in the plasma Clearance = (metabolism + excretion)/[Drug] To calculate the clearance, you have to know the administered dose and two measured parameters: the half-life, and the volume of distribu,on (Vd). Both of these parameters are determined by measuring the concentra,on of the drug in the plasma at different ,mes, and plo]ng the data as shown on the right. Note this is a semi-log plot (the data on one axis, the y-axis, is plojed in log format).

What factors influence the route by which a drug is administered?

primarily by the properties of the drug (ex. water or lipid soluble, ionization) and by the therapeutic objectives (ex. the disirability of a rapid onset of action, the need for long-term treatemtn, or restriction of delivery to a local site) Major routes include enteral, parenteral, and topical

Memory T Cell

produced by antigen sitmulation of naive T cells and surivve in a functionally quiescent state for many years afte r the antigen is eliminated mediate rpaid and enhanced (ie memory or recall) responses to second and subsequent exposures to antigens

structure of N. gonorrhoeae pili

progeny can vary pilus -antigen variation huge in bacteria escaping immune response

pyridoxal phosphate

prosthetic group that is the coenzye form of vitamin B6 used by all aminotransferase enzymes

How is ACC regulated by citrate and palmitate? How is it regulated by insulin and glucagon signaling?

rate limiting step of FA syn ACC present in inactive form as dimers in the cyto ALLOSTERIC activation: citrate (molecule cleved in teh cyto tp produce acetyl coA for FA syn causes ACC to polymerize into active form and produce malonyl CoA long chain fatty ACYL coA (like palmitate) inactivates and depolymerizes ACC (end product of FA syn - product inhib to prevent accumulation of excess FA chains) hormonal regulation: phosphorylation Like glycogen synthase, ACC is inactive when phosphorylated PKA (cAMP dependent) driven by glucagon and epinephrine will rend ACC inactive Insulin acts largely by reversing cAMP-dependent phosphorylation which activates ACC (a lot like glycogen syn)

Cytopathic effect

refers to structural changes in the host cells that are caused by viral invasion. The infecting virus causes lysis of the host cell or when the cell dies without lysis due to an inability to reproduce Enterovirus isolated in 1962. Identified as agent that caused cytopathic effect (CPE) in monkey cell cultures. detection of infectious virus particles can be determined based their ability to infect cultured cells and cause cytopathic effect (CPE) A plaque is an area of localized cytopathic effec

chylomicron remnants

rely primarily on ApoE for uptake into the liver since ApoB48 doesn't have the C terminus that binds to the LDLR what is left of the chylomicron after TAGs have been removed by LPL in the tissues - target now is the liver

T cell differentiation

results in the converstion of naive T cells into a population of effector T cells which function to eliminate microbes

transaminase

reversible enzymes of transamination that transfer amino groups from AA onto alpha-ketoglutarate to form glutamate all share a common reaction mechanism and utilizes a prosthetic group pyridoxal phosphate (PLP) occurs rapidly in all tissues but enzyme content varies (muscle has high levels, liver does not but are induced in liver in fasting)

If you compare intravenous administration to oral dosing, how would the plot of plasma concentration versus time differ? How is the concept of bioavailability related to these two plots?

see plot by plotting plasma concentrations of the drug versus time which reflects the extent of absorption of the drug and finding the AUC and comparing the particular route with teh intravenous route's area, the ratio of these two is the bioavailability IF THE TWO DOSES ARE equivalent bioavailability is the fraction of the administered drug that reaches the systemic circulation- this fraction is found by comparing the AUC

MHC haplotype

set of MHC alleles inhierited from one parent and therefore on one chromosome

apoB48

shorter version of the ApoB gene (48%) that acts as a scaffold for chylomicron lacks Cterminal region of ApoB100 and cannot bind LDLR so relies of ApoE for uptake by the liver

For the TCA cycle as a whole, what are the main substrates and products?

substrates: acetyl Coa, 3 NAD+, FAD, GDP (?) products: 2 CO2, 3 NADH, FAD, GTP

fatty acid synthase

synthesizes the FA makes FA in teh cytoplasm it is a protein consisting of 2 identical subunits each, folded onto 7 distinct functional domains 2 are important: acyl carrier protein (ACP) and the condensing enxyme (CE)

Naive T cell

t cell tha thas not previouls encountered antigen when stimulated by antigen, differentiate into effector lymphocytes, such as antibody-secreting B cells or helper T cells and CTLs have surface markers and recirculation patterns that are distinct from those of previously activated lymphocytes

RH antigens How do they cause transfusion reactions?

target cells for phagocytosis, may also fix complement

characteristics of rare variants

tend to be population specific tend to be newer (occured after the ancestors left africa) one cause: genetic drift, be chance this rare vairant might disappear or the variants are young (some occurred after the split)

In the term "ω-3 fatty acid", what does "ω-3" mean?

the carbonyl group is consdiered teh alpha position and the final position is the omega (regardless of number of carbon) The position of any double bonds is then indcated by counting backwards from teh omega carbon. This si not relevant for a saturated fatty acid and there is no omega label for a saturated fatty acid. So an omega-3 is a fatty acid where the double bond is 3 cards away from teh last carbon or the omega carbon

Effector T cell

the cells that perform effctor functions durin an immune response such as secreting cytokines (helper T cells) killing imcrobes (eg macrophages), killing microbe-infected host cells (CTLs), or secreting antibodies (differentiated B cells)

antigen presentation

the display of prptides bound by MHC molecules on the surface of an APC that permits specific regonition of TCDs and activation of T cells

What are patients with FH at much higher risk for atherosclerosis?

the half-life of circulating LDL is increased, leading to increased oxidation of the LDL, and therefore increased uptake by scavenger receptors on macrophages, leading to incread foam cell production

steady state of a drug

the point at which the amount of drug being adminstereed equals the amount being eliminated such that the plasma and tissue levels remain constant in teh case of IV administration an dfluctuate around a mean in the case of an oral fixed dosage a faster rate of infusion does not change the time needed to achieve steady state; only the steady-state concentration changes The steady-state plasma concentra%on is directly propor%onal to the infusion rate. For example, if the infusion rate is doubled, the plasma concentra%on ul%mately achieved at the steady state is doubled. Furthermore, the steady-state concentra%on is inversely propor%onal to the clearance of the drug Thus, any factor that decreases clearance, such as liver or kidney disease, increases the steady-state concentra%on of an infused drug (assuming Vd remains constant). Factors that increase clearance of a drug, such as increased metabolism, decrease the steady-state concentra%ons of an infused drug

Distribution phase

the process by which a drug REVERSIBLY leaves the bloodstream and enters the interstitium (extracellular fluid) and then the cells of the tissues. For a drug administered IV absorption isn't a factor and the initial phase (from immediate after administration through rapid fall in conc) = distribution phase (drug rapidly disappears from the circulation and enters teh tissues) delivery of a drug from the plasma to the interstitium primarily depends on cardiac output and regional blood flow, capillary permeability, the tissue volume ,the degree of binding of the drug to plasma and tissue proteins and the relative hydrophobicity of the drug

serology

the study of blood (serum) antibodies and their reactions with antigens. often used to refer to the diagnosis of infectious disease by detection of microbe-specific antibodies in the serum

Half-life

the time it takes to eliminate one half of the concentration of the drug if you double the dose, half life is the time it takes to get to the original dose delivery of drug to the organs of elimination depends: -blood flow -fraction of the drug in the plasma THerefore a large Vd has important influence on the half-life cuz drug elimination depends on th e amount of drug delivered to the liver or kidney per unit time. Any facror that increaes Vd can lead to an increase in teh half-life and extend teh duration of action of the drug (large Vd= a lot of sequestering)

ABO antigens How do they cause transfusion reactions?

they fix complement, which can lyse cells and target cells for phagocytosis

Metabolism

third major process of pharmacokinetics after distribution the drug may be biotransformed by metabolism by the liver or other tissues This can affect the bioavailability of the drug. In contrast to IV administration, which confers 100% bioavailability, oral administration of a drug often involves firstpass metabolism. This biotransformation, in addition to the drug's chemical and physical characteristics, determines the amount of the agent that reaches the circulation and at what rate. factors that affect distribution: blood flow, capillary permeability, binding of drugs to plasma proteins and tissues, hydrophobicity

Pore-forming toxins

virulence factors of S. aureus. The molecules damage not only phagocytic cells but also other cells (e.g., vascular endothelium, renal endothelium, neurons, and myocardial cells). These toxins exert their effect by creating channels in cell membranes that significantly disturb cellular homeostasis.

What do site infections of gram pos cocci depend on?

(1) host factors- • i.e.- Skin epithelial breach (trauma, inserted catheter, surgical excision, etc.) by S. aureus causing local skin infec*on or abscess (2) bacterial factors- • i.e.- Adhesins on the surface of Group A streptococcus that allow binding of the bacteria to pharyngeal epithelial cells subsequently leading to pharyngi*s • In rare cases, further spread of these pathogens to other organs and *ssues occurs via the bloodstream (hematogenous spread) and occasionally via the lympha*cs

What are the substrates and products of glycolysis?

* splits glucose into two components—two three-C sugars * Small amount of ATP/NADH generated = oxidative reaction * Can occur in the absence of oxygen/mitochondria—thus main energy generating for RBC/muscle with little mit/glucoseàfat in liver after meal

citrate synthase

** environment: intramitochondrial levels of OAA are low combines OAA and acetyl CoA to make citrate as first step of the TCA normal cell levels, OAA levels are low-> pathway is thus stimulated by generating more OAA (occurs thru pyruvate carbozylase which is activated when acteyl coA levels rise so if acetyl coa levels rise because the TCA is not moving fast enough, it iwll stiulate hte production of more OAA to allow the cycle to go faster)

What are some examples of targeted therapies that we have discussed in the course? How do these therapies block the activity of the target? How do you choose which patients should receive a targeted therapy?

-BCR/Abl inhibitors: inhibit kinase activity -driven by single oncogene (rare) -Anti-VEGF: inhibit angiogenesis/ inhibit receptors -Hormone therapies for breast cancer (competitive and non-competitive inhibitors; affect -perceptin for HER2, an EGFR receptor which will block receptor) -PARP inhibitors: induce lethality by blocking ss DNA break repair in cells alreadly lacking the ability to perform homologous recombination due to BRCA mutations -EGFR inhibitors: block dimerization and inhibit downstream signaling -imatinib (Gleevec) for CML cannot be cytotoxic (doesn't hurt normal cells) their cancer has to have the target as a driving function (EGFR inhibitors cannot be taken for Kras mutations)

How do insulin and glucagon/epinephrine signaling regulate the release of fatty acids from adipocytes?

-insulin inhibits FA release by antagonizing cAMP production (phosphatase activity) - HS: -glucagon/epinephrine signaling promotes the activation of protein kinase (PKA) which activates HSL by phosphorylation

Why does ubiquitin-dependent protein degradation require ATP, if protein hydrolysis is thermodynamically favored? What steps in ubiquitin-dependent degradation require ATP?

2 reasons: proteins exist in their most thermodynamically stable conformation (hydrophobic inside, hydrophilic outside), so it requires energy to be unfolded. This is why the ATPases of the 19S cap require ATP- to unfold the protein so that the core can have ACCESS to the protein at the core's active sites The thioester bond between the ubiquitin and E1 (which is then passed to E2) in the activation of Ub is a high energy bond and requires ATP in its formation. The final part of this pathway, the isopeptide bond, is low energy. Steps: the activation of ubiquitin by E1 the unfolding of substrates by ATPases in the proteasome complex

You are studying two drugs which have the same volume of distribution. Drug A has a half-life of 2 hours, and drug B has a half-life of 10 hours. Which of the following statements is most accurate? Drug A has a greater clearance than drug B Drug B has a greater clearance than drug A The clearances are the same The relative clearance cannot be determined from this data

A Given the same volume of distribution, drugs with a shorter half-life will show a greater clearance. This is evident by inspection of the equation Cl=0.693xVd/t1/2.

The genes that determine one's ABO blood group encode proteins with what type of functional activity? Glycosyl transferease Transcriptional activator Serine protease DNA polymerase Adenyl cyclase

A Glycosyl transferases transfer carbohydrates (or sugar) moieties onto other structures. The products of ABO genes transfer sugar moieties onto glycoproteins.

Regarding regulation and function of lipoprotein lipase, which statement is correct? It is secreted from the cell It functions in the cell cytoplasm Its expression decreases in adipose tissue in the fed state Muscle tissue downregulates its expression during fasting Its expression is inhibited by insulin

A Lipoprotein lipase is synthesized and secreted by muscle cells and fat cells, where it diffuses and binds to the inside of the capillary wall. In the fed state, its expression is increased in adipose tissue (an effect of insulin) so that more fat can be stored. It can also be upregulated by muscle cells (other hormones involved) when fasting so that more lipid is delivered to the muscle cells.

A protein drug may be administered by all of the following routes, except: Oral Intramuscular Intravenous Subcutaneous

A Protein drugs (such as insulin or therapeutic antibodies) cannot be administered orally, as they are broken down in the GI tract. Furthermore, they cannot be taken up across the enterocytes in an intact form. Therefore, a parenteral route (intramuscular, intravenous, or subcutaneous) is required.

Each of the following is a possible function of a P-glycoprotein, except: Transporting drugs into liver cells Transporting drugs into the bile Transporting drugs into the urine Transporting drugs out of cancer cells

A The P-glycoprotein is involved in transporting drugs from the inside of cells to the outside of cells. Thus it is used in all of the processes mentioned, except transporting drugs into liver cells. There are other classes of transporters that may be important for transporting drugs into cells, such as the organic anion transporting polypeptide (OATP) and the organic cation transporter (OCT) as mentioned in the notes. P-glycoproteins are used to transport drugs out of cells, and are thus important in the excretion step in both the liver and the kidney.

An important mechanism for eliminating excess cholesterol from the body is: Conversion of cholesterol to bile acids Decreasing synthesis of HDL Increasing production of LDL Decreasing absorption from the intestine Decreasing the rate of cholesterol synthesis

A The only mechanism of those listed that will allow the body to get rid of excess cholesterol is to convert it to bile acids/bile salts, which are then excreted into the bile duct. While many are recycled back to the liver, some is lost in the stool. The other mechanisms involve changes in body distribution or production of cholesterol, but can't by themselves get rid of extra cholesterol. Another mechanism that isn't listed is that the liver can excrete cholesterol directly into the bile duct.

The diagrams below show two MHC molecules. Peptides generated by the proteasome bind to which labeled feature?

A The proteasome will generate peptides that load class I MHC. The left cartoon is class I MHC (one transmembrane chain). Label A is the class I MHC peptide binding cleft.

In the figure below, some of the important molecules involved in T cell antigen recognition and activation are shown. Note that class II MHC, Lck, and zeta proteins are labelled. Other structures are identified as A B, C, D. Identify A. CD3 CD4 CD8 B7-1 LFA-1

B A shows binding class II MHC and has Lck bound to tail...properties only of CD4

Which of the following molecules serves as both a lymphocyte surface antigen receptor and as a secreted antigen binding effector molecule? T cell receptor Antibody Major histocompatibility complex molecule CD4 Toll like receptor

B Antibody is the only molecule listed that is has both secreted and membrane bound, and only secreted antibody of those listed performs antimicrobial effector functions.

Arginine plays a special role in the urea cycle because it Inhibits carbamoyl phosphate synthase Accelerates flux through the urea cycle Stimulates the TCA cycle Transports nitrogen groups out of the mitochondria

B Arginine is cleaved by arginase into urea and ornithine. Urea is released to the blood stream and ornithine is used to transport the nitrogen groups from the mitochondria to the cytosol, thus increased arginine will lead to a higher flux through the urea cycle. In addition it stimulates the production of N-acetylglutamate, an allosteric activator of carbamoyl phosphate synthase.

In the diagram of an IgG molecule above, which part is identical in sequence to the part labeled 2? 1 3 4 7 None of the above

B Both heavy and light chains are identical in an antibody molecule. Both 2 and 3 are the V domains of the light chains.

You are studying a drug that has a pKa of 8.0. In its protonated form, it is ionized. Which of the following statements is most accurate? This drug is a weak acid This drug is a weak base The drug will be better absorbed at a pH of 7 than a pH of 8 The pH will not affect the rate of absorption since it is close to neutral

B By definition, this is a weak base, because in its protonated form it is ionized. The drug will therefore be better absorbed at a pH greater than the pKa, as this will lead to a larger fraction in the deprotonated form, which can cross the membrane.

One way in which T cell antigen recognition is linked to gene expression is through a TCR signaling pathway that increases cytosolic calcium ion concentration, leading to movement of a cytosolic transcription factor into the nucleus. This pathway is targeted by widely used immunosuppressive drugs cyclosporin and tacrolimus. What is the target of these drugs, and what is the transcription factor? Protein kinase C and NF-kappa B Calcineurin and NFAT Phospholipase C AND AP1 ZAP70 AND cMyc Myeloperoxidase AND cFOS

B Cyclosporine and tacrolimus are calcineurin inhibitors, and calcineurin dephosphorylates P- NFAT, exposing a nuclear localization signal.

The function of oxygen in the electron transport is to: Drive the rotation of ATP synthase Accept electrons transported from cytochrome C Oxidize FADH2 Oxidize NADH

B Cytochrome C oxidase (complex IV) reduces O2 to water. The ATP synthase is driven by the proton gradient. Oxygen is not involved in the direct oxidation of NADH or FADH2.

Which of the following types of cell is most important in an effective immune response to M. tuberculosis? Cytotoxic T lymphocytes Helper T lymphocytes B-lymphocytes Natural killer cells

B Helper T-lymphocytes specific for M. tuberculosis can activate macrophages, making macrophages competent to kill the bacteria. The other types of cells listed have little role in the immune response to M. tuberculosis.

Fab

(fragment, antigen binding) proteolytic fragment of an IgG antibody molecule that includes one complete light chain paired with one heavy chain fragment containing the variable domain and only the first constant domain retains the ability to monovalently bind an antigen but cannot interact with IgG Fc receptors of cells or with complement . Therefore Fab preparations are used in research and therapeutic application swhen antigen binding is desired without activation of effector functions (Fab' fragment reatins the hunge region of the heavy chain)

Fc region

(fragment, crystalline) proteolytic fragment of IgG that contains only the disulfide-linked carboxyl-terminal regions of the two heavy chains. also used to describe the corresponding region of an intact Ig molecule that mediates effector function by binding to cell surface rece[tprs pr tje C1q complement protein. so named bc they crystallize out of solution

How do insulin, glucagon and epinephrine signaling regulate the rate of glycolysis in the liver? What is the role of PFK2 in this process? How is pyruvate kinase regulated?

* Conversion to fat: liver * Regulation: reciprocal manner with gluconeogenesis o Ratio of insulin signaling to glucagon/epinephrine alters the activity of enzymes in the pathway to favor one or the other * Insulin: favor glycolysis * Glucagon/epinephrine: favor gluconeogenesis o Must overcome problem that ATP inhibits PFK1, but we need high ATP and PFK1 working to make fat * F2,6BP - stimulates PFK1, overcomes allosteric effects of ATP * Synthesis is stimulated by insulin and inhibits gluconeogenesis * Substrate inhibition: low concentration of ATP, rate of substrate phosph is rapid; ATP increase, rate drops to 0 o F2,6BP suppresses substrate inhibition (can support glycolysis when ATP levels are high * Production: PFK2, also uses F6P but converts it to F2,6BP, which activates PFK1 o Feed forward - as F6P levels rise, more F26BP will be produced and stimulate PFK1 o Glucagon/epinephrine à cAMP rise à PKA activated à PFK2 phosphorylated and inactivated, as well as PK à decreased F2,6BP à decreased PFK1 activity à glycolysis slowed (PKA phosph PK) * Both turned off after phosphorylation! * Glut2 not regulated/saturated - fasting state will export glucose form gluconeo to blood o Insulin à degradation of cAMP à stimulation of phosphatases à activation of PFK2 and PK/stiulation of GK (not inhibited by G6P, can keep processing à lots of F2,6BP à stimulate PFK1 despite ATP levels, PK dephosph and active (presence of high levels of F1,6BP upstream will tend to stimulate this step despite ATP) * Glycolysis high

What are the three different metabolic fates of glucose?

* FATES: o Stored as glycogen o Oxidized by the pentose phosphate pathway o Enter glycolysis * All three require phosphorylation by hexokinase/glucokinase * Pathway used depends on level of activity of the rate-determining step for each o Glycolysis: PFK1, early in pathway o Glycogen: glycogen synthase o Pentose pathway: G6P dehydrogenase

What is the primary determinant of the rate of glycolysis in skeletal muscle? How do insulin, epinephrine and energy demand regulate the rate of glycolysis in muscle?

* Muscle fiber types o Type I: primarily oxidative, high mit density * Can burn glucose or FA, switches b/w fed and fasting * Doesn't store much glycogen * I-slow-red-ox: contracts more slowly, high resistance to fatigue o Type IIb: glycolytic, store abundant glycogen and creatine phosphate * Contract quickly, primarily glucose dependent no mater the state * Regulation: similar to RBC, main regulator is ATP level o ATP falls, increase rate of glycolysis in Type IIb fibers; produce lactate which will return to the liver * Resting muscle: fed/fasted and muscle fiber type o Fed: insulin increases uptake of glucose by putting more glut4 transporters on membrane * Type I: availability of glucose will allow it to use as primary fuel * Type IIb: always glucose dependent, less change in glucose transport b/w fed and fasted state (less insulin sensitive) * Stores extra as glycogen o Fasting: decrease glucose uptake by muscle * Type I: more pronounced effect; glut4 transporters internalized, transport decreases, rate of glycolysis slower * FA released—performs beta oxidation of FA * Type IIb: cannot oxidize FA, cannot shut off glucose supply when insulin falls (good thing it is less sensitive!) * Glycogen concentration decreases too though * Exercising muscle: ATP consumption rises o decreased inhibition of PFK1 and PK o AMP levels rise, stimulate PFK1 * AMP-dependent protein kinase (AMPK): phosphorylates key proteins to trigger fusion of Glut4-containing vesicles with membrane in both type I and II fibers (cAMP independent) o Increased epinephrine by sympathetic nervous system * Activate hormone sensitive lipase à increase FA in blood * Used by Type I to generate ATP * Type IIb: epinephrine binds to beta receptors to activate Gs à elevation of cAMP à increase PKA à activates glycogen breakdown

What is the difference between type I and type IIb fibers in terms of their reliance on glucose and their sensitivity to insulin?

* Preferred fuel: Type IIb muscle, no mitochondria * Fuel in fed state: Type I muscle, have mitochondria, highly insulin sensitive (use it after a meal but not in fasting state) * Based on energy demand (higher rate of contraction, more glycolysis) but... o Balance of insulin and epinephrine levels affect which fuels available for muscle * External glucose (glucose transport GLUT4) * Internal stores (glycogen breakdown)

What is the role of glycolysis in the red cell? What is the primary mechanism of regulation of glycolysis in this cell type?

* Preferred fuel: glycolysis, generates ATP (no mito) o Unable to metabolize FA; entirely glu dependent o Cannot convert pyruvate to ac coa, must be lactate * Regulation: simple feedback inhibition of the PFK1 by ATP o ATP sufficient, rate of glycolysis is slowed by inhibition of PFK1 * Product inhibition: PK inhibited by ATP o Feed forward: AMP levels rise as ATP levels drop, stimulates glycolysis by activating PFK1 à F1,6BP levels rise and stimulates PK; coordination of last step with first step o Glucose uptake: Glut1 transporter, low Km (1 mM) relative to blood glucose levels—operating close to saturation, rate doesn't change from fasting (4 mM) to fed (8 mM) state * HK phosphorylates à ATP sufficient, PFK1 inhibited, G6P accumulates à inhibits hexokinase, slowing rate of phosphorylation and glucose use à accumulation of glucose à equilibrates with blood glu levels due to bidirectional nature of Glut transporter o Rxn 2,3DPG made from 1,3DPG when conditions of low oxygen delivery

What are the three irreversible steps in glycolysis? Which enzymes catalyze these steps?

* Regulated steps Hexokinase/Glucokinase: Glu à G6P, converts ATP to ADP, used for all 1. Phosphofructokinase 1: F6P à F1,6BP, converts ATP to ADP, major regulated step of glycolysis * Usually rate-limiting step (first committed step) * Inhibited by ATP; stimulated by AMP (signifies energy depletion) * F2,6BP: activates PFK1 in liver allosterically, increases during insulin signaling (important for stim glycolysis when high ATP to make fat) 2. Pyruvate kinase: PEP à pyruvate, converts ADP to ATP (regulated so it can be shut off when liver switches to gluconeogenesis) * Inhibited by ATP * Activated by F1,6BP in liver (product of PFK1) to bypass ATP block * Inhibited when glucagon/cAMP/PKA pathway activated via direct PKA-dependent phosphorylation (in liver only) 3. pyrvate dehydrogenase is also irreversible (Pyruvate to acetyl coa but this isn't really part of glycolysis)

What signals does a dendritic cell need to be become a competent APC ("mature") capable of activating naive T cells?

-production of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). The combination of TLR signaling and cytokines activates the dendritic cells, resulting in several changes in phenotype, migration, and function. -When classical dendritic cells that encounter microbes at epithelial barriers are activated, they lose their adhesiveness for epithelia and begin to express the chemokine receptor CCR7, which is specific for chemoattracting cytokines (chemokines) produced by lymphatic endothelium and by stromal cells in the T cell zones of lymph nodes. These chemokines direct the dendritic cells to exit the epithelium and migrate through lymphatic vessels to the lymph nodes draining that epithelium. During the process of migration, the dendritic cells mature from cells designed to capture antigens into APCs capable of stimulating T lymphocytes. This maturation is reflected by increased synthesis and stable expression of MHC molecules, which display antigen to T cells, and of other molecules, called costimulators, that are required for full T cell responses. - Soluble antigens in the lymph are picked up by dendritic cells that reside in the lymph nodes, and blood-borne antigens are handled in essentially the same way by dendritic cells in the spleen.

What are the two general types of vaccines used to protect against pneumococcal infections?

1) based on protein carrier: pneumococcal conjugate vaccine, based on the successful approach for H. influenzae type B, was introduced in the United States for use in children.This vaccine now contains up to 13 of the most common serotypes found in that age group linked to a protein carrier that results in a more effective antibody response because, unlike vaccines consisting strictly of polysaccharide antigens, the presence of a protein recruits T cells to help. thus far been shown to be highly efficacious against invasive pneumococcal disease and somewhat effective at 2. based on polysaccharides: The antigenic diversity of the pneumococcus, however, is a significant barrier to developing a vaccine based on the polysaccharide capsular antigens. Nonetheless, most cases of pneumococcal pneumonia are caused by a limited number of serotypes. Accordingly, a vaccine based on those serotypes was approved for use in 1977. This vaccine now contains the capsular polysaccharides of the 23 most common serotypes and is recommended for the elderly and individuals with predisposing conditions.

How does electron transport lead to the generation of ATP? How is this process tied to oxidation of NADH and FADH2? (Please explain the general principles, you don't have to know the detailed functions of the different complexes).

1. Complex I accepts 2e- from NADH, passes them to UQ (ubiquinone), pumpes H+ 2. UQ with long hydrophobic tail swims over to CIII 3. CIII accepts 2e- from UQ, passes them to CytC, pumps out a H+ 4. CytC swims over to CIV 5. CIV accepts 2e-, passes them to O2 (to make 2 H2O) and pumps out a H+ 6. CII accepts e- from succinate (part of TCA that is in CII) or from FADH2 (coming from B ox), gives them to UQ but does no H+ pumping 7. All this makes an electrochemical gradient of H+ that ATP synthase uses to generate ATP The larger the proton gradient, the slower the rate of ETC because THEY ARE COUPLED; function of complex V as ATP synthase entirely dependent on the existence of the proton gradient- it is a bidirectional enzyme -CI is moving protons against the electrochemical gradient so e- tranport will occur at higher rates when ATP synthase (complex V) is also active in making ATP and dissipating the proton gradient -IF ATP levels rise too high, the enzyme tend to drive protons out of the matrix, further increasing the magnitude of the proton gradient. This will in turn slow the rate of electron transport, because the complexes in the electron transport chain have to pump protons against a steeper gradient

What are the major steps in the class I MHC antigen processing/presentation pathway? Where is the protein antigen located at the start?

1. Generation of antigens in the cytoplasm or nucleus -proteins that aren't suppose to be there or are messed up (antigenic proteins from viruses, leaked proteins from phagosomes, mutated genes that make proteins in tumors, and cell's misfolded proteins) are targeted for the ubiquitin-proteasome pathway 2. Proteolysis by specialized organelle and transport into the ER -proteins in the cytosol and MHC in the ER, so transporter associated iwth antigen processing (TAP) solves the problem. TAP binds proteasome-generated peptides on the cytosolic side of the ER membrane, then actively pumps them into the interior of the ER 3. Binding of peptides to newly synthesized class I molecules -Newly synthesized class I MHC molecules, which do not contain bound peptides, associate with a bridging protein called tapasin that links them to TAP molecules in the ER membrane. Thus, as peptides enter the ER, they can easily be captured by the empty class I molecules. If a class I molecule finds a peptide with the right fit, the complex is stabilized, released from association with TAP, and transported to the cell surface.

What is the relevance of MHC polymorphisms to human disease?

1. Harder to make vaccines that everyone will respond to 2. Not everyone will have an immunological response to every microbe (because their MHC molecules cannot find an immunodominant peptide to pick up and present to T cells) Immunodominance of some peptides derived from complex protein antigens depends on the structural constraints on peptide binding to different MHC molecules, including length and anchor residues and accounts for the inability of some individuals to respond to certain protein antigens. When any protein is proteolytically degraded in APCs, many peptides may be generated, but only those peptides able to bind to the MHC molecules in that individual can be presented for recognition by T cells. These MHC-binding peptides are the immunodominant peptides of the antigen. Even microbes with complex protein antigens express a limited number of immunodominant peptides. Many attempts have been made to identify these peptides in order to develop vaccines, but it is difficult to select a small number of peptides from any microbe that would be immunogenic in a large number of people, because of the enormous polymorphism (variability) of MHC molecules in the population. The polymorphism of the MHC also means that some individuals may not express MHC molecules capable of binding any peptide derived from a particular antigen. These individuals would be nonresponders to that antigen.

patient is A+ - fill out the chart for hemagglutination, including no test 1. Patient's RBCs with anti-sera 2. Patient's seum with RBCs

1. Nt. +. -. Nt. + (no such thing as anti-O or anti-RhD-) 2. NT. -.+. Nt. Nt Most people do not make anti Rh+ (and he definitely dosesn't) unless hx of preg or transfusion

What advantage does the bacterial capsule confer for these Gram-positive organisms?

1. The HA capsule is another antiphagocytic structure on the streptococcal surface. HA is found in great abundance in human connective tissue. Therefore, streptococci enveloped in an HA capsule have camouflaged themselves in a host antigen that does not elicit an immune response. Indeed, outbreaks of severe GAS infections are often associated with highly encapsulated strains of bacteria that appear mucoid when cultured on blood agar media. Interestingly, this capsule interferes with adherence of GAS to epithelial cells, and the organism may need to shed the capsule during the early stages of infection. 2.Exterior to the cell wall is a capsule that imparts a mucoid or "smooth" appearance to colonies on agar. Capsules are composed of porous zones of polysaccharide that completely envelop the cell. Thick polysaccharide capsules, much like carbohydrate O antigens on the surface of the lipopolysaccharide of some Gram-negative bacteria, do not activate complement efficiently in the absence of a specific antipolysaccharide antibody and thus serve to shield the underlying components of the bacterial cell surface. Pneumococci resist phagocytic clearance by expression of a polysaccharide capsule. The presence of a thick layer of surface polysaccharide, however, inhibits otherwise effective host clearance functions involving complement- and antibody-mediated phagocytosis. Expression of a capsule is particularly important for an organism to survive in the bloodstream, where the activity of complement is most pervasive. The basis for antigenic differences among serotypes lies in the chemical structure of the capsular polysaccharide. Various pneumococcal strains express capsules with distinct sugar constituents or the same array of sugars linked in various ways.

For each of the following amino acids, how would its amino groups end up in urea? Trace the steps involved (including transamination steps that might be required). Branched chain amino acid (leucine, valine, isoleucine) Non-branched chain amino acid (eg, glycine, proline,...etc) Glutamate

1. amino acids donate their amino groups to alpha-ketoglutarate (aminotransferase with PLP, reverse rxn) which can be oxidized to form NH3 and alpha-ketoglutarate (NH3 will go thru urea cycle) OR 2. glutamate can give its amino group to OAA which will become aspartate, an intermediate of the urea cycle If the glutamate is formed in the muscle, it can give its amino group to pyruvate to form alanine, which will go thru the blood stream to the liver (to form NH3 and pyruvate again)

By what major mechanisms do these Gram-positive bacteria evade host immune responses?

1. destruction of lymphocytes: S. aureus: Also, abscesses: from the point of view of the staphylococci, it represents a walled-off site protected from the host immune attack. The site may also be the source of toxins produced and secreted by the organism such as TSS toxin-1, staphylococcal enterotoxins, and staphylococcal enterotoxin-like molecules, which can result in TSS. ALso, S. aureus produces an unusually large number of virulence factors that either prevent the bacteria from being phagocytized or help them to survive in phagocytes after they are ingested. These factors include soluble enzymes, toxins, and cell-associated constituents. Also superantigens (cause TSS) which attach T cell to macrophage and cause lysis. Also destruction of neutrophils in abscesses (constant war between the two cia hemolysins) 2. evasion: GAS elicits two major antiphagocytic factors, the M protein and HA capsule. In addition, GAS are able to produce several proteins to degrade chemotaxins that recruit neutrophils to the site of infection, inactivate or degrade antibodies, and block antimicrobial peptide function. -M protein: a fibrillar, coiled-coil surface protein covalently attached to the cell wall of the pathogen that plays a role in adhesion to keratinocytes and prevents opsonization by complement through two mechanisms: 1) binds the host cell plasma protein, fibrinogen, which interferes with the alternative pathway of complement deposition by forming a dense layer on the bacterial surface 2) binds host complement control proteins that inhibit the formation of opsonins by the complement cascade -HA capsule: found in great abundance in human connective tissue. Therefore, streptococci enveloped in an HA capsule have camouflaged themselves in a host antigen that does not elicit an immune response. Indeed, outbreaks of severe GAS infections are often associated with highly encapsulated strains of bacteria that appear mucoid when cultured on blood agar media. Interestingly, this capsule interferes with adherence of GAS to epithelial cells, and the organism may need to shed the capsule during the early stages of infection. -capsule production: Pneumococci resist phagocytic clearance by expression of a polysaccharide capsule. The presence of a thick layer of surface polysaccharide, however, inhibits otherwise effective host clearance functions involving complement- and antibody-mediated phagocytosis.

How are chylomicrons metabolized

1. in bloodstream, they get Apo C-II (activates lipoprotein lipase) and Apo E (promotes uptake of the chylomicron remnant by the liver- doesn't have the C terminal of the ApoB to bind with LDLR) from HDL (the exchanger). 2. lipoprotein lipase removes TAGs 3. apo C-II returned to HDL 4. apoE facillitates uptake of lipid-depleted rembabt particle bythe liver

What are the major steps in the class II MHC antigen presentation/processing pathway. Where is the protein antigen located at the start?

1. ingestion of the antigen -Dendritic cells and macrophages may internalize extracellular microbes or microbial proteins by several mechanisms, including phagocytosis, receptor-mediated endocytosis, and pinocytosis. With or somtimes without a recognition event. 2. proteolysis in endocytic vesicles -after internalization into APCs by any of these pathways, the microbial proteins enter acidic intracellular vesicles, called endosomes or phagosomes, which may fuse with lysosomes. In these vesicles the proteins are broken down by proteolytic enzymes, generating many peptides of varying lengths and sequences. 3. Association of peptides with class II molecules -Class II MHC-expressing APCs constantly synthesize MHC molecules in the (ER). Each newly synthesized class II molecule carries with it an attached protein called the invariant chain (I i ), which contains a sequence called the class II invariant chain peptide (CLIP) that binds tightly to the peptide-binding cleft of the class II molecule. Thus, the cleft of the newly synthesized class II is prevented from accepting peptides in the ER -Late endosomes/lysosomes also contain a class II MHC-like protein called DM, whose function is to exchange CLIP in the class II MHC molecule with higher-affinity peptides that may be available in this compartment -Once the class II MHC molecule binds tightly to one of the peptides generated from the ingested proteins, this peptide-MHC complex becomes stable and is delivered to the cell surface. If the MHC molecule does not find a peptide it can bind, the empty molecule is unstable and is degraded by proteases in the vesicles.

You need to determine how much drug to administer each day to a patient taking an oral medication. You are planning to give the drug in a single pill once per day. For an orally administered drug with a bioavailability of 0.3, and a clearance of 0.5 mL/min, how much drug do you need to give if the target concentration is 1 microgram/mL? (1 microgram=1x10-6g)? 2.4 mg 0.72 mg 40 micrograms 5 mg

A To solve this, use the equation: Dosing Rate=Target Concentration x Clearance/F, where F equals bioavailability. Plugging in the numbers, dosing rate =1 x 10-6 (g/mL) x 0.5 (mL/min)/ 0.3 =1.66 x 10-6g/min 1.66 x 10-6g/min x 3600 min/day=2.4 mg/day

The major histocompatibility complex is a large genetic locus (found on human Chromosome 6), which includes the genes encoding MHC molecules. Which of the following is an important feature of these genes? There are many different alleles of each MHC gene within human populations There are thousands of different MHC genes in any one individual DNA segments in the MHC recombine in immature dendritic cells to form functional genes MHC genes are expressed only on dendritic cells Females only expresses MHC genes inherited from their mother and males only from their father

A a is what it means to be highly polymorphic. b is a common misunderstanding; polymorphism at population level not individual. c is wrong because only TCR and Ig genes undergo somatic recombination. d is wrong because all nucleated cells express class I MHC< and B cells and macrophages express class II MHC. e is just plain made up genetics.

Which of the following molecules contributes to naive T cell entry into lymph nodes, but not effector T cell entry into infected tissues? L-selectin LFA-1 IL-2 receptor CD3

A Naïve T cells bind to HEV via L-selectin on the T cell. Effector T cells do not express L-selectin. Both naïve and effector T cells used LFA-1 to bind to HEV and peripheral tissue vascular endothelial cells, receptively.

Which antibody isotype(s) activate(s) the complement system? IgG1 IgM IgA IgE

A and B Only secreted IgG and IgM bind C1 and activate complement. IgG1 is one of the Ig subtypes that do this (IgG3 is the other).

Which of the following would you expect after a meal that consists solely of protein? Choose all that apply. Increased uptake of amino acids by the muscle to promote protein synthesis The insulin/glucagon ratio is high The liver uses glucogenic amino acids for gluconeogenesis The liver starts consuming glucose

A and C A and C are correct. Some insulin will be released, but the insulin/glucagon ratio will still be fairly low. The presence of some insulin will stimulate uptake of amino acids and protein synthesis in muscle. The liver will not consume glucose but rather will use amino acids to make glucose.

Which antibody isotype(s) directly protect(s) us against pathogens in the intestinal lumen? IgM IgG IgD IgE IgA

A and E IgA is transcytosed across the intestinal epithelial cells from lamina propria into the lumen via the poly Ig receptor. (IgM is also transported across the intestinal epithelial cells via poly Ig receptor, and IgG via FcRN..but much less than IgA).

How do you calculate the loading dose for a drug?

A delay in achieving the desired plasma levels of drug may be clinically unacceptable. Therefore, a "loading dose" of drug can be injected as a single dose to achieve the desired plasma level rapidly, followed by an infusion to maintain the steady state. Loading doses can be given as a single dose or a series of doses. Loading doses are given if the %me required to achieve half-life is rela%vely long and the therapeu%c benefit of the drug is required immediately (for example, lidocaine for arrhythmias). Disadvantages to the use of loading doses include increased risk of drug toxicity and a longer %me for the concentra%on of the drug to fall if excess drug level occurs. A loading dose is most useful for drugs that are eliminated from the body rela%vely slowly. Such drugs require only a low maintenance dose in order to keep the amount of the drug in the body at a therapeu%c concentra%on. However, without an ini%al higher dose, it would take a long %me for the amount of the drug in the body to reach a therapeu%c value that corresponds to the steady-state level. remember only half-life affects the time it takes to get to the steady state (4 half-lifes) so if you increase the rate, you increase the does but not the time it takes to get to the half-life. So a loading dose is this higher rate to get to the steady state faster by infusing at a rate with a higher steady state to account for the time required to get to steady state

How can a two compartment model be used to model plasma drug concentrations after administration of a single dose?

A two compartment model uses one central compartment for blood +highly perfused tissues, and this is connected to a peripheral compartment representing all other tissues. Drug is injected in the central compartment and rises rapidly, then it rapidly distributes to the peripheral compartment. In most cases, drug metabolism and elimination occur from the blood, so drug must return to the central compartment for metabolism and excretion. The two-phase graph in part C represents the central compartment concentration in this model. The sum of A and B. Typically the rate of distribution is much faster than the rate of elimination (often determined by the rate at which drug returns to the blood compartment for elimination)

If a patient is A- and needs plasma, what can we give her?

A, AB, or O because plasma doesn't have RBCs and those 3 types will not carry antibodies against A

Bioavailability

AUC = area under curve the fraction of administered drug that reaches teh systemic circulation If 100 mg of a drug administered orally and 70 mg absorbed unchanged, the bioavailability if 0.7 or 70% determining this is important for calculating drug dosages for non-intravenous routes of administration affected by route drug is administered as well as the chemical and physical properties of the agent, affects its bioavailability determined by comparing plasma levels of a drug after a particular route of administration with plasma drug levels achieved by IV injection, in which the total agent rapidly enters the circulation. When teh drug given orally, only part of the administered dose appears in the plasma. By plotting plasma conc of the drug vs time, the AUC can be measured which reflects the extent of absorption of the drug. Bioavailbility of a drug administered orally is the ratio of the area calculated for oral administration compared with teh area calculated for IV injection if doses are equivalent Factors that affect it: first pass hepatic metabolism, solubility of the drug, chemical instability

How is M. tuberculosis infection acquired?

Almost all tuberculous infections result from inhaling infectious particles that were aerosolized by coughing, sneezing, or talking. The initial source of infection is the lung in almost all cases. These so called droplet nuclei dry while airborne, can remain suspended for hours, and when inhaled can reach the terminal air passages. A cough or sneeze can produce thousands of droplet nuclei, as can talking for several minutes. Accordingly, the air in a room occupied by a person with pulmonary TB may remain infectious even after the person has left the room. Fortunately, prolonged exposure and multiple aerosol inocula are generally required to establish infection. Brief contact carries little risk, and infection rarely occurs outdoors because ultraviolet light kills M. tuberculosis. Large drops of respiratory secretions or contaminated inanimate objects infrequently result in transmission. Its rapid spread requires crowded living conditions and a population with little native resistance. Certain risk factors such as illicit drug use, excess alcohol use, homelessness, and HIV infection are interrelated and lead to an increased risk of both TB reactivation and transmission.

What is the role of aminotransferases and glutamate dehydrogenase in ammonia disposal?

Amino transferases collect all of the amino groups onto glutamate. Some of these are then transferred to OAA to make aspartate, which contributes its amino groups directly to the urea cycle. The rest is oxidized by glutamate dehydrogenase (mito) to release ammonia, which is captured by a separate reac-on in the urea cycle

Below is a recreation of a panel testing the serum of a patient discovered to have an antibody against ABO-compatible blood cells. See if you can figure out which one it is. Hint: The eight different known donors all have different combinations of antigens. If the patient's serum does not agglutinate the cells of a particular donor, then the patient does not have antibodies against any of those antigens.

Anti-K antibody - The serum contains an antibody that binds and agglutinates red blood cells that express the K antigen but no other red blood cells.

By what general mechanisms do antibodies protect against extracellular pathogens and toxins?

Antibodies bind to and block, or neutralize, the infectivity of microbes and the interactions of microbial toxins with host cells Antibodies coat microbes and promote their ingestion by phagocytes: when several antibody molecules bind to a microbe, an array of Fc regions is formed projecting away from the microbial surface. If the antibodies belong to certain isotypes (IgG1 and IgG3 in humans), their Fc regions bind to a high-affinity receptor for the Fc regions of γ heavy chains, called FcγRI (CD64), which is expressed on neutrophils and macrophages. The phagocyte extends its plasma membrane around the attached microbe and ingests the microbe into a vesicle called a phagosome, which fuses with lysosomes. Antibody-mediated phagocytosis is the major mechanism of defense against encapsulated bacteria, such as pneumococci. The polysaccharide-rich capsules of these bacteria protect the organisms from phagocytosis in the absence of antibody, but opsonization by antibody promotes phagocytosis and destruction of the bacteria. Antibody-Dependent Cellular Cytotoxicity Natural killer (NK) cells and other leukocytes may bind to antibody-coated cells and destroy these cells. NK cells express an Fcγ receptor called FcγRIII (CD16), which is one of several kinds of NK cell-activating receptors. FcγRIII binds to arrays of IgG antibodies attached to the surface of a cell, generating signals that cause the NK cell to discharge its granule proteins, which kill the opsonized cell. This process is called antibody-dependent cellular cytotoxicity (ADCC)

What are the jobs of antibodies?

Antibodies prevent infections by blocking the ability of microbes to bind to and enter host cells. Antibodies also bind to microbial toxins and prevent them from damaging host cells. In addition, antibodies function to eliminate microbes, toxins, and infected cells from the body. Although antibodies are a major mechanism of adaptive immunity against extracellular microbes, they cannot reach microbes that live inside cells.

What are the functionally distinct domains (regions) of antibody molecules?

Antibodies use their antigen-binding (Fab) regions to bind to and block the harmful effects of microbes and toxins, and they use their Fc regions to activate diverse effector mechanisms that eliminate these microbes and toxins The binding of antibodies to Fc and complement receptors occurs only after several Ig molecules recognize and become attached to a microbe or microbial antigen. Therefore, even the Fc-dependent functions of antibodies require antigen recognition by the Fab regions. This feature of antibodies ensures that they activate effector mechanisms only when needed, that is, when they recognize their target antigens. In each Ig molecule, there are two identical Fab regions that bind antigen and one Fc region that is responsible for most of the biologic activity and effector functions of the antibodies.

what is the functional role of lipoproteins ?

Apo A : Core protein of HDL; activates LCAT (enzyme that triggers reverse cholesterol transport from cells to HDL) ApoB 48 and ApoB100: expressed form the same gene, made by the small intestine, liver respectively B100: (liver) full length protein (100% for "100"); acts as scaffold for the VLDL particle and therefore also found in teh derivative particles IDL and LDL. Major binding site for the LDL receptor (thus responsible for uptake of the LDL particle by the liver) B48: (small intestine) shorter version 48%; scaffold for a chylomicron (lacks Cterminal region, cannot bind the LDL receptor and thus remnants rely on ApoE for uptake by the liver) ApoC: activates LPL (lipoprotein lipase) Apo E: triggers clearance of VLDL particles and all chylomicron remnants HDL synthesized with only ApoA; VLDL syn w/ only ApoB100; chylomicron syn w/ only ApoB48. C and E secreted by hte liver and intestine and sent into blood stream where they bind the nascent lipotportine particles and can be trasnfered between HDL, VLDL, and chylos. HDL great at exchanging lipoproteins. B100 has low affinity w/o E

What limits the body's ability to dispose of ammonia? How can liver damage lead to problems with ammonia disposal?

Availability of urea cycle components including enzyme amounts and the amount of intermediates in the pathway such as arginine, possibly activity of glutamine synthase in peripheral tissues. The liver is the primary site of urea synthesis so liver damage can lead to elevations in ammonia (ex. scerosis from liver failure from drinking). Lack of arginine in the diet (like the cats) leads to toxic levels of ammonia because the urea cycle is missing an intermediate. Ornithine can replenish the intermediates of the urea cycle matched system between substrate and intermediates since a substrate is an intermediate (arginine) so should be consuming the right proportions for proper function arginine is also a regulator of carbamoyl phosphate synthetase 1 (CPSI), first step in the urea cycle asparatate aminotrasferase (AST) in the blood is a marker for liver damage - specific aminotransferase to produce aspartate from OAA and glutamate for the urea cycle

In the diagram of an IgG molecule above, which statement accurately describes the part labeled 7? Is an antigen binding site Does not contain hypervariable loops Is part of the light chain Is identical to part 2 Is identical to domains found in IgE, IgA, and IgM

B Hypervariable loops are only in V domains, which are at the N-terminal ends of light and heavy chains (upper ends in diagram). A is wrong because the antigen binding site is made up of the V domains of H and L chains. D is wrong because, although both 2and 7 are Ig domains, each Ig domain in a heavy chain or a light chain differ in sequence from the others. E is wrong because, you are told this is an IgG molecule; heavy chain constant regions of IgG ,A, E, M have sequences found only in their isotypes, and 7 is part of the heavy chain constant region, so it will be different from domains in other isotypes.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes - abbreviated to MELAS- is a condition that results from mutations in mitochondrial DNA. One of the problems that can occur in a patient with MELAS is lactic acidosis (L in MELAS). Explain why blood lactate levels may be elevated in a patient with MELAS. The defective mitochondria produce more lactate. The cells are more reliant on glycolysis. Increased levels of ROS promote lactate production. Beta oxidation is inhibited, promoting lactate production.

B If mitochondria are defective, the rate of ATP production by mitochondria will be impaired, leading to a greater reliance on glycolysis for energy needs. In addition, the defective mitochondria are less capable of oxidizing NADH, so this will promote the reduction of pyruvate to lactate. Finally, because pyruvate may not be oxidized as efficiently in the mitochondria, it has a higher chance to be converted to lactate. The mitochondria themselves do not produce lacate. Although ROS may increase, this is not directly responsible for lactate production. The same is true for beta oxidiation: it may occur at a lower rate, but this would not directly promote lactate production.

What would be the effect of doubling the frequency of administration of an oral medication, assuming the total administered dose remains the same? The average plasma concentration would double The peak concentrations would be decreased The trough concentrations would be decreased The half-life of the drug would be decreased

B Increasing the frequency of administration of the drug without changing the dose will decrease the peak concentration, and also increase the trough concentration, so that they more closely surround the average concentration. The average plasma concentration would be no different, and there would be no effect on the half-life of the drug. In general, therapeu#c dosing of a drug seeks to maintain the peak (highest) plasma drug concentra#on below the toxic concentra#on, and the trough (lowest) drug concentra#on above the minimally effec#ve level . This can be accomplished most efficiently using con%nuous drug delivery by intravenous (con%nuous infusion), subcutaneous (con%nuous pump or implant), oral (sustained-release tablet), and other routes of administra%on. In many cases, however, the dosing regimen must also consider pa%ent convenience. Frequent small doses (usually oral) can be administered to achieve minimal varia%on in steady-state plasma drug concentra%on, but this strategy subjects the pa%ent to the inconvenience of frequent drug administra%on.

Which antibody isotype(s) is(are) normally most abundant in newborn babies? IgM IgG IgD IgE IgA

B Maternal IgG is transported into baby's circulation via the neonatal Fc receptor (FcRN). No other isotype is efficiently transported across the placenta.

Regarding the composition and function of lipoprotein particles, which statement is accurate? The fatty acids that form triglycerides present in VLDL are synthesized exclusively in the liver LDL can be taken up by receptor mediated endocytosis in most tissues IDL arises from processing of LDL by lipoprotein lipase Chylomicrons contain a high proportion of cholesterol relative to trigylceride HDL can deliver cholesterol to tissues in a process called reverse cholesterol transport

B Most cells express LDL receptors, and will use this mechanism to meet their cholesterol needs, rather than synthesize it de novo. You may have chosen A, however, this is incorrect (watch the concept video!). In the fasting state, the liver still produces VLDL. In this case, the lipids that are assembled into triglycerides and packaged into VLDL are derived from free fatty acids that were released into the blood stream, taken up by the liver, and then packaged into VLDL. In the fed state, a much larger proportion of the fatty acids in a VLDL particle are derived from those synthesized by the liver. C is incorrect because IDL arises from processing of VLDL. D is incorrect because chylomicrons contain more triglyceride than cholesterol. E is incorrect because reverse cholesterol transport is involved in removing cholesterol from tissues and transporting it back to the liver.

Which antibody isotype(s) activate(s) cells by simultaneously binding to antigen and to Fc receptors on phagocytes? IgM IgG IgD IgE IgA

B Only secreted IgGs bind to FcRs on phagocytes.

Proteasome inhibitors would most likely have which of the following effects on immunity? Impairment of helper T cell-dependent antibody responses against bacterial infections Impairment of CD8+ T cell responses against viral infections Impaired CD4+ T cell activation of macrophage killing of phagocytosed fungi Defective dendritic cell migration from infected tissues into lymph nodes

B Proteasomes are essential to the class I antigen processing pathway to generate peptides from proteins in the cytosol. Viral proteins are made in the cytosol, and CD8+ T cells are class I MHC restricted.

Like vitamins, our body depends on certain amino acids from the diet because They are destroyed in the lysosome The cell cannot synthesize their carbon backbone They are metabolized faster than other amino acids They are needed for transamination reactions

B Some amino acids just can't be made from scratch by human cells. Proteins are degraded in the lysosome, but the amino acids are released. There is no difference in the catabolism of amino acids that is based on whether they are essential or not. And all amino acids can undergo transamination.

anaplastic lymphoma kinase (ALK)

Besides EGFR, the other major therapeutic target that has shown clinical benefit in lung cancer (name comes from the fact that it was first identified in lymphoma). Like EGFR, ALK is a tyrosine kinase. Unlike EGFR, ALK is usually activated by translocation in lung cancer. ALK activation can be detected by immunohistochemistry (left), and the translocation directly detected by fluorescence in situ hybridization (FISH, right). ALK-positive lung cancers usually respond to targeted ALK inhibitors. Two are currently FDA approved, crizotinib and ceritinib, and several others are in development. Note that this is one of the few examples of a translocation driving a carcinoma - this mechanism is more commonly seen in sarcomas and hematopoietic neoplasms

The principle of reciprocal regulation is best reflected by: The ability of citrate to stimulate acetyl CoA carboxylase. The ability of malonyl-CoA to inhibit carnitine acyl transferase I. The ability of acetyl-CoA to inhibit pyruvate dehydrogenase. The ability of acetyl-CoA to stimulate pyruvate carboxylase.

B The ability of an intermediate of one metabolic pathway to directly inhibit the opposing pathway is an example of reciprocal regulation. In this case, the product of the rate-limiting step in fatty acid synthesis (malonyl-CoA) inhibits the entry of fatty acids into the mitochondrion for beta-oxidation. The other statements are all true, but they are not examples of reciprocal regulation. The ability of citrate to stimulate acetyl CoA carboxylase is an example of "feed-forward" regulation, where an upstream metabolite stimulates a downstream enzyme. Answer C is an example of feedback inhibition. Answer D is also an example of a "feed-forward" mechanism—if acetyl-CoA builds up due to slowing of the TCA cycle, activation of pyruvate carboxylase produces more oxaloacetate to stimulate the TCA cycle. This is also an example of linkage between two important pathways in the fasting state. Once the liver has enough ATP, the rise in acetyl CoA from beta oxidation stimulates pyruvate carboxylase to generate oxaloacetate for gluconeogenesis.

Which of the following is used to detect M. tuberculosis in respiratory secretion samples (sputum)? The Gram stain The acid-fast stain Purified Protein Derivative (PPD) Antibiotic susceptibility testing

B The acid-fast stain is the usual stain for M. tuberculosis in patient samples. PCR and culture can also be used to detect the organism in patient samples. M. tuberculosis is not readily detected by Gram stain because it often does not take up the stain and so it cannot be seen (if it does stain in Gram stain, it stains Gram positive). PPD is a reagent used when performing tuberculin skin testing on patients. Antibiotic susceptibility testing is important for M. tuberculosis, but it is not used in the initial detection of the organism.

The drug tamoxifen is an antagonist of the estrogen receptor, and is used to treat breast cancer in patients whose tumors express high levels of the estrogen receptor. In a clinical study, researchers examined the response of patients to tamoxifen in relation to the relative activity of the CYP2D6 enzyme. EM=extensive metabolizer (eg, high activity of CYP2D6), IM=intermediate metabolizer, PM=poor metabolizer. How could you explain this relationship? Tamoxifen is the active drug which is inactivated by CYP2D6 Tamoxifen is a prodrug that is activated by CYP2D6 The conversion of tamoxifen to 4-hydroxytamoxifen is unlikely to affect activity Drugs that inhibit CYP2D6 would be unlikely to affect the efficacy of tamoxifen

B The data suggests that extensive metabolizers (high activity of 2D6) is associated with a better outcome. Thus the most likely possibility is that CYP2D6 converts tamoxifen from a less active prodrug to a more active drug. This is indeed the case--hydroxytamoxifen is about 100x more potent that tamoxifen. Drugs that inhibit CYP2D6 would be likely to decrease the effectiveness of tamoxifen and must be avoided in breast cancer patients treated with tamoxifen.

Which of the following matched pairs is correct? Saturated fatty acids: low melting point Unsaturated fatty acids: enhance membrane fluidity Trans fatty acids: found as a component of membrane lipids Saturated fatty acids: contain more double bonds

B The double bonds in unsaturated fatty acids produce kinks in the hydrocarbon chain, which enhances fluidity of the membrane, because the tails don't pack together as tightly. Saturated fatty acids do not contain double bonds which leads to a higher melting point (hydrocarbon chains pack together more tightly). Trans-fatty acids are a by-product of hydrogenation of unsaturated fats and are not found naturally.

Which statement best distinguishes the endogenous and exogenous pathways of cholesterol metabolism? The endogenous pathway transports cholesterol, while the exogenous pathway transports cholesterol esters The endogenous pathway involves ApoB100, while the exogenous pathway involves ApoB48 The endogenous pathway transports dietary lipids, while the exogenous pathway transports lipids synthesized by the liver The endogenous pathway involves chylomicrons while the exogenous pathway involves VLDL Lipoprotein particles of the endogenous pathway are substrates of lipoprotein lipase, but those of the exogenous pathway are not

B The exogenous pathway refers to dietary cholesterol and lipids, which are packaged into chylomicrons containing ApoB48. The endogenous pathway transports lipids/cholesterol synthesized in the liver, and transported by VLDL particles containing ApoB100. Both particles are substrates of lipoprotein lipase. Both pathways transport cholesterol and cholesterol esters (mostly the latter) though the relative amounts can vary.

You are studying a drug which has a volume of distribution of 4L. Which of the following is most likely for this drug? It binds poorly to plasma proteins and easily passes through cell membranes It cannot cross cell membranes It easily passes the blood brain barrier It is rapidly metabolized in the liver

B The fact that the Vd is equal to plasma volume (4L) suggests that the drug cannot cross cell membranes. This volume of distribution would be expected for a protein therapeutic, such as an antibody (like herceptin (trastuzumab)). A compound that easily passes through cell membranes would have a much larger volume of distribution. A compound with such a limited volume of distribution is also unlikely to have properties that would allow it to pass the blood-brain barrier. The Vd alone does not tell you whether the compound will be rapidly metabolized by the liver.

The "ABO" blood group antigens are best described by which of the following? Monosaccharides Oligosaccharides Fatty acids Peptides Nucleic acids

B The genes determining the ABO structure encode for enzymes that catalyze the transfer of sugar structures onto the oligosaccharide end of membrane glycoproteins. The resulting differences in sugar structure created the antigenic differences between the group A, B, O, and AB cells.

Which of the following best describes the frequency of RhD antigens (frequency of Rh positive individuals) in most populations? Greater than 80% of males are positive; less than 20 % of females are positive Greater than 80% of males and females are positive Greater than 80% of females are positive; less than 20 % of males are positive Less than 20% of males and females are positive About 50% of both females and males are positive

B The genes encoding the Rh proteins are on chromosome 1, not on the X or Y chromosome. Hence Rh type is not linked to gender and >80% of all individuals are RhD+.

Which of the following mechanisms is utilized by Gram-positive cocci to evade the host immune response: Production of toxins that damage immune cells Elaboration of polysaccharide capsule that interferes with complement activation Expression of M protein that inhibits complement activity All of the above

D

The ability of the statin drugs to lower LDL levels in the blood is best explained by: Decreased rate of cholesterol being incorporated into VLDL. An increased rate of clearance of LDL from the blood stream. Inhibition of HMG CoA synthase. A decreased rate of conversion of VLDL to LDL in the blood stream. An increased rate of reverse cholesterol transport by HDL.

B The statin drugs inhibit HMG CoA reductase (not HMG CoA synthase). This leads to a lowering of cellular cholesterol, which is sensed by a protein that interacts with SREBP. As a result, SREBP moves to Golgi, where it is processed by proteases, which allows the domain containing the transcription factor to move to the nucleus. Key target genes of SREBP include HMG CoA reductase and the LDL receptor. HMG CoA reductase will be inhibited by the drug, but increases in the LDL receptor will bring more LDL into the cell, thereby lowering blood LDL concentrations.

Pyruvate dehydrogenase: Catalyzes an energetically reversible reaction. Is activated by NAD+. Is inhibited by pyruvate and ADP. All of the above. None of the above.

B This reaction is thermodynamically highly favored (ΔGo'=-33 kJ/mol), and thus is not considered reversible. The enzyme complex is activated by its substrates (pyruvate, CoA, and NAD+) and inhibited by its products (acetyl-CoA and NADH). Note that the enzyme is also sensitive to cellular energy depletion (activated by ADP). Some of these effects are due to direct binding to the PDH enzyme complex, others are due to regulation of the kinase that phosphorylates PDH.

What is the physiologic function of class I and class II major histocompatibility complex (MHC) molecules? Protecting unfolded proteins from degradation Displaying peptides for recognition by T lymphocytes Presenting antigens to B cells Internalizing proteins into antigen presenting cells

B a and d can't be right, because MHC binds peptides, not proteins; c is wrong because, although it might be possible that there are clones of B cells whose BCR can recognize an MHC-peptide complex, these would be rare, while all T cells see this form of antigen.

Which of the following is true about class I MHC molecules? Expressed by CD4+ T cells but not CD8+ T cells Expressed by all nucleated cells Recognized by human CD4+ T cells Not polymorphic

B a is wrong following that b is correct; d is wrong-actually more polymorphic than class II

Dendritic cells are the most important antigen presenting cells for which type of lymphocyte? B cells Naïve T cells CD4+ helper T cells CD8+ cytotoxic T lymphocytes

B a is wrong-follicular dendritic cells (FDC), which are not protein processing APCs, display antigens on their surface to B cells, (covered in IMM 9); although DCs can present antigen to effector T cells helper T cells can also be activated by antigen presented by macrophages or B cells ( helper) and CTL by any nucleated cell (CTL) ( c and d are wrong).

CD28

B7 proteins are recognized by a receptor called CD28, which is expressed on virtually all T cells. The binding of CD28 on T cells to B7 on the APCs generates signals in the T cells that work together with signals generated by TCR recognition of antigen presented by MHC proteins on the same APCs. CD28-mediated signaling is essential for the responses of naive T cells; in the absence of CD28-B7 interactions, antigen recognition by the TCR is insufficient for T cell activation. The requirement for costimulation ensures that naive T lymphocytes are activated fully by microbial antigens, and not by harmless foreign substances (or by self antigens), because, as stated previously, microbes stimulate the expression of B7 costimulators on APCs.

What are the effects of insulin and glucagon signaling on fatty acid uptake and release by adipocytes?

Because of some of the complexiUes in lipid transport, the storage or release of faTy acids from adipose cells requires the acUvity of lipases in each direcUon. These lipases are different: one is involved in releasing faTy acids from the fat cell (hormone sensiUve lipase), whereas one is required to convert the triglyceride in circulaUng lipoprotein parUcles (principally chylomicrons and VLDL) into faTy acids, to allow the fat cell to take up the faTy acids (lipoprotein lipase). Signaling by glucagon or epinephrine in adipose cells sUmulates the acUvity of hormone sensiUve lipase, which is present within the fat cell. This causes release of faTy acids into the circulaUon. This should make sense as a reacUon of fasted state, or as a result of sympatheUc acUvaUon (epinephrine), as it represents mobilizaUon of fuels from the adipose cell to the circulaUon. Note that this activity of hormone sensiUve lipase is also inhibited by the acUon of insulin. the acUon of insulin causes the adipocyte to synthesize and secrete an enzyme called lipoprotein lipase. This enzyme allows the fat cell to gain access to circulaUng triglycerides that are abundant in the fed state. The enzyme releases faTy acids from VLDL or chylomicrons that are circulaUng in the blood; the faTy acids are taken up by the fat cell and stored as trigylcerides

How are reactive oxygen species formed? How can the presence of uncoupling proteins prevent the accumulation of reactive oxygen species?

Before the e- get to CytC, they are very high energy and can be transferred directly to O2 to generate superoxide (O2-) at complexes I and III especially when rate of ETC is slowed O2-> Superoxide (O2-) > hydrogen peroxide (H2O2) -> hydroxyl radical (OH* - very very bad) -> damage to lipids, DNA, proteins (esp mDNA) superoxidase to hydrogen peroxide can be converted to water by enzyme catalase (mainly found in peroxisomes in cytoplasm) or to water by enzyme glytathione peroxidase (found in mito and cyto, esp. important to red blood cells) ANOTHER WAY: UNCOUPLING PROTEINS function as proton channels, which enable the proton gradient to be dissipated bc hte proton gradient is lower, it is easier for e- to move down the ETC and therefore lower likelihood of e- to react with O2 at C1 or C3 to form ROS (ex. UCP2)

Besides EGFR, what other (potential) therapeutic targets exist in lung cancer? If a patient's lung tumor does not contain an EGFR mutation, what approach could you take to identify an appropriate therapy?

Besides EGFR, the other major targeted therapy that has shown clinical benefit in lung cancer is ALK, which can be activated by translocation (not point mutation) in lung cancer. ALK-positive lung tumors frequently respond to ALK inhibitors. ALK-positive lung cancers usually respond to targeted ALK inhibitors. Two are currently FDA approved, crizotinib and ceritinib, and several others are in development. Perform an oncopanel on the tumor cell (with normal cells as well for germline comparison) to see if patient would qualify for a different targeted therapy (Note KRAS mutations too downstream to benefit from EGFR inhibitor)

The diagrams below show two MHC molecules. CD4 binds which labeled part?

F Class II MHC is on the right--two chains chain form the peptide binding site. CD4 binds to class II, at a non polymorphic site ( the Ig domain)

transfusion reaction

Blood transfusion reactions occur when preformed antibodies in a transfusion recipient bind to and cause the destruction of the donor red blood cells. Blood transfusion reactions may be targeted to antigens of the "ABO" blood group system. This system is controlled by several independent genes which code for enzymes that attach different sugars to the oligosaccharide end of glycoproteins or glycolipids present on the membranes of red blood cells, platelets, lymphocytes, endothelial cell, and epithelial cells

A. How does the cellular distribution of expression of class I MHC and class II molecules differ? B. How does this correlate with the functions of class I-restricted (CD8) T cells and class II-restricted CD4 T cells?

By segregating the class I and class II pathways of antigen processing, the immune system is able to respond to extracellular and intracellular microbes in different ways best able to defend against these microbes CD4: Extracellular microbes are captured and ingested by APCs, including B lymphocytes and macrophages, and are presented by class II molecules, which are expressed mainly on these APCs (and on dendritic cells). Because of the specificity of CD4 for class II, class II-associated peptides are recognized by CD4 + T lymphocytes, which function as helper cells. These helper T cells help B lymphocytes to produce antibodies, and they help phagocytes to destroy ingested microbes, thereby activating the two effector mechanisms best able to eliminate microbes that are internalized from the extracellular environment.Neither of these mechanisms is effective against viruses and other pathogens that survive and replicate in the cytoplasm of host cells. CD8: Cytosolic antigens are processed and displayed by class I MHC molecules, which are expressed on all nucleated cells—again, as expected, because all nucleated cells can be infected with some viruses. Class I-associated peptides are recognized by CD8 + T lymphocytes, which differentiate into CTLs. The CTLs kill the infected cells and eradicate the infection, this being the most effective mechanism for eliminating cytoplasmic microbes. This function of MHC-associated antigen-processing pathways is important because the antigen receptors of T cells cannot distinguish between extracellular and intracellular microbes.The segregation of class I and class II antigen presentation pathways ensures the correct, specialized immune response against microbes in different locations.

How do statins lower LDL cholesterol? What is hte role of SREBP in this process?

By suppressing liver cholesterol syn, which lowers cholesterol levels in teh liver cell, leading to activatin of SREBP which will increase expression of the LDL receptor, which causes increased uptake of LDL from teh blood (also act as a competitive inhibitor of HMG-Coa reductase)

Which of the following is a characteristic of most of the pathogenic Gram-positive cocci? They are most often transmitted from human to human by fecal-oral transmission They are difficult to culture, requiring specially supplemented blood agar to grow They are often found in the nares, pharynx, or on the skin of healthy individuals They lack the ability to make pore-forming toxins

C

Which of the following is an example of a disease mediated by a toxin produced by Gram-positive cocci? Consolidated pneumonia due to Streptococcus pneumoniae Bone infection (osteomyelitis) due to Staphylococcus aureus Staphylococcal scalded skin syndrome Pharyngitis due to group A streptococcus

C

The least common ABO blood type across all race/ethnic donors is? A B AB 0

C 2.5-7% of all individuals are blood type AB.

How many different MHC molecules are typically expressed on one person's dendritic cells? 0 2 10-15 5000 10 million

C A person inherits 3 class I genes from each parent and at least 3 Paris of genes encoding alpha and beta of class II molecules, from each parent. Both parental alleles of each gene are co-dominantly expressed. If the parents do not share any alleles, there would be 12 different MHC molecules inherited, and since question asks about a DC, both class I and class II would be expressed. Only c is in the ball park.

In the diagram of an IgG molecule above, which parts form an antigen binding site? 1 + 4 2 + 3 1 + 2 5 + 6 1 + 7

C Answer clear from explanations of previous questions—antigen binding site formed by V domains of heavy and light chains.

Rheumatoid arthritis (RA) is a T cell-mediated autoimmune disease that leads to inflammation and damage to joints. CTLA-4-Ig (Belatacept) is an Ig fusion protein drug approved for the treatment for RA. Which of the following correctly explains its mechanism of action? Binds CTLA-4 on T cells, blocking costimulation Binds B7-1 and B7-2 on T cells, generating costimulatory signals Binds B7-1 and B7-2 on APCs, blocking costimulation Binds CTLA-4 on T cells, generating inhibitory signals

C CTLA-4 has the B71/2 binding portion of CTLA-4, which function as native CTLA-4 functions, to bind B7s and keep them from binding to CD28, preventing costimulatory signaling. Not A or D, CTLA-Ig is not anti-CTLA-4.

Pheochromocytoma is a tumor of the adrenal gland that secretes epinephrine. This can lead to sudden attacks of headache, perspiration and anxiety. If you measure the blood, which of the following metabolic abnormalities would you observe? Decreased circulating amino acids Decreased free fatty acids Increased glucose Increased chylomicrons Increased bile acids

C Epinephrine is a hormone that will make fuels available in the blood stream, including glucose, fatty acids, and amino acids (by stimulating muscle breakdown). Chylomicrons are only available in the fed state, and epinephrine would not be able to increase their production. Bile acids are never found in the blood, as they are secreted into the bile duct (headed to the intestine).

Which type of inflammation is associated with the formation of granulomas? Acute inflammation Pyogenic inflammation Chronic inflammation Sporadic inflammation

C Granulomas are one pattern of response seen with chronic inflammation (note that there are others). Granulomas are associated with specific causes, such as infection with M. tuberculosis. Granulomas do not occur with acute inflammation or "pyogenic" inflammation (formation of pus, usually as a type of acute inflammation). "Sporadic" inflammation does not have a clinical meaning.

If you wanted to develop a drug that blocked clonal expansion of T cells, which of the following would be a logical candidate? Monoclonal antibody specific for interferon-gamma Monoclonal antibody specific for TNF Monoclonal antibody specific for interleukin-2 Monoclonal antibody specific for TGF-beta Monoclonal antibody specific for IL-10

C IL-2 is the autocrine growth factor that drives T cell clonal expansion

Which of the four different antibodies shown in the figure above is an IgM? 1 2 3 4

C IgM is only Ig that forms pentamers (secreted form, not membrane form).

Regarding fatty acid synthesis, which statement is incorrect? Acetyl-CoA is transported from the mitochondrion to the cytoplasm in the form of citrate. The activation of pyruvate dehydrogenase will help in the synthesis of fatty acids from glucose. Malonyl-CoA is an allosteric activator of fatty acid synthase. Acetyl-CoA carboxylase activity is activated by citrate.

C Malonyl-CoA is a substrate of fatty acid synthase, not an activator of the enzyme. All other answers are correct.

You are studying the metabolism of a new drug in a population. You identify a subset of individuals that metabolize the drug at a higher rate than the rest of the population. A genetic polymorphism that results in which of the following would best explain this higher rate of metabolism? An increase in the Km of a P450 enzyme that metabolizes the drug An effect on the promoter that decreases the expression level of a P450 enzyme that metabolizes the drug An increase in the kcat of the P450 enzyme that metabolizes the drug A decrease in the stability of the P450 enzyme that metabolizes the drug

C Only choice C would increase the rate of the enzymatic reaction that modifies the drug. If the Km is increased, the rate of the reaction would be decreased (as long as the drug is being used at a concentration that is not saturating the enzyme). All of the other choices would decrease the rate of the reaction.

The TAP1 and TAP2 proteins encode the components of an ATP-driven pump that transports peptides from where to where? Extracellular fluid into cytosol Cytosol into lysosome Cytosol into endoplasmic reticulum Cytosol out to extracellular fluid Nashville to Chattanooga

C Peptides generated in the cytosol by the proteasomes need to be translocated into the ER lumen, where the peptide bind end of newly made class I MHC polypeptides is located. TAP serves this function.

Regarding Phase I and Phase II metabolism, which statement is most accurate? Phase I reactions involve conjugation of molecules to drugs Phase II reactions are carried out by cytochrome P450 enzymes Phase I reactions typically involve oxidation of substrates Phase II reactions are excretion reactions that remove the drug from the body

C Phase I reactions typically involve oxidation of substrates, although other reactions are possible. These are carried out by cytochrome P450 enzymes. Phase II reactions involve conjugation of molecules to drugs. Although these reactions may facilitate excretion, they are not the excretion step itself.

Most of the MHC molecules on the surface of cells... Have no bound peptides Have bound peptides derived from bacterial proteins Have bound peptides derived from normal self proteins Have bound peptides derived from viruses

C Self proteins are not distinguished from microbial proteins in both ag processing pathways, and self proteins far outnumber microbial proteins ( c is right, b is wrong, d is wrong). Without peptide, MHC molecules are unstable and will not make it to surface, or will be recycled from surface ( a is wrong).

During a myocardial infarction (heart attack), blood flowing to the heart muscle is interrupted by formation of a blood clot (thrombus), resulting in blockage of a coronary artery. Which of the following is likely to occur in cardiac muscle cells? Pyruvate kinase will be inhibited. Lactate production will decrease. Pyruvate dehydrogenase will become less active. The rate of electron transport will increase.

C The lack of oxygen causes a decrease in the rate of electron transport. ATP levels will fall, which would tend to promote activity of PDH. However, because the rate of electron transport is slowed, NADH will tend to accumulate. Because NAD+ falls and NADH rises, pyruvate dehydrogenase slows down. The pyruvate will instead be converted to lactate using lactate dehydrogenase. This allows a molecule of NADH to be converted to NAD+ (the pyruvate is reduced to lactate using the electrons in NADH). This regenerates NAD+ that can be used to support ATP generation in the absence of oxygen by glycolysis.

The Mantoux tuberculin skin test (TST) is used to determine prior infection with Mycobacterium tuberculosis (mTB), a microbe that survives inside phagocytes, and requires T cell mediated immunity for eradication. The test is performed by intradermal injection 0.1 ml of a purified protein derivative (PPD) of Mycobacterium tuberculosis. The presence of an indurated (hard) and red area at the injection site of 10mm diameter or greater is interpreted as a positive test. Based on what you know about T cell immune responses, which of the following is the most accurate description of what is happening at the site of a positive PPD test? Clonal expansion PPD-specific naive T cells Clonal expansion of PPD-specific memory T cells generated from a previous infection with mTB Activation of macrophages by memory T cells generated from a previous infection with mTB Activation of macrophages by Toll-like receptor ligands in the PPD preparation Neutrophil influx due to endothelial activation by the PPD

C The positive test is due to memory Th1 cells respond to the antigen by activating macrophages. A, B are wrong since clonal expansion is when naïve T cells respond to antigen, and happens in lymph nodes, not in peripheral tissue sites. Not D or E, because purified protein is use for test, without TLR ligands.

You administer a 1 gram dose of a drug, and then measure the plasma concentrations over time. Based on analysis of the elimination phase, you extrapolate back to determine C0 and measure it to be 0.005 g/L. What can you conclude? The drug is highly protein bound in the plasma The drug cannot cross cell membranes The drug can cross cell membranes and bind to cell components You cannot make any additional conclusions from this data

C This data allows you calculate the volume of distribution of the drug. Vd=administered dose/C0. Here the calculated Vd=1g/0.005g/L=200L. Since this is much larger than total body water (42 L) it suggests that the drug is not retained in the plasma nor distributed just to body water, but must enter cells and bind to other components of the cell, suggesting it can cross cell membranes.

You are developing a new drug that you hope patients will be able to take as a pill. In your pharmacokinetic analysis of the drug, you find that the bioavailability is 0.1. All of the following provide a reasonable explanation for this low bioavailability, except: The drug is not absorbed by the GI tract The drug is almost fully metabolized by the liver during its first pass through the portal system The drug is eliminated mostly by the kidney The drug is unstable in the stomach

C To determine bioavailability, you measure the concentration of the drug in the plasma over time. You compare an oral dose to a dose delivered by IV. You then measure the area under the curve in both conditions, and take the ratio of the oral dose to the IV dose. If 100% of the oral dose is absorbed and makes it to the blood stream unchanged, then the bioavailability is 1 (100%). However, if the drug is poorly absorbed, if it is rapidly metabolized in the liver, or if it is unstable in the stomach, the bioavailability will be much lower. Because the kidney eliminates drug from the systemic circulation, the rate of elimination by the kidney will be the same regardless of whether the drug is administered IV or orally, so is not a factor in determining bioavailability.

You are studying a new antibiotic. You administer a 1 gram dose of the antibiotic over 30 minutes or over a 3 hour period, in both cases using intravenous administration. You measure plasma concentrations as shown in the graph. What can you conclude from these data? The half-life is shorter when the drug is administered more rapidly The half-life is longer when the drug is administered more rapidly There is no effect of the rate of dosing on the half-life The bioavailability is greater when the drug is administered more rapidly

C You can determine the half-life from this data by looking at the rate of decline in the drug concentration after the infusion stops. Inspection of the data will show that the half-life is independent of the rate of administration of the drug. In both cases the half life is one hour. For example, for the rapidly administered dose, you can see that the drug concentration drops from 100 mg/L at one hour to 50 mg/L at two hours, and 25 mg/hour at three hours, for a half-life of one hour. For the slowly administered drug, the concentration drops from 60 mg/L at three hours to 30 mg/L at four hours, and 15 mg/L at five hours. Therefore, the half life is also one hour in this case. A constant half-life at different drug concentrations is characteristic of so-called "first order" kinetics. This behavior is observed as long as the drug metabolizing enzymes are not saturated. Note that since both drugs are administered IV, bioavailability is not an issue in this experiment.

Which of the following is true about class II MHC molecules? Expressed by all nucleated cells Expressed by naïve T cells Recognized by human CD4+ T cells Bind nucleic acids

C a is wrong-class I, not class II is on all nucleated cells; b is wrong, Naïve T cells express class MHC (as do all cells), but not class I MHC; d is wrong-only peptides

carnitine acyl transferase 1

CAT1 or CPT1 special transport system moves long chain FA into the mito matrix - this enzyme is the first step (makes acyl-carnitine) RLS for B ox is mvoement of FA into mito matrix located on the outer mito membrane where it hooks teh OH group of carntine onto the acetyl group of acetyl coa a special transporter exchanges this for carnitine and then CATII reverse the reaction

CD40

CD40 receptors on activated DCs Another set of molecules that participate in T cell responses are CD40 ligand (CD40L, or CD154) on activated T cells and CD40 on APCs. These molecules do not directly enhance T cell activation. Instead, CD40L expressed on an antigen-stimulated T cell binds to CD40 on APCs and activates the APCs to express more B7 costimulators and to secrete cytokines (e.g., IL-12) that enhance T cell differentiation. Thus, the CD40L-CD40 interaction promotes T cell activation by making APCs better at stimulating T cells. These issues are of practical importance because enhancing the expression of costimulators may be useful for stimulating T cell responses (e.g., against tumors), and blocking costimulators may be a strategy for inhibiting unwanted responses. Agents that block B7:CD28 are used in the treatment of rheumatoid arthritis, other inflammatory diseases, and graft rejection, and antibodies to block CD40:CD40L interactions are being tested in inflammatory diseases and in transplant recipients to reduce or prevent graft rejection.

CD40L

Cd40Ligand on activated T cells Another set of molecules that participate in T cell responses are CD40 ligand (CD40L, or CD154) on activated T cells and CD40 on APCs. These molecules do not directly enhance T cell activation. Instead, CD40L expressed on an antigen-stimulated T cell binds to CD40 on APCs and activates the APCs to express more B7 costimulators and to secrete cytokines (e.g., IL-12) that enhance T cell differentiation. Thus, the CD40L-CD40 interaction promotes T cell activation by making APCs better at stimulating T cells.

What is latent tuberculosis?

Cellular immunity and tissue hypersensitivity usually appear 3 to 8 weeks after infection and are marked by a positive tuberculin skin test. In most affected individuals, this response controls infection (although viable organisms may persist in the tissues), no symptoms develop, and the only evidence of infection is a positive tuberculin skin test. The bacteria have become latent. Nearly all TB in previously infected patients is the result of endogenous reactivation. The most common site of reactivation is the apex of the lung Endogenous reactivation usually occurs within 2 years after initial infection but can occur at any time thereafter. Clearly, any impairment of the cellular immune system can render a person vulnerable to reactivation of latent mycobacteria. Subtle depression of the immune system resulting from stress or hormonal factors may go undetected. Other factors include malnutrition, therapy with corticosteroids or other immunosuppressive drugs, malignancy, and endstage renal disease. Worldwide, the most important cause of reactivation is coinfection with HIV. The higher frequency of certain histocompatibility types (i.e., human leukocyte antigen or HLA) in persons who develop active TB suggests a genetic predisposition. In 25% of cases, 5 years after infection, Ghon complex, in which an area of lung inflammation is associated with enlarged hilar lymph nodes draining the area, can occur

How does S. aureas create abscesses/boils?

Coagulase binds fibrin to form walled off pockets protecting the bacteria from phagocytes which can happen all over the body. The development of an abscess is a complex process that involves both bacterial and host factors. S. aureus infections causes a rapid and extensive influx of leukocytes (e.g., neutrophils). Chemotactic factors, derived both from bacteria and complement, are made in large amounts. S. aureus secretes coagulase that causes formation of clots. Protein A is released where it may bind antibodies reducing opsonization. S. aureus lyse neutrophils and red blood cells that have entered the infection area by the production of cytolysins (leukocidins and hemolysins). The lysed neutrophils pour out large amounts of lysosomal enzymes, which damage surrounding tissue.

How do cytokines affect Th subset differentiation and how can Th differentiation be targeted to treat autoimmune or allergic disease?

Cytokines direct Th differentiation often with postiive feedback loops that lead to increased polarization with chronic infections Il12 and IFNgamma -> Th1 cells Il4 -> Th2 cells Il 1, Il6, il 23 TGFbeta -> Th17 cells targeting cytokines invovled in Th1/Th17 differentiation or fxn have been used to treat autoimmunity and targeting cytokines involved in Th2 differentiation or fxn are being tried for treatment of allergic disease

Gram-positive cocci in chains are identified on a Gram stain from a throat culture. The identified bacteria are negative by testing for catalase and produce a wide zone of clear hemolysis on a blood agar plate. Which bacteria most likely caused this throat infection? Staphylococcus aureus Streptococcus pneumoniae Viridans-group streptococcus Group A streptococcus

D

Important effects of insulin in the fed state in the liver include all of the following, except: Activation of acetyl-CoA carboxylase. Activation of PFK2. Activation of pyruvate kinase. Activation of hormone sensitive lipase.

D Activation of the insulin signaling pathway opposes effects of PKA in many tissues by lowering cAMP levels and activating protein phosphatases that dephosphorylate many of these enzymes. In fatty acid synthesis, a key effect is the dephosphorylation and activation of acetyl-CoA carboxylase. PFK2 and pyruvate kinase are also dephosphorylated to activate glycolysis. However, in adipocytes, dephosphorylation of hormone sensitive lipase would inactivate its activity. It is useful to remember that one of the most important effects of insulin is to suppress the release of fatty acids from adipose cells; it does so by favoring dephosphorylation of hormone sensitive lipase.

All of the following pairs describes a TCA cycle intermediate and a direct metabolic product involved in another biological pathway, except: Alpha-keto glutarate: can be converted to glutamate Citrate: used for fatty acid synthesis Oxaloacetate: can be converted to aspartate Malate: used to make methionine Succinyl CoA: used to make porphyrins (for heme synthesis)

D All others are correct (see last slide of TCA cycle video). also malate is made from citrate to make fatty acids

In the figure below, the label "C" indicates one of the same structural domain shown in the cytoplasmic tails of several of the proteins. What is this domain? Immunoglobulin-like domain ( Ig domain) Immunoreceptor tyrosine inhibitory motif (ITIM) Src homology domain-2 ( SH2) Immunoreceptor tyrosine activation motif (ITAM) Zinc finger domain

D C shows a feature in cytoplasmic tail of zeta chain, also seen in CD3 chains, which become phosphorylated...has to be ITAM

The TCA and the urea cycle are connected through metabolites. Which of the following statements explains the relationship of these two pathways? The TCA cycle fixes CO2 in form of carbamoylphosphate in the mitochondria which then enters the urea cycle Transaminases produce alpha-ketoacids that reduce the rates of the TCA cycle The TCA cycle maintains the NAD+/NADH ratio needed to perform the urea cycle The urea cycle produces fumarate which enters the TCA cycle and generates oxaloacetate that can be transaminated to aspartate for the urea cycle

D Carbamoyl phosphate synthase has nothing to do with the TCA cycle. The urea cycle does not consume NAD+ and many of the alpha-ketoacids produced by transaminase are converted into intermediates of the TCA cycle and this will increase flux through this cycle.

Clearance can be best defined as: The amount of drug that is eliminated per unit time The amount of drug that is metabolized per unit time The half life of the drug divided by the volume of distribution The volume of plasma that is cleared of drug per unit time

D Clearance is the volume of plasma that is cleared of the drug per unit time. By "cleared" we mean that the active drug is removed; therefore clearance consists of both metabolism and excretion of the drug. Clearance does not directly refer to the amount of drug that is eliminated or metabolized. Finally, clearance is calculated by the equation Cl=0.693xVd/t1/2, so the description above is inverted.

The most common ABO blood group, across all race/ethnic donors is? A B AB O

D Group O is the most common, ranging from ~40% in Asians to ~55% in Hispanic and North American Native Americans.

Which antibody isotype(s) is(are) responsible for allergies and immediate type hypersensitivity reaction? IgM IgG IgD IgE IgA

D Mast cells have IgE -specific Fc receptors that bind IgE. Antigen binding to IgE bound to a mast cells activates release of granules that mediate allergic reactions (called immediate hypersensitivity reactions).

The electrons from NADH can enter the electron transport chain by: Donating its electrons to oxygen. Converting ADP to ATP. Pumping protons to the intermembrane space. Transferring its electrons to FMN in complex I.

D NADH binds to a specific site on NADH dehydrogenase, which brings it in proximity to a bound co-factor called FMN. The reduced FMN can then transfer electrons to iron-sulfur clusters. The movement of electrons is associated with pumping of protons. Ultimately the electrons are handed off to ubiquinone (coenzyme Q). NADH dehydrogenase does not directly produce ATP or donate electrons to oxygen.

Which of the following statements about antigen recognition and T cell costimulation is correct? Either costimulation alone or antigen recognition alone can activate naive T cells Either costimulation alone or antigen recognition alone can activate effector T cells Costimulation without antigen recognition results in naive T cell death Antigen recognition alone without costimulation can result in death or prolonged inactivation of naive T cells Concurrent antigen recognition and costimulation inhibits T cell activation

D Not A, because naïve T cells both antigen induced and costimulatory signals to be activated. Not B or C because costimulation alone does not do anything to naïve or effector T cells. Not E, opposite of case for naïve T cells.

Proteolysis of proteins into peptides that bind to class II MHC takes place in which compartment? The endoplasmic reticulum The nucleus The cytosol Phagolysosome Cell surface

D Proteins from outside the cell are endocytosed or phagocytosed, the endosomes or phagosomes then fuse with lysosomes, and peptide are generated that will load onto class II MHC.

Which of the following is a correct statement about immunoglobulin (Ig) domains? Found only in Ig molecules Found in some antibodies but not others Found only in antibodies and T cell receptors Widely found in many cell surface proteins Found in class II but not class I MHC molecules

D The Ig domain is found in hundreds of proteins, in and out of immune system; therefore A and C are wrong. B is wrong because all antibodies (heavy and light chains) have Ig domains. E is wrong because both class I and class II MHC proteins have Ig domains (although we have not covered MHC structure yet, so that may not have been clear).

Reactive oxygen species (ROS) are toxic to cells because The cell has no defense against them. They inhibit the electron transport chain. They directly consume NADPH. They damage lipids, DNA and proteins.

D The cell has multiple enzymes to quickly convert ROS to water. ROS do not inhibit the ETC per se, they are simply a byproduct. Although NADPH production is important to combat ROS, NAPDH is not consumed directly by NADPH (instead compounds such as reduced glutathione are used).

How do you classify the

Hemolysis pattern: Beta: Serotype Lancified Group Group A: S. pyrogenes Group B: S. agalactiae Groups C, F, G Alpha: S. pneumoniae & Viridians- group streptococci Gamma: Viridians- group streptococci

The synthesis of ketone bodies during a prolonged fast is best explained by: Muscle cells run out of amino acids so that glucose can no longer be produced. Liver cells have exhausted their supply of glycogen and revert to fatty acids to feed the brain. The brain sends an endocrine signal to the liver to begin producing ketone bodies. Levels of fatty acids released by adipocytes exceed the needs of the liver to meet its energy needs.

D The key driver of ketone body synthesis is the increased rate of release of fatty acids from adipocytes. Once fatty acid levels rise high enough for the liver to meet its energy needs, the rate of the TCA cycle slows, because beta oxidation produces high amounts of NADH that can support oxidative phosphorylation. As NADH rises further, beta oxidation would tend to slow as well, because NAD+ is required for this process. However, the NAD+ can be regenerated by reducing acetoacetate to beta-hydroxybutryate, allowing beta oxidation to continue. For all of this to occur, it is critical that insulin levels fall, so that the release of fatty acids from adipocytes increases. Glucagon and epinephrine also rise, stimulating fatty acid release. The brain does not directly send a signal to the liver. The rise in fatty acids and synthesis of ketone bodies decreases the requirement for glucose synthesis by the liver, thereby sparing muscle. This process begins well before muscle cells run out of amino acids and much later than glycogen breakdown.

This figure above shows four different forms of antibodies. Each is a different... Idiotype Allotype Isotope Isotype

D These structures differ in heavy chains. From diagrams this can be inferred because the number of heavy chain Ig domains in any one is different from others (1 and 2 differ from 3 and 4), or the basic units form multimers (via heavy chain binding to the J chain) (1,3) or do not (2,4). Isotypes are distinguished by their heavy chains. An idiotype is the unique binding site structure of one clone of antibodies. An allotype is one of different polymorphic allelic forms of antibodies; an isotope has nothing to do with antibodies.

You are studying the interaction between two different drugs, A and B. You find that addition of drug B shortens the half-life of drug A. Which of the following mechanisms could best explain the effect of drug B on drug A? Drug B could inhibit the activity of a P450 enzyme that metabolizes drug A Drug B could block the excretion of drug A by a P-glycoprotein Drug B could promote binding of drug A to the receptor that is responsible for its therapeutic effect Drug B could activate a nuclear receptor that regulates transcription of a P450 enzyme that metabolizes drug A

D This problem describes the phenomenon of induction. The most likely possibility is that drug B increases expression of a P450 enzyme that metabolizes drug A. If drug B inhibited a P450 enzyme that metabolizes drug A, the half-life of drug A would increase (this is the phenomenon of inhibition). If drug B blocked a P-glycoprotein, this is unlikely to affect the rate of metabolism of drug A, though it could affect the rate it is excreted from the body. If drug B promotes binding of drug A to its receptor, it might increase its efficacy, but would not affect its half-life.

Triglycerides are delivered to the adipose tissue: By the action of hormone sensitive lipase. In the form of fatty acids bound to serum albumin. In the form of triglycerides in VLDL secreted by intestinal epithelial cells. In the fed state.

D Trigylcerides are delivered to adipose tissue in the fed state, from chylomicrons (intestine) and liver (VLDL), via the action of lipoprotein lipase. Hormone sensitive lipase releases fatty acids from adipocytes in the fasting state, where they enter the blood to bind serum albumin. VLDL is secreted by the liver not intestinal epithelial cells.

Which of the following statements about peptide binding to MHC molecules is true? Each allelic form of MHC molecule specifically binds only one particular peptide Then peptides that bind to class I MHC molecules are longer than those that bind to class II MHC molecules Peptides stay bound to MHC molecules for only a few minutes Each MHC molecule binds and displays only one peptide at a time Peptides derived from microbial proteins are loaded onto MHC molecules at the cell surface

D a is wrong-MHC molecules have broad specificities for peptides; b is wrong- the opposite is true. The class I MHC cleft is closed at the ends, the class II cleft is open; c is wrong—remarkably slow off rates..days; d is right because ther is only one peptide binding cleft per molecule; e. wrong- loaded in ER

What are some of the differences between conventional chemotherapy and targeted therapy in terms of side effects and treatment regimens of these agents?

DNA damaging agents, non selective, administered in "rounds"; dosed to kill off rapidly dividing cells; side effects include hair loss, oral ulcers, neutropenia/immunocompromised Conventional chemotherapy treatments: DNA damaging agents, alkylating agents -non-selective -requires intermittent doses (cycles) to allow healthy cells to recover -side effects: hair loss, nausea (high rate of gut epithelial proliferation, oral ulcers, neotropenia (neutrophils have short half-lives)/immunocompromise Targeted Therapy -selective (targets don't play a role in normal tissues) so -can be taken over long term and doesn't need cycles (ex. BCR/Able inhibitors -Tk inhibitor that inhibits kinase necessary for proliferation)

How does uncoupling affect the rate of ATP generation, electron transport, and the rates of upstream metabolic pathways (TCA cycle, PDH, glycolysis)?

Decrease rate of ATP generation, increase rate of electron transport and upstream pathways. the uncoupling effects of DNP allow for overdrive of the ETC (except complex 5) and the TCA - lost the brakes on the pathway but aren't generating ATP so all of your resources are being used up to be converted into heat (PE from e- have to go somewhere, most of these reactions are exothermic) - high metabolic cells (ex. skin) do have have ATP do they die (lesions) but heat is most toxic

How is selectivity of protein degradation determined in the ubiquitin-proteasome system?

Different ubiquitin chains have different shapes, which are recognized by different binding proteins Hundreds of different E3 enzymes that have different selectivity for different substrates; By the ubiquitin tagging pathway - how many ubiquitin are attached and which ubiquitin lysines are attached (shape of tail)

What are the effects of glucagon signaling on glycogen synthesis, glycolysis and fatty acid synthesis in liver cells?

During fasUng, there is no incoming supply of nutrients from the gut. Instead, the liver, muscle, and adipose begin to mobilize fuel supplies to help the liver provide glucose for the brain. As insulin levels drop, adipose Ussue will begin to release faTy acids, providing fuel for muscle and other body Ussues so that they don't need to consume glucose, in effect sparing glucose for the brain. Muscle will release amino acids by breaking down protein, but it does not release glucose into the circulaUon. The amino acids are processed by the liver and converted into glucose via gluconeogenesis. Under condiUons of prolonged fasUng, the liver will begin to produce ketone bodies due to the high rate of beta oxidaUon in the liver. These can be used by the brain as fuel. The generaUon of ketone bodies depends on release of lots of faTy acids from adipose Ussue.

In the diagram of an IgG molecule above, which part interacts with complement and F receptor proteins? 1 2 4 5 6

E 6 is the Fc region (maybe ambiguous if the bracket includes the C terminal domains on both heavy chains; strictly speaking an Ig Fc does include both chain]. It is the Fc region that interacts with Fc receptors (Duh) and complement.

Which of the following is a NOT metabolic product of cholesterol? Cholesterol ester Progesterone Estrogen Vitamin D LDL

E Although LDL contains cholesterol and cholesterol esters, LDL is not considered a metabolic product of cholesterol; instead, it is a particle in which cholesterol is transported in the blood stream. All of the other compounds are derived (sometimes in multiple steps) from cholesterol.

The rate of beta-oxidation in the liver will depend on each of the following factors, except: The rate of release of fatty acids from adipose tissues. The activity of acetyl-CoA carboxylase. The amount of carnitine. The availability of NAD+. The levels of NADPH.

E Beta oxidation in the liver first depends on the availability of substrate, fatty acids that are released from adipose cells. Next, for beta oxidation to be active, fatty acid synthesis needs to be turned off. This means inactivating acetyl coA carboxylase, so that malonyl coA levels are low. Remember malonyl coA inhibits CAT-1 (carnitine acyltransferase 1). This reaction requires carnitine. NAD+ is required for beta oxidation to be effective. NADPH is not involved in beta oxidation so its levels will not affect the rate of this reaction.

A substrate of a cytochrome P450 enzyme may include all of the following, except: Nonpolar drugs oxygen NADPH cholesterol glucuronic acid

E Glucuronic acid is a substrate of phase II reactions, not a cytochrome P450 enzyme. All of the other components are possible substrates of P450 enzymes. Remember from the cholesterol metabolism session that cytochrome P450 enzymes are involved in the conversion of cholesterol to bile acids in the liver.

During exercise, stimulation of the TCA cycle (otherwise known as the citric acid cycle or Kreb's cycle) results principally from which of the following? Allosteric activation of isocitrate dehydrogenase by increased NADH. Allosteric activation of fumarase by increased ADP. A rapid decrease in the concentration of four-carbon intermediates. Product inhibition of citrate synthase. Decrease in the NADH/NAD+ ratio.

E Like pyruvate dehydrogenase, a major regulator of the flux through the TCA cycle is the NADH/NAD+ ratio. If this ratio is high, it means that little NAD+ is available to act as a cofactor in the oxidative steps of the cycle. This will tend to slow down the cycle.

Which of the following tissues would be expected to have the highest rate of beta oxidation? Brain Red blood cells Type IIb muscle fibers during exercise Liver in the fed state Type I muscle fibers in the fasted state at rest

E The red cell cannot do any beta oxidation at all, as it lacks mitochondria. The brain does not do beta oxidation because long-chain fatty acids do not easily cross the blood-brain barrier, and the mitochondria may also be defective in processing long chain fatty acids. Note, however, that the brain definitely uses its mitochondria to support ATP production (glycolysis yields pyruvate that is then processed to acetyl coA and then oxidized by the TCA cycle). Type IIb fibers have few mitochondria and will use glucose during exercise. In the fed state in the liver, the rate of beta oxidation is low because the liver is synthesizing fatty acids. In the fasted state, Type I muscle fibers, rich in mitochondria, will rely on beta oxidation for energy (even at rest) to spare glucose for the brain.

What happens to the rate of electron transport if oxygen is not available? What happens to the magnitude of the proton gradient? What happens to the NADH/NAD ratio?

ETC stops (electron carriers become saturated) magnitude of the proton gradient goes up (cannot be released thru complex 5) NADH/NAD ratio goes- PDH, TCA, and Beta Ox will make NADH for a little while without being able to hand the e- off to the ETC the metabolic processes that are indicated on this diagram are all coupled tightly together. For example, if the cell has sufficient ATP, the rate of proton movement back into the matrix will slow, leading to a reduced rate of electron transport, and thus accumulation of NADH. Because pyruvate dehydrogenase, beta oxidation, and the TCA cycle all require NAD+, the rates of these reactions will also slow. Similarly, if a cell does not have sufficient oxygen, this will slow the rate of electron transport, because the electrons have nowhere to go. NADH will again accumulate, leading to loss of NAD+, and thus the rates of the TCA cycle, fatty acid oxidation, and pyruvate dehydrogenase will also slow. It is therefore useful to think of all of these pathways as functionally coupled together.

What are the manifestations of enterovirus infections? For enterovirus D68? For poliovirus?

Enterovirus D68: A. Fatal CNS infection with enterovirus 68. CDC identified enterovirus 68 RNA in cerebrospinal fluid using reverse transcriptase-polymerase chain reaction and sequencing. (RNA genome so have to use RT step). B. Enterovirus isolated in 1962. Identified as agent that caused cytopathic effect (CPE) in monkey cell cultures. Physical and immunological properties similar to C. Outbreaks of polio-like illness in 2014 were associated with enterovirus D68 infections. Sequencing of genomes showed a novel strain of D68 virus. Poliovirus: Poliomyelitis is inflammation of the gray matter of the spinal cord and brain due to infection with poliovirus, with extreme cases showing flaccid paralysis of limb muscles and paralysis of respiratory muscles. Disease can range in severity: 1. Inapparent infection (90-95% of infected individuals). 2. Abortive polio (4-8%): fever, sore throat, headache. 3. Aseptic meningitis or non-paralytic polio (1%): More headache, higher fever, stiff neck, cerebrospinal fluid pleocytosis. 4. Paralytic polio (0.1%): Prodrome of sore throat, headache, vomiting lasting 1-2 days. Major illness follows by about 5 days: meningitis followed by paralysis. Incubation period = 7-14 days.

How do the fasting state, a protein-only meal, and a mixed carbohydrate/protein meal differ in terms of relative levels of glucagon and insulin that are circulating? How would each of these states affect the rate of muscle protein breakdown and amino acid catabolism in the liver?

Fasting state: high glucagon, epinephrine, cortisol, low insulin ** in the muscle, you have increased muscle protein breakdown to provide carbon skeletons to the liver to power gluoneo ** muscles use FAs from adipose for ENRG **released UNBRANCHED AA to liver **liver uses FAs from adipose and AA from muscle for ENRG **liver releases glucose (first) and ketone bodies (later) ** dispose of ammonia thru urea cycle FED with protein: insulin and glucogon both elevated (tho insulin not as much as with carbs)- a lot like fasting except AA from diet, not muscle **Muscles increase uptake of AA and protein synthesis stimulated (insulin effects) **liver uses AA for ENRG (taken up and catabolized) ** liver releases glucose for brain ** converts AA carb skeletons for use in glcuoneo ** detox of ammonia thru urea cycle

neonatal Fc receptor

FcRn an IgG-specific Fc receptor that mediates the transport of maternal IgG across the placenta and the neonatal intestinal epithelium FcRN reseumbles a class I MHC molecule An adult form of this receptor functions to protect plasma igG antibodies from catabolism The neonatal Fc receptor (FcRn) is expressed in placenta, endothelium, phagocytes, and a few other cell types. In the endothelium, FcRn plays a special role in protecting IgG antibodies from intracellular catabolism ( Fig. 8-2 ). FcRn is found in the endosomes of endothelial cells, where it binds to IgG that has been taken up by the cells. Once bound to the FcRn, the IgG is recycled back into the circulation, thus avoiding lysosomal degradation. This unique mechanism for protecting a blood protein is the reason why IgG antibodies have a half-life of about 3 weeks, much longer than that of other Ig isotypes and most other plasma proteins.

When people develop upper respiratory tract infections, often one can feel the lymph nodes in the neck have grown larger. What accounts for this increase in size? The lymph nodes usually go back to normal after an infection is cleared. What accounts for this decrease in size?

First, naive T cells must migrate between blood and lymphoid tissues throughout the body, until they encounter dendritic cells within a lymph node or the spleen that display the antigens the T cells recognize. The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps that result in an increase in the number of antigen-specific T cells and the conversion of naive T cells to effector and memory cells cytokines stimulate the proliferation of the antigen-activated T cells, resulting in a rapid increase in the number of antigen-specific lymphocytes, a process called clonal expansion. Some of these activated lymphocytes undergo the process of differentiation, which results in the conversion of naive T cells into a population of effector T cells, which function to eliminate microbes. Many of the effector T cells leave the lymphoid organs, enter the circulation, and migrate to any site of infection, where they can eradicate the infection. Some effector T cells may remain in the lymph node, where they function to eradicate infected cells at that site or provide signals to B cells that promote antibody responses against the microbes. As effector T cells eliminate the infectious agent, the stimuli that triggered T cell expansion and differentiation also are eliminated. As a result, most of the cells in the greatly expanded clone of antigen-specific lymphocytes die, returning the system to a resting state, with memory cells being the cells remaining from the immune response. This sequence of events is common to CD4 + T lymphocytes and CD8 + T lymphocytes, although there are important differences in the properties and effector functions of CD4 + and CD8 + cells,

Complex I, II, III, IV, V

Flow of the ETC: 1. Complex I (NADH dehydrogenase) oxidizes NADH, and the electrons are passed to an electron carrier in the membrane called ubiquinone (UQ in the image; also known as coenzyme Q). During electron transport, energy from the electrons is used to pump protons from the matrix side to the inner membrane space. The NADH is provided by reactions catalyzed by PDH, beta oxidation or the TCA cycle, all of which occur in the mitochondrial matrix. 2. The reduced ubiquinone (UQH in the image) is oxidized by complex III. Again electrons are transported to another electron carrier, cytochrome C, a protein in the inter membrane space. As electrons are transported, more protons are pumped out of the matrix. 3. Cytochrome C is oxidized by complex IV. In this case the electrons are passed onto oxygen to yield water. As the electrons move, protons are again pumped out of the matrix. 4. Complex II can also contribute electrons to the chain. They may come directly from oxidation of succinate, as complex II is a component of the TCA cycle. Alternatively, they can come from FADH2 generated by beta oxidation. Complex II will reduce ubiquinone but it does not pump protons. 5. The proton pumping by complexes I, III and IV generates a proton gradient across the inner membrane (the membrane potential inside the matrix is negative relative to the other side). This creates an electrochemical gradient for protons to move back across through complex V (ATP synthase) , which generates ATP. -bidirectional enzyme so when ATP levels rise too high, it iwll tend to drive protons out the matirx, further increasing the magnitude of hte proton gradient (slowing the rate of electron transport by creating a steeper gradient)

What are the effects of insulin signaling on glycogen synthesis, glycolysis and fatty acid synthesis in liver cells?

Following a meal, insulin secretion is stimulated whereas glucagon secretion is inhibited. Epinephrine levels will typically be low due to the relative predominance of parasympathetic tone (rest and digest!). In the presence of insulin, tissues are stimulated to take up glucose, helping keep glucose levels constant. The uptake of glucose by muscle is especially important under these conditions, although both liver and adipose will also consume glucose. Liver and muscle will also take up amino acids and convert them to protein (muscle) or metabolize them to fat (liver). The liver will store some of the glucose as glycogen, but convert much of it to fat to make triglycerides. These are exported as VLDLs to adipose tissue. In the periphery, lipoprotein lipase is activated by insulin, stimulating the uptake of fatty acids from chylomicrons and VLDLs into fat cells. Note that the metabolism of glucose by the brain is not affected by the insulin/glucagon axis-it prefers to consume glucose if glucose is available, but can also get by on ketone bodies during starvation Note how acUvaUon of these pathways will consume glucose, helping keep blood glucose levels constant following a meal.

How does an increase in insulin signaling and a decrease in glucagon/epinephrine signaling favor glycolysis and glycogen storage in the liver in the fed state?

How does an increase in insulin signaling and a decrease in glucagon/epinephrine signaling favor glycolysis and glycogen storage in the liver in the fed state? in the fed state insulin is high and glucagon signaling is low. This will decrease the rate of faky acid release from adipocytes, thereby lowering acetyl CoA produc-on in the mitochondria. As a result, pyruvate will be consumed by pyruvate dehydrogenase; furthermore, pyruvate carboxylase will be less ac-ve. These effects have a strong inhibitor influence on the rate of gluconeogenesis. In addi-on, the high levels of F-2,6-BP will tend to inhibit fructose 1,6 bisphosphatase (preven-ng fu-le cycling from fructose 1,6-bisphphosate back to fructose 6- phosphate). Overall the rate of glycolysis is increased, and the pyruvate will be further metabolized to acetyl CoA by pyurvate dehydrogenase. The acetyl CoA will be used for faky acid synthesis. remember insulin activates a RTK which activates AKT which inhibits GSK3 which normally inhibits glycogen synthase

Why do macrophages accumulate excess cholesterol if LDL levels are elevated?

If LDL hangs out in the circulation, it gets oxidized. Monocytes migrate from the blood into tissues differentiating into macophages (which can be promoted by oxidation of LDL) can use scavenger receptors to recognized teh oxidized LDL (scavenger receptors are not regulated by cholesterol levels like LDLR) = Foam cells Foam cells have so much cholesterol that it perturbs their function, thereby releasing growth factors and metalloproteinases that lead to matrix degrataion

How are babies protected from infection in utero and during the first six months of life?

IgG antibodies thru the placent and then thru the breast milk Switching to the IgG isotype prolongs the duration an antibody lasts in the blood and therefore increases the functional activity of the antibody. The neonatal Fc receptor (FcRn) is expressed in placenta, endothelium, phagocytes, and a few other cell types.

Compare the types of antigens recognized by IgM vs. IgG antibodies, and explain why?

IgG: Switching to the IgG isotype prolongs the duration an antibody lasts in the blood and therefore increases the functional activity of the antibody.; class switch to IgG (and E, and A) depend on helper T cells that recognize the same antigen as B cells so since the T cells only recognize peptides derived from protein antigens, most IgG, E, and A antibodes are also specific for protein antigens IgM membrane bound antibodies will bind almost anything (germinal center activation). The antigen receptors of naive B lymphocytes, which are mature B cells that have not encountered antigen, are membrane-bound IgM and IgD. Some of the progeny of IgM and IgD expressing B cells may secrete IgM, and other progeny of the same B cells may produce antibodies of other heavy-chain classes Secreted IgA is a dimer and therefore has four antigen-binding sites, and secreted IgM is a pentamer, with 10 antigen-binding sites.

IgA

Immunoglobulin A is produced in mucosal lymphoid tissues, transported across epithelia, and binds to and neutralizes microbes in the lumens of the mucosal organs. Microbes often are inhaled or ingested, and antibodies that are secreted into the lumens of the respiratory or gastrointestinal tract bind to these microbes and prevent them from colonizing the host. This type of immunity is called mucosal immunity (or secretory immunity). The principal class of antibody produced in mucosal tissues is IgA. In fact, because of the vast surface area of the intestines, IgA accounts for 60% to 70% of the approximately 3 grams of antibody produced daily by a healthy adult. The propensity of B cells in mucosal epithelial tissues to produce IgA is because the cytokines that induce switching to this isotype, including transforming growth factor β (TGF-β), are produced at high levels in mucosa-associated lymphoid tissues, and the IgA-producing B cells are predisposed to home back to mucosal tissues. Also, some of the IgA is produced by a subset of B cells, called B-1 cells, which also have a propensity to migrate to mucosal tissues; these cells secrete IgA in response to nonprotein antigens without T cell help. also plays a role in neonate passive immunity thru the breast milk

What are the outcomes of initial (primary) tuberculosis? What are the risk factors for primary progressive tuberculosis?

In primary infection, airborne droplet nuclei reach the alveoli where multiplication begins. This primary infection usually involves the middle lung zone, where airflow is greatest. There, the bacteria are ingested by alveolar macrophages, which may eliminate small numbers of bacilli. However, M. tuberculosis multiplies mostly unimpeded, destroying the macrophage. During this early lymphohematogenous dissemination, the organisms preferentially localize in certain tissues, including lymph nodes, vertebral bodies, and meninges but most importantly the apices (upper parts) of the lungs. During the days and weeks before an effective cellular immune response develops, the organisms grow uninhibited in the initial pulmonary focus and the additional sites. Primary infection can have various outcomes. Cellular immunity and tissue hypersensitivity usually appear 3 to 8 weeks after infection and are marked by a positive tuberculin skin test. In most affected individuals, this response controls infection (although viable organisms may persist in the tissues), no symptoms develop, and the only evidence of infection is a positive tuberculin skin test. However, in some cases, the immune response does not control the primary infection, and progressive primary TB develops. This manifestation usually affects the very young, the elderly, and persons with advanced AIDS. In such individuals, the primary focus directly progresses to worsening pneumonia, and the very young may develop tuberculous meningitis. The most important consequence of lymphohematogenous dissemination is seeding of the lung apices, where either progressive primary or secondary disease can occur. Certain risk factors such as illicit drug use, excess alcohol use, homelessness, and HIV infection are interrelated and lead to an increased risk of both TB reactivation and transmission.

CTLA4

Proteins homologous to CD28 (found on T cells) also are critical for limiting and terminating immune responses. Thus, different members of the CD28 family are involved in activating and inhibiting T cells. The prototypes of the inhibitory receptors are CTLA-4, which, like CD28, recognizes B7-1 and B7-2 on APCs, and PD-1, which recognizes different but structurally related ligands on many cell types. Both CTLA-4 and PD-1 are induced in activated T cells, and genetic deletion of these molecules in mice results in excessive lymphocyte expansion and autoimmune disease. CTLA-4 and PD-1 are also involved in inhibiting responses to some tumors, and PD-1 inhibits responses to some chronic viral infections. These discoveries are the basis for the use of antibodies that block CTLA-4 or PD-1 to enhance immune responses to tumors in patients with cancer.

For each of the following amino acids, how would its amino groups end up in urea? Trace the steps involved (including transamination steps that might be required). Branched chain amino acid (leucine, valine, isoleucine)

Liver lacks the enzymes to catabolize the branched AA leucine, isoleucine, and valine so these pass thru the liver to go to the muscle as an alternative ENRG source (note here that then the amino group has to get back to the liver for the urea cycle) Note that both parts of this process use α-‐‐ ketoglutarate to accept amino groups and glutamate to donate amino groups. Also these reactions are thermodynamically reversible, as you can see from this example in which the reac;ons run in opposite directions with respect to the production of glutamate. 1. a transaminase that is specific for the branched chain amino acid transfers the amino group onto α-‐‐ketoglutarate to form glutamate and alpha-keto acid 2. A different amino transferase is used to transfer the amino group from glutamate onto pyruvate (note pyruvate is an α-‐‐keto acid). This regenerates α-‐‐ketoglutarate and produces alanine, which is then released into the blood stream to go to the liver 3. Alanine donates the amino back to alpha ketoglutarate to form glutamate in the liver, generating pyruvate and an alpha keto acid

What are the main structural and functional differences between MHC class I and class II molecules?

MHC Class I - α chain noncovalently associated with a protein called β 2 -microglobulin that is encoded by a gene outside the MHC. -The amino-terminal α1 and α2 domains of the class I MHC molecule form a peptide-binding cleft, or groove, that is large enough to accommodate peptides of 8 to 11 amino acids. -The floor of the peptide-binding cleft is the region that binds peptides for display to T lymphocytes, and the sides and tops of the cleft are the regions that are contacted by the T cell receptor. -The polymorphic residues of class I molecules, that is, the amino acids that differ among different individuals' MHC molecules, are located in the α1 and α2 domains -Some of these polymorphic residues contribute to variations in the floor of the peptide-binding cleft and thus in the ability of different MHC molecules to bind peptides. -Other polymorphic residues contribute to variations in the tops of the clefts and thus influence recognition by T cells. The α3 domain is invariant and contains the binding site for the T cell coreceptor CD8 but not CD4 MHC Class II consists of two chains, called α and β. -The amino-terminal regions of both chains, called the α1 and β1 domains, contain polymorphic residues and -form a cleft that is large enough to accommodate peptides of 10 to 30 residues. -The nonpolymorphic β2 domain contains the binding site for the T cell coreceptor CD4.

What does antigen processing accomplish?

MHC molecules are capable of displaying peptides, but not intact microbial protein antigens. Therefore, mechanisms must exist for converting naturally occurring proteins into peptides able to bind to MHC molecules. Extracellular proteins that are internalized by specialized APCs (dendritic cells, macrophages, B cells) are processed in endocytic vesicles and displayed by class II MHC molecules, whereas proteins in the cytosol of any nucleated cell are processed by cytoplasmic organelles and displayed by class I MHC molecules. These two pathways of antigen processing involve different cellular organelles and proteins. They are designed to sample all the proteins present in the extracellular and intracellular environments. The segregation of antigen-processing pathways also ensures that different classes of T lymphocytes recognize antigens from different compartments

Human leukocyte antigens (HLA)

MHC molecules expressed on the surface of human cells. first identified as alloantigens on the surface of white blood cells (leukocytes) that bound serum antibodes from individuals prveioulsy exposed to other individual's cells (eg mothers or transfusion recipients)

What cells are responsible for presenting MHC class I-restricted antigens to CD8 cells in the lymph node versus the periphery, and why is this important?

Macrophages, DCs, and B cells are responsible for presenting MHC Class 1 restricted antigens to CD 8 cells in the lymph modes (especially the DCs) because they express the receptors for the cytokines that create the chemotaxis gradient to the lymph nodes. this recognition provides the initiating, or first, signal for T cell activation. Also, One feature unique to CD8 + T cell activation is that its initiation often requires cytoplasmic antigen from one cell (e.g., virus-infected cells) to be cross-presented by dendritic cells so the DC has to take the viral peptide to the lymph node to activate the CD8. Another characteristic of CD8 + T cells is that their differentiation into fully active cytotoxic T lymphocytes (CTLs), and into memory cells, may require the concomitant activation of CD4 + helper T cells. When virus-infected cells are ingested by dendritic cells the APC may present antigens from the cytosol in complex with class I MHC molecules and from vesicles in complex with class II MHC molecules. Thus, both CD8 + T cells and CD4 + T cells specific for viral antigens are activated near one another in the lymph node. The CD4 + T cells may produce cytokines or membrane molecules that help to activate the CD8 + T cells. all infected nucleated cells present in the periphery to indicate to the CTLs that they need to be killed

How do you calculate the dosing rate for an oral drug or an IV drug?

Maintenance of dose Drugs are generally administered to maintain a steady-state concentra%on within the therapeu%c window. To achieve a given concentra%on, the rate of administra%on and the rate of elimina%on of the drug are important. It takes four to five half-lives of a drug to achieve steady-state systemic concentra%ons. The dosing rate can be determined by knowing the target concentra%on in plasma (Cp), clearance (CL) of the drug from the systemic circula%on, and the frac%on (F) absorbed (bioavailability), according to the equa%on above. For IV infusion, the bioavailability is 1, and the equa%on simplifies as shown.

What is the role of NADPH in fatty acid synthesis?

NADPH acts as the electron donors in the oxidation steps of the FA syn The B carbonyl is reduced to CH2 by a process that is similar to the reversal of B ox where first the keto group is reduced to a hydroxyl by NADPH, water is removed, and then resultant double bond is reduced by NADPH before hte acyl group is transferred from ACP to CE 2NADPH are required per acetyl added: to syn 1 mol of palmityl coA, 14 NADPH are needed (much supplied by PPP but some can be generated from OAA released by citrate lyase)

How do antibodies target the specific cell-mediated killing of infected cells?

Natural killer (NK) cells and other leukocytes may bind to antibody-coated cells and destroy these cells. NK cells express an Fcγ receptor called FcγRIII (CD16 - high Kd), which is one of several kinds of NK cell-activating receptors. FcγRIII binds to arrays of IgG antibodies attached to the surface of a cell, generating signals that cause the NK cell to discharge its granule proteins, which kill the opsonized cell. This process is called antibody-dependent cellular cytotoxicity (ADCC). Cells infected with enveloped viruses typically express viral glycoproteins on their surface that can be recognized by specific antibodies and this may facilitate ADCC-mediated destruction of the infected cells. ADCC is also one of the mechanisms by which therapeutic antibodies used to treat cancers eliminate tumor cells. Immunoglobulin E antibodies activate mast cell and eosinophil-mediated reactions that provide defense against helminthic parasites and are involved in allergic diseases. This IgE-mediated reaction illustrates how Ig isotype switching optimizes host defense. B cells respond to helminths by switching to IgE, which is useful against helminths, but B cells respond to most bacteria and viruses by switching to IgG antibodies, which promote phagocytosis by FcγRI (CD64, low Kd for IgG)

What is the difference between an essential and a nonessential amino acid? What about a glucogenic and ketogenic amino acid?

Nine amino acids are essential in humans. 'Essential' means that the carbon skeleton cannot be synthesized by the body, and therefore these amino acids can only be obtained from the diet. Arginine is only required during periods of growth and is not considered essential in the adult. What happens to the amino groups? The first step of catabolism is transamination. In this process, the amino groups from the amino acids are transferred to alpha ketoglutarate to make glutamate. Next, the glutamate may be oxidized to generate ammonia and alpha ketoglutarate, or the glutamate may undergo transamination to donate its amino group to oxaloacetate to generate aspartic acid. The ammonia and aspartic acid then enter the urea cycle. Therefore, all amino groups that end up in urea must transit through either glutamic acid, aspartic acid, or both. 1. get added to alpha ketoglutarate to make glutamate which will then become ammonia and alpha ketoglutarate 2.added to alpha ketoglutarate to make glutamate that will donate amino to make aspartic acid and alpha ketoglutarate. What happens to carbon skeletons (what defines glu vs. keto): The initial transamination reaction also yields a corresponding alpha-‐‐keto acid (carbon skeleton), which will then enter the TCA cycle, either as acetyl CoA (ketogenic amino acid) or any other TCA cycle component (glucogenic). Glucogenic carbon skeletons can be used to generate glucose, whereas ketogenic skeletons can be used to generate ATP or ketone bodies

Latency

Of an infection, a period in which the infection is present in the host without producing overt symptoms. The time that elapses between a stimulus and the response to it. In Lyme disease, stage 3 infection, In untreated patients, diverse objective manifestations of late stage Lyme disease can occur months to years after disease onset, reflecting the ability of the spirochete to establish a chronic infection in many tissue sites. Patients, particularly those in the United States, may suffer from repeated episodes of pauciarticular arthritis (i.e., arthritis involving a few joints), the most common presentation of late Lyme disease due to chronic infection of the joints. Another example of prolonged latency followed by appearance of clinical signs of persistent infection in Lyme disease is a late skin manifestation called acrodermatitis chronica atrophicans, which has been observed primarily in Europe after infection with B. afzelii. This skin lesion usually begins with bluishred discoloration and swollen skin on an extremity. Rarely, neuro symptoms are also latent TB can also be a latent bacteria

proteins of B. burgdorferi

OspA: a plasmid encoded, major outer surface protein (OspA) that, although not required for persistence in the tick vector, plays a critical role in protection of B. burgdorferi from antibodies present in the blood meal from immune hosts and may also promote tick midgut colonization by binding to tick midgut cell receptors. (in the tick) OpC: When the tick feeds on a mammalian host, the spirochetes are exposed to a higher temperature and to the contents of mammalian blood. In response, the spirochete undergoes a number of phenotypic changes. Most notably, expression of OspA decreases, and expression of OspC, a second outer surface protein encoded on a different plasmid, increases. An important example of the downregulation strategy is the seroreactive major outer surface protein OspC, which is expressed on the B. burgdorferi surface in feeding ticks and is required for the spirochete to initiate infection in the mammal. The protein is no longer required after day 8 of infection, and expression of the ospC gene is rapidly downregulated. downregulation of ospC expression is essential for B. burgdorferi to persist in the mammalian host Plasmin proteases: During the blood meal, the spirochetes replicate and invade the gut wall to spread throughout the tick, including to the salivary glands. Interestingly, the host protease plasmin, present in ingested blood, binds to and becomes activated on the bacterial surface and is required for efficient tick dissemination. VisE: Production of the outer surface protein VlsE is increased concomitant with the decrease in OspC production, and VlsE shares some general structural features with OspC. Unlike OspC, however, VlsE is subject to continual antigenic variation during an active infection, providing a mechanism for immune evasion while allowing sustained production of the protein.

How do different classes of antibodies protect us from toxins and from microbial pathogens?

a. IgG: Neutralize toxins and microbes, opsonize microbes, classical pathway complement activation, ADCC, neonatal immunity. b. IgM: classical pathway complement activation. c. IgA: mucosal immunity by neutralizing toxins and microbes. d. IgE: immediate hypersensitivity via mast cell degranulation, defense against helminth infection via eosinophils.

PD-1

Proteins homologous to CD28 also are critical for limiting and terminating immune responses. Thus, different members of the CD28 family are involved in activating and inhibiting T cells. The prototypes of the inhibitory receptors are CTLA-4, which, like CD28, recognizes B7-1 and B7-2 on APCs, and PD-1, which recognizes different but structurally related ligands on many cell types. Both CTLA-4 and PD-1 are induced in activated T cells, and genetic deletion of these molecules in mice results in excessive lymphocyte expansion and autoimmune disease. CTLA-4 and PD-1 are also involved in inhibiting responses to some tumors, and PD-1 inhibits responses to some chronic viral infections. These discoveries are the basis for the use of antibodies that block CTLA-4 or PD-1 to enhance immune responses to tumors in patients with cancer.

What reaction is catalyzed by pyruvate carboxylase? How is the activity of this enzyme regulated? What is the connection to fatty acid metabolism?

Pyruvate carboxylase is a mitochondrial enzyme that converts pyruvate to oxaloacetate, in a reac-on that consumes ATP and bicarbonate. Like other reac-ons that involve carboxyla-on, it requires the cofactor bio-n. Acetyl CoA is an important posi-ve regulator of pyruvate carboxylase, and as we will see it also inhibits the major enzyme that consumes pyruvate, pyruvate dehydrogenase. When fatty acids are metabolized, they create acetyl coa (when insulin drops and glucagon/epi rise, rate of fatty acid release by the adipocytes increases). Therefore, the rise in acetyl CoA is an important signal that promotes the rate of gluconeogenesis.

What are the main routes by which pyruvate can be metabolized in the body?

Pyruvate dehydrogenase catalyzes the removal of carbon dioxide from pyruvate. This provides an important mechanism for generating energy, as the acetyl CoA can be further oxidized by the citric acid cycle (also known as the tricarboxylic acid cycle or Kreb's cycle). The acetyl coA can also be used to make fats. Thus PDH provides a mechanism for turning glucose or amino acids (through pyruvate) into fat. However, human cells do not possess a mechanism for going the other direction! There is no way to convert acetyl CoA into pyruvate. What this means is that this is a one way street, and thus you cannot make glucose from fats (or technically speaking, from the faTy acids; the glycerol from the TG can be used to make fat because it can be converted to pyruvate). That's why during starvaUon, when fats are the only fuel available, the body begins making ketone bodies pyruvate decarboxylase turns pyruvate into OAA (for FA syn or gluconeo) can become alanine thru transaminase

acetyl coa carboxylase

RLS of FAT syn - inactive when phosphorylated (makes sense bc insulin stimulates this) present in inactive form as a dimer in the cytoplasm Allosteric: activation: citrate (what is cleaved in the cytoplasm to create acetyl coa) causes the enxyme to polymerize into active form to produce malonyl coa inhibition: long chain FA causes inactivation and depolymerization (product inhibition) Phosphorylation: PKA (AKA camp dependent protein kinase)- phosphorylates and inactiavtes (glu/epi) insulin reverses cAMP dependent phosphorylation and activates the ACC parallels the regulation of glycogen synthase

HMG-CoA reductase

RLS of producing cholesterol from acetyl coA

In general, what are the main regulators of the TCA overall?

Rate of oxidation thru the TCA is tightly coupled to rate of mito ox and ETC -If NADH accumulates or ATP accumulates, TCA will slow/stop -OAA is limiting (flux can be increased by increasing OAA) *** if acetyl CoA accumulates but ATP is low -> OAA created for TCA *** if acetyl CoA accumlates and ATP is high -> OAA will be used to make glucose (what happens in liver fasting state) -> this is also good because gluconeo will use up the NADH accumulation which will prevent the ETC from slowing down and ROS from forming at complexes 1 and 3

How and why does resistance to targeted therapy develop? How could this potentially be avoided?

Resistance develops as a result of selection for subclones with additional mutations that block or reduce the activity of the drug, e.g. T790M mutation in EGFR inhibition. In theory, this could be avoided by combination with therapeutic strategies that don't select for (ideally, that would select against) the resistant subclone(s), such as checkpoint blockade immunotherapy.

Catalase/coagulase

S. aureus secretes many enzymes and toxins that are almost certainly directed toward the struggle with phagocytes. Catalase converts hydrogen peroxide to water and may help counteract the neutrophils' ability to kill bacteria by the production of oxygen free radicals. Coagulases convert fibrinogen to fibrin and may help prevent the organisms from being phagocytized, since white cells penetrate fibrin clots poorly.

What are the major toxin-mediated diseases caused by Gram-positive cocci?

S. aureus: many strains of the bacterium secrete potent exotoxins that can cause signs of illness at sites distant from the bacterial infection. These illnesses include toxic shock syndrome (TSS), caused by toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxin serotypes A through X; staphylococcal scalded skin syndrome (SSSS), caused by exfoliative toxin serotypes A and B; and staphylococcal food poisoning (SFP), caused by ingestion of staphylococcal enterotoxin serotypes A through E and I. Staphylococcal enterotoxin F was renamed TSST-1 because of its association with TSS and its lack of ability to cause food poisoning. TSS is a serious condition that results from focal infections at any body site by toxin-producing S. aureus, but vaginal mucosal and respiratory infections are most likely to lead to the illness. SSSS, another serious illness, occurs most often in neonates who have acquired focal infections, often of the upper respiratory tract, by exfoliative toxin-producing staphylococci. SSSS characterized by extensive sloughing of the skin. Two exotoxins, known as exfoliative toxins A and B, cause these symptoms. Exfoliative toxins are highly tissue-specific serine proteases that cause separation of the layers of the epidermis at the desmosomes. Exfoliative toxin production by S. aureus does not contribute to systemic infections by the bacteria.

bacterial serotyping

Serotypes are groups within a single species of microorganisms, such as bacteria or viruses, which share distinctive surface structures. ex. Group A Strep Rebecca Lancefield first used serological reactivity to extracted cell wall antigens from various streptococci/enterococci to divide them into groups lettered A through U. Many streptococcal species cannot be assigned to any group because there are no antisera that react to their cell wall antigens.- one way to distinguish them

What is the clinical significance of MHC polymorphism for and why did it evolve on population basis?

Some people are able to present peptides to T cells that other people are not such that they can mount an immune defense that some people cannot mount. Variability protects the population as a whole. Because the polymorphic residues determine which peptides are presented by which MHC molecules, the existence of multiple alleles ensures that there are always some members of the population who will be able to present any particular microbial protein antigen. MHC polymorphism may have evolved because it ensures that a population will be able to deal with the diversity of microbes and at least some individuals will be able to mount effective immune responses to the peptide antigens of these microbes. Thus, everyone will not succumb to a newly encountered or mutated microbe.

Lck

Src family nonreceptor tyrosine kinase that noncovalently associates with the cytoplasmic tails of CD4 and CD8 molecules in T cells and is involved in the early signaling events of antigen-induced T cell activation. mediates tyrosine phosphorylation of the cytoplasmic tails of CD3 and zeta proteins of the TCR complex

What are the manifestations of Lyme disease?

Stage 1- localized infection The ability of B. burgdorferi to multiply and establish infection in the skin of the mammalian host is reflected in one of the characteristic signs of localized infection or stage 1 Lyme disease in humans, the erythema migrans rash The spirochetes are highly motile (flagella) and probably still coated with the host protease plasmin; thus, over a period of days, they are able to spread through the skin, resulting in expansion of the rash, leaving a blanched central area, and a bull'seye appearance. Stage 2- disseminated infection Some but not all strains of B. burgdorferi are capable of further multiplication and dissemination in humans in the following days to weeks, spreading to multiple tissues, including the nervous system, musculoskeletal tissues, and the heart. This stage is known as early disseminated infection or stage 2 Lyme disease. Stage 3- Late stage Later, in late stage or stage 3 Lyme disease, the rate of bacterial multiplication appears to be significantly reduced or is kept in check by the host defenses, resulting in the very low number of bacteria present in tissues. These bacteria, however, are not eradicated by the host immune response. Although the bacterial properties that allow the spirochete to cause infection in a variety of tissues are still being defined, adherence of the spirochete to host cells and extracellular matrix (ECM) is likely one critical factor in colonization of diverse tissues. In vitro studies have demonstrated that B. burgdorferi utilizes several binding pathways to attach to diverse cell types and to ECM. Spirochetal binding to cells and ECM can be mediated by recognition of glycosaminoglycans,

What is GAS?

Streptococcus pyogenes, also known as the group A streptococcus (GAS), are best understood in terms of mechanisms of disease Historically, the group A streptococci (GAS;S. pyogenes) have been the most important pathogens to humans in the streptococcal family. primarily presents as acute pharyngitis, or "strep throat." The other common site of infection is in the skin and soft tissues, resulting in a group of infections called pyoderma. The delayed nonsuppurative (immune-based) sequelae of GAS infection, acute glomerulonephritis (AGN) and acute rheumatic fever (ARF), are more commonly encountered in developing countries, probably because of frequency of disease and poor access to medical care.

What are the substrates and products of pyruvate dehydrogenase? How do the levels of the substrates and products affect the activity of the enzyme?

Substrates: pyruvate, NAD+, CoA Products: Acetyl CoA, NADH, CO2 The activity of the enzyme is stimulated by its substrates and inhibited by its products - DIRECT INHIBITIION:NADH and Acetyl CoA directly inhibit (product inhibition) - INDIRECT INHIBITION: In addition, these metabolites regulate the phosphorylation state of the enzyme: PDH is inactive when phosphorylated, and active when dephosphorylated. The kinase responsible is called pyruvate dehydrogenase kinase (PDK) -> mitochondrial matrix. NADH and acetyl CoA stimulate the kinase, turning off PDH -INDIRECT STIMULATION: the substrates of the enzyme, including pyruvate, NAD+, and CoA, all inhibit the kinase, leading to activation of PDH. -IN MUSCLES: calcium increases can stimulate activity of a phosphatase that will activate PDH ADP stimulates PDH as high ADP indicates need for more energy

What are the key steps in fatty acid synthesis, and what would be the metabolic consequences of inhibiting these steps?

Synthesis of malonyl CoA by acetyl CoA carboxylase (ACC) and synthesis of fatty acids by fatty acid synthase (FAS). Inhibiting ACC (activated by citrate and insulin; inhibitors are long chain FA and glucagon so telling you that inhibiting it will lead to burning of fat) may lead to activation of beta oxidation as well as inhibiting fat synthesis, so may help boost oxidation of fats. - way to make a weight loss pill Inhibiting FAS enzyme would be predicted to block fat synthesis but perhaps not activate beta oxidation, as malonyl CoA would accumulate which would inhibit CAT1. Inhibiting FAS may be useful in other contexts, however, such as in blocking proliferation of cancer cells that rely on synthesis of new lipids (phospholipids) for cell growth. FAS is regulated by the P13k/AKT pathway and the RAS-MAP-kinase pathway- so influenced by growth factor signaling

ABO antigens What types of antibodues are formed and why?

T cell independent B cell response -> IgM -always first response

How do B and T lymphocytes differ in the types of antigens they recognize and the way they "see" antigen?

T cells recognize peptides presented by MHC (class 1 or 2) molecules B cells recognize almost all molecules (lipids, etc.) The antigen receptors of B lymphocytes—namely, membrane-bound antibodies—can recognize a variety of macromolecules (proteins, polysaccharides, lipids, nucleic acids), in soluble form or cell surface-associated form, as well as small chemicals. Therefore, B cell-mediated humoral immune responses may be generated against many types of microbial cell wall and soluble antigens. The antigen receptors of most T lymphocytes, on the other hand, can see only peptide fragments of protein antigens, and only when these peptides are presented by specialized peptide display molecules on host cells. Therefore, T cell-mediated immune responses may be generated only against protein antigens that are either produced in or taken up by host cells.

How is gonorrhea diagnosed and treated?

a. PCR and molecular tests diagnose gonorrhea. Gram stain of urethral exudate can be used for men. There are other Neisseria species found in the vagina of women, so gram stain is not useful. Genital and extra-genital infections can be diagnosed by culture. b. Gonorrhea is treated with cephalosporin or intramuscular ceftriaxone. Simulteanous treatment with azithromycin or doxycycline is recommended to reduce emergene cand possible co-infection with C. trachomatis.

What are the benefits of targeted therapy as opposed to conventional chemotherapy? What are the risks? What factors determine whether a patient will (or will not) benefit from a particular targeted therapy?

Targeted therapy is more selective than conventional chemotherapy, and generally has fewer adverse effects (doesn't affect healthy tissues as much). However, nearly all patients develop resistance due to selection for resistant subclones (see question 4). Benefit is predicted by the presence of the targeted mutation, lack of downstream mutations that bypass the target (e.g. KRAS mutation for EGFR inhibitors), histology, and epidemiologic factors.

immune desfense against which types of infections dpends on Th1 cells and how do the Th1 cells work to clear them?

Th1 cells help clear intravellular pathogens by secreting cytokines that induce classical macrophage activation kids exposed to leishmania didn't get sick (macrophages activated) and high levels of IgG

defense against which types of infections depend on Th17 responses or on Il-17 and what does il-17 do?

Th17 cells help protect from extracellular bacteria by secreting cytokines which augment inflammation and increase production of anti-microbial peptides at epithelial surfaces

immune defense against which types of infections depend on Th2 cells and how do they work to clear the infections?

Th2 cells recruit eosinophils (via Il-5) and mast cells (via IgE isotype switching) which secrete toxic products to kill helminths

What are the advantages and disadvantages of the inactivated and oral poliovirus vaccines?

The 1997 recommendation of the Advisory Committee on Immunization Practice was for two doses of killed vaccine followed by two doses of live vaccine. This provides a safer vaccination protocol with the advantages of both types of vaccines. In 1999 the ACIP recommended four doses of IPV at 2, 4, 6-18 month and 4-6 years.

ABO antigens consist of what types of moiety (chemical structures)?

The ABO blood group system is controlled by genes which code for enzymes that attach different sugars to the oligosaccharide end of glycoproteins or glycolipids present on the membrane of RBCs, platelets, lymphocytes, endothelial cells and epithelial cells.

How has poliovirus infection been eliminated from many countries?

The Americas were declared free of indigenous wild poliovirus in 1994. The remaining 10 cases per year of poliomyelitis in US were vaccine-related As a result of an international immunization campaign using the live vaccine, wild poliovirus was eliminated from the Western Hemisphere in 1994. Worldwide, the campaign led by the WHO has resulted in a reduction of poliomyelitis cases to 667 in 2003, down 100 fold from 1988. However, wars and resistance from some tribal and religious leaders to the immunization program have led to pockets of infection that have been hard to eliminate. The number of cases rose in 2004 (1189) and 2005 (1831), declined to 223 by 2012, but rose to 406 in 2013. According to the data provided by the Global Polio Eradication Initiative, there were a total of 359 cases of WPV associated polio reported globally in 2014, of which 340 (95 percent) occurred in the 3 remaining endemic countries -- Afghanistan, Nigeria and Pakistan ((90 percent) were reported byPakistan) At this time, endemic wildtype poliovirus has been eliminated from all but 2 countries, Pakistan and Afghanistan. Wild poliovirus has been re-introduced into various countries, notably Somalia with 190 cases in 2013. The goal remains to eradicate poliovirus from the world.

What is the relative importance of the TCA cycle in generating NADH/FADH2 in the liver in the fasting state, the fed state, or when the liver is primarily oxidizing glucose?

The TCA cycle is not as important in the fasting state due to high rates of beta oxidation- the liver is meeting its NADH/FADH2 needs thru beta ox so OAA can be used to make gluconeo for the brain (coa supplied by formation of ketone bodies after 2 days of fasting). - lowest TCA contribution (becomes depleted) It is also not as critical in the fed state following a high carbohydrate meal as PDH is highly active, generating NADH. (beta ox is also inhibited as you are making fat from excess glucose and malonyl coa will inhibit CAT1); TCA is lower because the citrate is being shipped out to supply ACC with OAA/acetyl coa (slow glucose) The TCA cycle is most critical under conditions where the cell is fully oxidizing acetyl CoA provided by either PDH or beta oxidation. This might occur under conditions of limiting glucose availability in the liver or in exercising muscle. - muscle doesn't make fat so it will burn thru beta ox if it has mito and will burn glucose if it has that (or is slow twitch)

How can the process of ischemia and reperfusion lead to hte production of ROS? How can we intervene therapeutically to minimize these effects?

The TCA cycle is regulated allosterically at the 3 irreversible steps: citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Ischemia leads to accumulation of succinate via accumulation of NADH—a result of the TCA cycle moving backwards in its later steps. Without oxygen, so ETC stops and electron carriers are saturated. But succinate dehydrogenase (complex II) is reversible so you allow the carriers to dissipate their electrons by allowing fumerate to carry them away (fumerate comes from other pathways) to make succinate and you get high levels of succinate in the blood during ischemia. COenzyme Q is driving this thermodynamically because it desperately want to put its e- somewhere (drive is from e- putting the TCA in reverse to release saturation)- the enzyme succinate drhydrogenase (complex II) is NOT driving this (Coenzyme Q is) which is why we didn't see much happen with the inhibitor w/o O2 Upon reintroduction of oxygen, the accumulated succinate drives more electrons into the electron transport chain - Q will preferentially take from teh built up succinate at complex II, such that complex I cannot transport electrons (they are saturated because Q is ignoring them). The accumulated electrons move onto oxygen to produce ROS (this is a place where O2 can make ROS, the other is complex III). w/o O2, electrons are safely in their carriers (but cannot make ATP), but re-introducing O2 allows electrons to have a place to go -> ROS Inhibiting succcinate dehydrogenase, and thus blocking succinate accumulation, may be an effective way of preventing reperfusion injury.

What are the two general patterns of manifestations of sexually transmitted infections?

a. Some pathogens (Neisseria gonorrhoeae and Chlamydia trachomatis) cause non-ulcerating infection of genital mucosa (urethra of men and cervix of women). In women, it can be asymptomatic or cause mild discomfort and vaginal discharge. In men, STIs can cause symptomatic urethritis. b. Other pathogens (Treponema pallidum or syphilis) cause a focal infection of the skin or mucosa resulting in a local lesion and lymphadenopathy (disease affecting the lymph nodes, often in the groin area). c. Most pathogens can spread from initial site of infection.

What is the relevance of the TCA cycle to amino acid catabolism and glucose production?

The carbon skeletons of many amino acids can be converted into a TCA cycle intermediate. Subsequently, glucogenic AA carbon skeletons can be converted into oxaoloacetic acid using steps in the TCA cycle. Therefore, the use of oxaloacetic acid as a key intermediate in gluconeogensis connects amino acid catabolism and glucose synthesis. All of the amino acids in blue can contribute to net glucose production. The ones in yellow contribute to acetyl coA generation. The ketogenic AA can support energy needs of the cell but they cannot support net glucose production (for the same reason that faJy acids cannot). Note that some of the amino acids are both blue and yellow as they can contribute to both.

By what mechanisms does antibody cooperate with complement to protect against infections?

The classical pathway, is initiated by certain isotypes of antibodies attached to antigens. The most abundant complement protein in the plasma, C3, plays a central role in all three pathways. C3 is spontaneously hydrolyzed in plasma at a low level, but its products are unstable, rapidly broken down, and lost. The classical pathway of complement activation is triggered when IgM or certain subclasses of IgG (IgG1, IgG2, and IgG3 in humans) bind to antigens (e.g., on a microbial cell surface). As a result of this binding, adjacent Fc regions of the antibodies become accessible to and bind the C1 complement protein (which is made up of a binding component called C1q and two proteases called C1r and C1s). The attached C1 becomes enzymatically active, resulting in the binding and sequential cleavage of two proteins, C4 and C2. C4b (one of the C4 fragments) becomes covalently attached to the antibody and to the microbial surface where the antibody is bound, then binds C2, which is cleaved by active C1 to yield the C4b2a complex. This complex is the classical pathway C3 convertase, which functions to break down C3, and the C3b that is generated again becomes attached to the microbe. Some of the C3b binds to the C4b2a complex, and the resultant C4b2a3b complex functions as a C5 convertase, which cleaves the C5 complement protein. Late steps of complement activation are initiated by the binding of C5 to the C5 convertase and subsequent proteolysis of C5, generating C5b ( Fig. 8-8 ). The remaining components, C6, C7, C8, and C9, bind sequentially to a complex nucleated by C5b. The final protein in the pathway, C9, polymerizes to form a pore in the cell membrane through which water and ions can enter, causing death of the microbe. This poly-C9 is the key component of the membrane attack complex (MAC), and its formation is the end result of complement activation. the complement system provides stimuli for the development of humoral immune responses. When C3 is activated by a microbe by the alternative pathway, one of its breakdown products, C3d, is recognized by complement receptor type 2 (CR2) on B lymphocytes. Signals delivered by this receptor stimulate B cell responses against the microbe. This process is described in Chapter 7 (see Fig. 7-5 ) and is an example of an innate immune response to a microbe (complement activation) enhancing an adaptive immune response to the same microbe (B cell activation and antibody production). Complement proteins bound to antigen-antibody complexes are recognized by follicular dendritic cells in germinal centers, allowing the antigens to be displayed for further B cell activation and selection of high-affinity B cells. This complement-dependent antigen display is another way in which the complement system promotes antibody production.

Why is ketoacidosis more likely to occur in patients with Type I diabetes than Type II diabetes? Insulin levels are lower in patients with Type I diabetes. Patients with Type II diabetes metabolize ketone bodies faster so they don't accumulate Insulin resistance in Type II diabetes leads to accelerated utilization of ketone bodies by muscle. Insulin resistance in the liver suppresses ketone body generation.

The development of ketoacidosis requires a very low insulin state that is much more likely to occur in Type I diabetes (failure of insulin production) compared to Type II diabetes (insulin resistance). There is no evidence that patients with Type II metabolize ketone bodies faster, or that insulin resistance would lead to increased use of ketone bodies by muscle. Answer D is wrong in that insulin resistance, if anything, might be expected to promote ketone body generation. The essential idea is that lack of insulin leads to unrestrained release of fatty acids from adipocytes, which then return to the liver to drive ketone body formation.

IL-12

The differentiation of CD4 + T cells to the T H 1 subset is driven by a combination of the cytokines IL-12 and IFN-γ (see Fig. 5-18 ). In response to many bacteria (especially intracellular bacteria) and viruses, dendritic cells and macrophages produce IL-12, and NK cells produce IFN-γ. When naive T cells recognize the antigens of these microbes, the T cells are exposed to IL-12 and IFN-γ. These two cytokines activate transcription factors that promote the differentiation of the T cells to the T H 1 subset. T H 1 cells produce IFN-γ, which not only activates macrophages to kill the microbes, but also promotes more T H 1 development and inhibits the development of T H 2 and T H 17 cells. Thus, IFN-γ increasingly polarizes the response to the T H 1 subset.

superantigens

The exotoxins involved in TSS include toxic shock syndrome toxin-1, the cause of all menstrual TSS cases and one-half of nonmenstrual cases, and staphylococcal enterotoxins, particularly enterotoxin serotypes B and C. These three exotoxins are produced by the bacteria in high concentrations, and that may be why they cause TSS. The toxins have been referred to as superantigens because of their novel way of interacting with T lymphocytes and macrophages. Superantigens cross-link one chain (β-chain) of the T-cell antigen receptor with major histocompatibility complex class II molecules on macrophages. The effect of this interaction is a massive release of cytokines from macrophages and T cells that mediate TSS.

How does the innate immune system influence the type of T helper effector response?

The generation of these subsets is regulated by the stimuli that naive CD4 + T cells receive when they encounter microbial antigens ( Fig. 5-18 ). Several important principles underlie these differentiation pathways. First, each subset is induced best in response to the types of microbes that subset is designed to combat. These are excellent examples of how the adaptive immune response is specialized to protect against an enormous variety of microbes. Second, the most important signals for the differentiation of naive CD4 + T lymphocytes into distinct subsets of effector cells are cytokines produced by APCs and other cells at the time of antigen stimulation. The set of cytokines secreted by the APCs will vary depending on the types of microbes; therefore the pathways of CD4 + T cell differentiation and the subsets of effector T cells generated are determined by the nature of the infection. Third, each effector T cell subset produces cytokines that amplify itself and inhibit the other subsets. Thus, each type of response becomes increasingly polarized with prolonged stimulation. Fourth, the differentiation of these subsets is associated with the activation of transcription factors that stimulate production of various cytokines. Also, epigenetic changes in cytokine gene loci result in commitment to a particular cytokine profile and therefore to a distinct subset.

Capsid

The genome is protected within a protein coat called the capsid, and the genome plus capsid is called the nucleocapsid. Capsids are usually of two forms, icosahedral (symmetry derived from an icosahedron or a structure formed from 20 triangular faces) or helical, although occasionally they are more complex structures (e.g., poxviruses). symmetry of capsid (helical, icosahedral or complex) is a criterion for the classification of viruses

How does B. burgdorferi damage the human host?

The host immune response to the B. burgdorferi infection causes injury to the host tissues. Stage 1 Local skin infection at the tick bite site results in erythema migrans, which reflects infiltration of lymphocytes and macrophages. Stage 2. Disseminated infection (stage 2) includes transient colonization of the bloodstream. At this stage some degree of vascular damage, including mild vasculitis or hypercellular vascular occlusion, may be seen in multiple sites, suggesting that the spirochetes colonize the vessel wall. In fact, microscopic analysis of mice infected with fluorescently labeled B. burgdorferi has demonstrated that the spirochete attaches to the vessel wall in stages, first transiently binding, then stably binding, followed by penetration of the endothelium and localization in the underlying tissue. Stage 2 of disease is often heralded by signs and symptoms reflecting colonization of the skin, nervous system, heart, and musculoskeletal sites, such as secondary erythema migrans lesions, excruciating headache, mild neck stiffness, and migratory pain in joints, bursae, tendons, muscle, or bone. Neurologic abnormalities can include meningitis and neuritis. Inflammatory manifestations of ocular infection can include conjunctivitis, iritis, choroiditis, or panophthalmitis. Cardiac involvement may result in fluctuating degrees of atrioventricular block or myopericarditis. These clinical manifestations are likely to be a result of direct infection of the affected tissue, because spirochetes have been detected in or recovered from most of these sites during this stage of the illness B. burgdorferi is not known to produce toxins that directly damage any tissue. Rather, the spirochete persists in infected tissues and thereby elicits an immune response that causes "bystander" injury to the host.its genome encodes an unusually large number of lipoproteins, which are potent stimulators of proinflammatory cytokine production via tolllike receptors. Moreover, it has recently been demonstrated that the intracellular pattern recognition receptor NOD2, which recognizes muramyl dipeptide (MDP), a component of the cell wall of Gramnegative and Grampositive bacteria, is important for recognition of B. burgdorferi and induction of cytokine production by human peripheral blood mononuclear cells following exposure to the spirochete. Consistent with this, infected tissues show an infiltration of lymphocytes and macrophages, and sometimes plasma cells and/or neutrophils.

How is B. burgdorferi infection acquired by humans?

The infection is acquired by the bite of an infected deer tick. Humans are "accidental" hosts for B. burgdorferi because spirochetes from infected people are not transmitted to other hosts. In most cases, small vertebrates, such as the whitefooted mouse, participate with the Ixodes sp. (deer) tick to maintain the reservoir. Ixodes scapularis ticks are the arthropod vectors that transmit the spirochete Borrelia burgdorferi to humans causing Lyme disease

How can M. tuberculosis be detected in patient samples?

The initial diagnostic approach includes a careful history, direct examination of sputum or exudates, and a chest radiograph. Direct examination of sputum can yield a rapid presumptive diagnosis. Importantly, contagiousness correlates with sputum smear positivity. Acidfast stains are rapid and relatively sensitive, especially with cavitary pulmonary TB. The yield increases by examining sputa collected on three separate days. Early morning sputa have the best yields because pulmonary secretions accumulate during sleep. Acid fast staining must be used in microscopy The gold standard for diagnosis of TB is culture.Detection of colonies on solid media usually takes 3 to 6 weeks. Radiometric culture techniques accelerate the diagnosis by early detection of radioactive CO released by organisms metabolizing Clabeled palmitic acid, providing results within 7 to 14 days. If growth of tubercle bacilli occurs, it is important to test for antibiotic susceptibility. Overall, the process may take 6 or more weeks. More sensitive nucleic acid amplification methods for rapid diagnosis are occasionally used in practice but have not replaced smear and culture.

first pass effect

The liver is the main organ of drug metabolism. Orally administered drugs are oJen absorbed in the gastrointes%nal (GI) tract and transported directly to the liver via the portal circula%on. In this manner, the liver has the opportunity to metabolize drugs before they reach the systemic circula%on. must be taken into account when designing dosing regimens because, if hepa%c metabolism is extensive, the amount of drug that reaches the target %ssue is much less than the amount (dose) that is administered orally. One such drug is the an%arrhythmic drug lidocaine, which has a bioavailability of only 3% when taken orally (must be given parenterally) . Par%cularly ac%ve sites include the skin, the lungs, the gastrointes%nal tract, and the kidneys. The gastrointes%nal tract deserves special men%on because this organ, like the liver, can contribute to the first-pass effect by metabolizing orally administered drugs before they reach the systemic circula%on In contrast, drugs that are administered intravenously (IV), transdermally, or subcutaneously enter the systemic circula%on directly and can reach their target organs before hepa%c modifica%on

What are the major histopathologic types of lung cancer? How has this classification changed over time, and why?

The major histopathologic subtypes are adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Until recently, the first two (and most other types except for small cell) were lumped together as "non-small cell carcinoma". However, this classification is no longer standard of care since adenocarcinoma is more likely to contain targetable mutations and respond to targeted therapy (particularly EGFR inhibition), and since angiogenesis inhibitors are contraindicated in squamous cell carcinoma because of the risk of pulmonary hemorrhage.

acute rheumatic fever

The most feared sequela (nonsuppurative sequelae (non-pus-forming secondary manifestations)) of GAS infection is acute rheumatic fever, a significant cause of valvular heart disease in the preantibiotic era and now in developing countries. Pharyngitis is the only type of streptococcal infection that can lead to ARF. The clinical manifestations of ARF (known as the Jones Criteria) appear 1 to 4 weeks following strep throat and may include carditis, polyarthritis, chorea (a neurological tic disorder resulting in uncontrollable dancelike movements), subcutaneous nodules, and a distinctive rash called erythema marginatum. The most common manifestations are carditis and polyarthritis. Eventually, all these acute manifestations resolve. The primary reason streptococcal pharyngitis is treated with antibiotics is to prevent ARF and the permanent heart damage that may follow the acute carditis. The ongoing inflammation in the heart can lead to extensive mitral and/or aortic valvular scarring and stenosis. This manifestation, called "rheumatic heart disease," the most compelling evidence suggests that ARF may be an autoimmune disease in which the body's own tissues are attacked by the immune system in a misguided attempt to eradicate the streptococci. GAS possess a number of surface constituents that appear immunologically identical to host tissue components. In particular, there is immunological cross-reaction between GAS antigens (such as certain M proteins) and tissues in the heart, synovium, and neurons in the brain. Such GAS M-types (called rheumatogenic strains) are more frequently associated with ARF

acute poststreptococcal glomerulonephritis (APSGN)

The other important nonsuppurative sequela of GAS infection caused by only a few M-types. Unlike ARF, APSGN may follow either a pharyngitis or pyodermal infection. Also unlike ARF, treatment with antibiotics does not affect the occurrence of this complication. In some outbreaks, the attack rate of APSGN has been as high as 40%, suggesting that susceptibility is common, if not universal. The pathogenic mechanism of APSGN is also incompletely understood, but it is thought that immune complexes consisting of streptococcal proteins and antibodies are deposited in the glomerular basement membrane and lead to complement fixation with subsequent renal injury. Like ARF, APSGN usually occurs 1 to 4 weeks after an infection. Patients with APSGN have blood and elevated protein in their urine, and they may go on to renal failure and require dialysis.

Why do we treat group A streptococcal infections?

The primary reason streptococcal pharyngitis is treated with antibiotics is to prevent ARF and the permanent heart damage that may follow the acute carditis. People who have had ARF are susceptible to further exacerbations when they acquire subsequent streptococcal pharyngitis. The ongoing inflammation in the heart can lead to extensive mitral and/or aortic valvular scarring and stenosis. This manifestation, called "rheumatic heart disease," leading ultimately to death from heart failure if the affected valves are not replaced. Furthermore, the turbulent flow of blood across a scarred or deformed valve can predispose to bacterial endocarditis. Fortunately, ARF and rheumatic heart disease can be prevented by eradicating the bacteria with antibiotics before a fulminant immunological response is mounted. This is the most critical reason for diagnosing and treating strep throat aggressively. Studies have shown that treatment with a full course of penicillin initiated up to 9 days after the onset of sore throat can effectively prevent ARF. Failure to complete a full course of treatment may result in ARF. Patients who develop ARF are usually given prophylactic antibiotics until well into adulthood or even for life to prevent repeat streptococcal infections that will inevitably worsen any ongoing heart damage

What is the determinant of the rate that a drug approaches steady state?

The sole determinant of the rate that a drug approaches steady state is the t1/2, and this rate is influenced only by the factors that affect the half-life. The rate of approach to steady state is not affected by the rate of drug infusion. Although increasing the rate of drug infusion concomitantly increases the rate at which any given concentra%on of drug in the plasma is achieved, it does not influence the %me required to reach the ul%mate steady-state concentra%on. This is because the steady-state concentra%on of drug rises directly with the infusion rate. The drug concentra%on is 90 percent of the final steady-state concentra%on in 3.3 %mes t1/2. Thus, a drug will reach steady state in about four half-lives.

How do viruses spread in the body?

The stages of viral infection in the host organism are: entry, primary replication at the site of entry, spread through the host, secondary replication at new sites, persistence or clearance by the host immune response, and transmission or release from the host organism.

The major factors that determine which helper T cell subsets will be generated in an immune response are: The type of cytokines present when T cells are activated by antigen Adhesion molecules on the antigen presenting cells The type of costimulatory molecules on the antigen presenting cells The amount of oxygen available in the lymphoid tissue

The type of cytokines present when T cells are activated by antigen

What is the potential significance of having arginine as a component of the urea cycle, in terms of the rate of the cycle and how much ammonia it can process?

The urea cycle has "feed-forward" regulation where you can increase the amount of any of the components of the cycle and increase the flux of the urea cycle. Arginine is an amino acid which is also an intermediate in the cycle so the rate of the urea cycle is automatically linked to the amount of available AA

What properties of dendritic cells make them the most efficient APCs for initiating primary T cell responses to foreign antigens?

There are two major populations of dendritic cells. 1. The majority of dendritic cells in tissues and lymphoid organs belong to the classical subset. In the skin, the epidermal dendritic cells are called Langerhans cells. 2. Plasmacytoid dendritic cells are named because of their morphologic resemblance to plasma cells; they are present in the blood and tissues. Plasmacytoid dendritic cells are also the major source of type I interferons in innate immune responses to viral infections. Why they are good: 1. DCs form networks in the epithelia and subepithelial; the same cells are present in the T cell-rich areas of peripheral lymphoid organs and, in smaller numbers, in most other organs. The epithelial layers are where most infections start so they are the sentinels waiting for infection. 2. DCs in lymph nodes are in the same regions as the T cells 3. DCs use various membrane receptors to bind microbes, such as lectin receptors for carbohydrate structures typical of microbial but not mammalian glycoproteins. These captured microbes or their antigens typically enter the dendritic cells by receptor-mediated endocytosis; some soluble antigens may enter by pinocytosis. At the same time as the DCs are capturing antigens, products of the microbes stimulate innate immune reactions by binding to Toll-like receptors (TLRs) and other sensors of microbes in the dendritic cells, as well as in parenchymal cells and resident macrophages in the tissue. This results in production of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). The combination of TLR signaling and cytokines activates the DCs, resulting in several changes in phenotype, migration, and function (immature to mature)- important because DCs will bind to and endocytose many different types of molecules but only present the peptides, thereby not limiting the T cell to peptides (in a way) 4. MOST IMPORTANT: naive T lymphocytes continuously recirculate through lymph nodes and also express CCR7 (which is what DCs express when they lose their adhesiveness for epithelia and begin to express the chemokine receptor CCR7 as they start to mature), which promotes their entry into the T cell zones of lymph nodes. Therefore, dendritic cells bearing captured antigen and naive T cells poised to recognize antigens come together in lymph nodes. This process is remarkably efficient; it is estimated that if microbial antigens are introduced at any site in the body, a T cell response to these antigens begins in the lymph nodes draining that site within 12 to 18 hours.

How are Rh antigens determined and how are they inherited?

a. The RH system has 2 genes encoding for 2 Rh proteins (RHD and RHCE). They encode for 2 Rh integral membrane proteins on the RBC. i. RhD is present in some people who are Rh+ and absence in other people who are Rh-. ii. RHCE gene is present in all people but there are some SNPs in the gene that encodes for amino acid variant s in the protein. Some of these variants create antigen differences between individuals. 1. Codon 103: Serine is recognized as Rh(C) while Proline is recognized as Rh(c) 2. Codon 226: Alanine is recognized as Rh(E) and Proine is recognzied as Rh(e) b. One haplotype is inherited from each parent and the resulting Rhesus type of the individual depends on their genotype.

What significant finding is present on the second X-ray that is not present on the first one, and where is it located? How would you work up this finding? What additional information would you like to obtain, and how would you obtain it?

There is a shadow, likely a neoplasm, on the middle lobe of the right lung, near the peripheral airway. Location (small cell tend to form clonal patches in the bronchioles) and hx of non-smoking suggests an adenocarcinoma. I would like information about what type of tissue the growth is and if it is dysplastic or neoplastic. If it is dysplastic, I would like to know the grade and stage of the tumor as well as its genetic profile. To do this, I would order a surgical biopsy with a pathology consult and an oncopanel to see if it qualifies for an EGFR inhibitor targeted therapy.

Where do naïve T cells and DCs meet and how do they get there?

They meet in secondary lymphoid organs (lymph nodes and spleen, etc). 1. mature DCs: activated DCs lose their adhesiveness for epithelia and begin to express receptors for the chemokine receptor CCR7, which is specific for chemoattracting cytokines (chemokines) produced by lymphatic endothelium and by stromal cells in the T cell zones of lymph nodes. These chemokines direct the dendritic cells to exit the epithelium and migrate through lymphatic vessels to the lymph nodes draining that epithelium 2. naive mature T cells: Normal naive T cell recirculation involves naive T lymphocytes that continuously recirculate through lymph nodes and also express CCR7, which promotes their entry into the T cell zones of lymph nodes Therefore, dendritic cells bearing captured antigen and naive T cells poised to recognize antigens come together in lymph nodes. This process is remarkably efficient; it is estimated that if microbial antigens are introduced at any site in the body, a T cell response to these antigens begins in the lymph nodes draining that site within 12 to 18 hours.

What will happen to the activity of PDH, beta oxidation, and the TCA cycle if oxygen is not available? Why?

They will slow down/stop because the ETC will stop (its carriers will become saturated with electrons) -they are all functionally coupled together increased levels of NADH (nowhere to put electrons) will inhibit PDH, alpha-ketoglutarate, and third step in beta ox

Ubiquinone

UQ or coenzyme Q electron carrier that takes electrons from complex 1 or complex II to complex III has long hydrophobic tail and dissuses within the inner mito membrane

How are proteins modified with ubiquitin?

Ubiquitin conjugation system forms isopeptide bond b/t amino group of lysine side-chain of protein and C-terminus of ubiquitin.: Ub is activated (by phosphorylation) by E1 E1 transfers Ub onto E2 E2 then transfers Ub onto substrate, under the "direction" of E3 Some E3s (RING-type) have receptor components that bind specific substrates and brings them in close proximity to E2 to facilitate the transfer of Ub onto substrate Other E3s (HECT) actually take the Ub from E1 and "hands it off" to the substrate.

How are amino groups transported from peripheral tissues for disposal by the liver?

Via glutamine (all tissues-collecting all the free amonia from catabolism of AA and nucleic acids); alanine (principally muscle, takes branched AA from muscle to live via 2 transaminase rxns- reversible process) substrate concentrations will drive direction of transaminase (a lot of pyruvate and ammonia from high catabolism will drive production of alanine)

What are the steps in viral replication?

Viral replication takes place in the host cell by the following steps: binding, entry, uncoating, transcription of mRNA, translation of viral proteins, replication of the input genome, assembly of progeny viral particles, and egress.

Envelope

Virus particles or virions are composed of complexes of nucleic acid (genome) and protein, sometimes with a lipid membrane envelope presence or absence of envelope is a criterion for the classification of viruses Viruses bind to specific receptors on the cell surface and usually enter by one of 3 pathways, fusion of the envelope with the surface plasma membrane, receptor-mediated endocytosis followed by fusion with the endosome membrane, or lysis of the endosome.

How do viruses enter host cells?

Viruses bind to specific receptors on the cell surface and usually enter by one of 3 pathways, fusion of the envelope with the surface plasma membrane, receptor-mediated endocytosis followed by fusion with the endosome membrane, or lysis of the endosome. A host cell may be permissive or non-permissive, leading to a productive or non-productive infection, respectively.

What criteria are used to classify viruses?

Viruses have been classified into family, genus, and species, based on the following criteria: type of genomic nucleic acid (RNA or DNA; ss or ds; for ss genomes, positive strand = same sense as viral mRNA or negative strand = complementary to viral mRNA), symmetry of capsid (helical, icosahedral or complex), presence or absence of envelope, mode of replication, and tropism (preferred cell type for replication) or type of pathology. Recently, sequence analysis of viral genomes has refined and revised some of the classification of viruses

How would you measure the volume of distribution (Vd)? What does it mean if the volume of distribution is similar to the plasma volume? Why can it vastly exceed total body water?

Volume of distribution= administered dose/extrapolated concentration of drug in plasma back to time zero Vd plasma volume = 4 L (drug is large or stuck to blood proteins) Vd extracellular fluid = 14 L (drug has low MW but is hydrophilic but can't get thru lipid membranes) Vd total body water = 42 L (low MW and is hydrophobic so can move thru cell membranes into the intracellular fluid) If the Vd is similar to the plasma volume, the drug has a large molecular weight or binds extensively to plasma proteins and is too large to move out thru the endothelial slit juncetions ofht ecapillaries so all is effectively trapped within teh plasma compartment Vd >> total body water drug distributes to several comparments avidly binding cellular components such as lipids and proteins Vd is calculated not actual and is a useful parameter for calculating the loading dose of a drug requried to achieve aparticlular plasma concentration

What are the steps in pathogenesis of N. gonorrhoeae?

a. The bacteria binds to epithelial cells. b. Enters by endocytosis. c. Passes through the host, killing it, and exits into the subepithelium. d. In the subepithelium, replicating bacteria elicit a strong inflammatory (PMN) response, causing damage to the epithelium and forming exudative pus.

What are some possible metabolic fates of pyruvate?

What are some possible metabolic fates of pyruvate? * Lactate (oxygen limited/no mitochondria for cells using glycolysis for energy primarily)à bloodsteam to liver o Allows regeneration of NAD +for glycolysis to continue under anaerobic conditions o Lactate Dehydrogenase: Electrons from NADH are transferred to pyruvate, producing lactate and regenerating NAD o NAD/NADH: in presence of oxygen, cells normally keep this ratio high, enabling glycolysis to proceed efficiently o Cori cycle: muscle exercises anaerobically and generates lactic acid à dumps to blood stream to liver (not O deprived) à liver reoxidizes it back to pyruvate à gluconeogenesis (in fasting state/epinephrine) to make it glucose again * Muscle can continue to oxidize glucose without oxygen by relying on the liver * Acetyl CoA (mitochondria present, using both for energy) à Ac CoAà TCA cycle/make fat in fed state o Pyruvate dehydrogenase (PDH): pyruvate enters mitochondria, oxidative decarboxylation to produce CO2, NADH, and acetyl CoA o TCA cycle uses acetyle coA to generate 3 NADH, 1 FADH2 * Glucose (via gluconeogenesis in fasting state in liver) à oxaoloacetate (also pathway used in cell to increase rate of TCA cycle) * Alanine (transamination)

What are the roles of NAD/NADH and NADP/NADPH in the cell? How are these roles distinct from one another?

What are the roles of NAD/NADH and NADP/NADPH in the cell? How are these roles distinct from one another? NADP+ is a phosphorylated version of NAD+. The presence of the phosphate means that various metabolic enzymes can be tailored to recognize either NAD+/NADH or NADP+/NADPH. As a result, the enzymes that carry out catabolic reac-ons generally only oxidize NADH rather than NADPH. In contrast, the enzymes that carry out anabolic reac-ons only use electrons stored in NADPH. You can therefore think of NAD+/NADH or NADP+/NADPH as two separate "currencies" in the cell that enable electron flow in catabolic reac-ons to be kept separate from electron flow in anabolic reactions. The pentose phosphate pathway is regulated so that virtually all of the NADP+ is reduced to NADPH. This is important because the NADPH is essen-al for cellular biosynthesis. In contrast, the liver will regulate the NAD+/NADH ra-o in the opposite direc-on, to keep NAD+ available for biological oxida-on reac-ons. If mitochondria are available, and ATP needs to be produced, the mitochondria will rapidly oxidize any NADH to NAD+

What controls muscle glycogen levels? How is regulation of muscle glycogen breakdown different than that of liver glycogen breakdown?

What controls muscle glycogen levels? How is regulation of muscle glycogen breakdown different than that of liver glycogen breakdown? muscles do not have glucagon receptors -epinephrine acts on a different GPCR, activating PKA - PKA doesn't just phosphorylate glycogen phosphorylase so that other mechanisms can contribute, ex. high calcium levels will activate phosphorylation of glycogen phosphorylase so that level of glycogen breakdwon is equivalent to level of contraction in the cell. - energy depletion (high levels of AMP) also activate AMP kinase, to stimulate glycogen phosphorylase glucose in muscle supports contraction and glucose in liver is for circulation (to the brain)

What enzymes control the production and breakdown of glycogen, and how are they regulated by insulin or glucagon/epinephrine?

What enzymes control the production and breakdown of glycogen, and how are they regulated by insulin or glucagon/epinephrine? Enzymes for production: 1. phosphoglucomutase (converts G6P to G1P) then UDP gets added 2. Glycogen synthase adds UDP-glucose to glycogen strand (must have 4 glucoses) 3. Glycogen branching enzyme creates the 1-6 branches Insulin signaling via RTKS promotes glycogen synthesis (RTK - PI3K-PIP3-AKT double negative activates glycogen synthase and stimulating GLUT4)Insulin also favors the ac-va-on of protein phosphatases that promote dephosphoryla-on of glycogen synthase. In contrast, glucagon and epinephrine signaling will inhibit the phosphatase. Glucagon and epinephrine inhibit the phosphatase via the G protein pathway (PKA) Enzymes that lead to the breakdown: 1. glycogen phosphorylase hydrolyzes glycogen from the end of the chain 2. Phosphoglucomutase changes G1P back to G6P 3. To fully degrade the polymer, the ac-vity of a debranching enzyme is required. A glucosidase is also required to remove the 1,6 linkages. Glycogen phosphorylase is regulated in opposite manner to glycogen synthase: Only active in phosphorylated state; No-ce that both enzymes tend to be phosphorylated or dephosphorylated at the same -me (phosphorylated in the fas-ng state and dephosphorylated in the fed state) glycogen synthase is phosphorylated by GSK3 and glycogen phosphorylase is phosphorylated when PKA is active. Glucagon signaling activates PKA which phosphorylates phosphorylase kinase which phosphorylates glycogen phosphorylase (this is bc glycogen phosphorylase is activated by multiple signals, ex. calcium in the muscle so that level of contraction is coordinated with level of glycogen breakdown)

What is the relevance of the branched structure of glycogen?

What is the relevance of the branched structure of glycogen? The high concentra-on of glucose 6-phosphate would create a strong osmo-c load on the cell, causing water to enter and swell the cell, causing it to lyse (pop open). To solve this problem, the glucose is assembled into a polymer, which decreases its osmo-c ac-vity. Each glycogen molecule is nucleated by a protein called glycogenin (G). Glucose molecules are linked together through 1,4 linkages and 1,6 branches. The enzymes that build and break down glycogen can only work on the ends, so therefore branching accelerates the rate of glycogen synthesis and breakdown by providing more ends to work on. Glucose monomers are added and removed from the "non-reducing" ends of the polymer (the ends without the alpha carbon

Can populations be distinguished with genetic markers?

Yes, if you look at many thousands of genetic markers and combin the info about pop diff, it is possible to group ppl into geo pop (harder in cosmopolitan pops with a lot of admixture) ex. computer program recapitulate the map of europe caveats: individuals were selected for geo ancestry (all grandparents from same country) AND sampled populations that were quite separated so you saw sharp distinctions (and not the rainbow continuation) - we also saw sharp, not replicable distincitions in Linnaeus and Agassiz' maps of race that were due to social na dcultural difference

How does C. trachomatis replicate in host cells? How do the bacteria benefit from intracellular replication? How does C. trachomatis damage the host?

a. They are obligate intracellular parasites. They take two forms: elementary body and reticulate body. The EB is infectious and enters the host. The EB becomes RB, which is the replicating form. RB replicates and then daughter RB become EB to exit, kills the host, and infect more host cells. b. Bacteria can use amino acids, nucleotides and ATP from the host. c. C. trachomatis damages the host by recruiting an immune response. This immune response however provides little protection from the pathogen.

ApoE

triggers clearance of some VLDL particles and all chylomicron remnants by targeting these particles of the liver (that's how IDL gets sent there)

Acid fast stain

a hallmark of mycobacteria Mycobacteria have the unusual property of retaining basic dyes when treated with acidic solutions. -> a consequence of the mycobacterial envelope, which contains waxes composed of longchain branched hydrocarbons. The most abundant wax, mycolic acid, is an αalkylhydroxy fatty acid covalently linked to the cell wall. The name Mycobacteria reflects the presence of mycolic acid in the organisms. The waxy barrier greatly reduces permeability to many molecules, including Gram stain, and mycobacteria are neither Grampositive nor Gramnegative. However, they can be stained with special techniques such as briefly heating in the presence of a basic red dye called fuchsin. In some cases, detergent is added to the stain. The specimen is then treated with 3% hydrochloric acid in ethanol, which removes the stain from nearly all organisms except mycobacteria (thus, they are acid fast). The smear is then counterstained with a blue dye to provide a contrasting background. Mycobacteria appear as slender red rods. Fluorochrome dyes are now commonly used instead of fuchsin because they are more easily detected by fluorescence microscopy

What is the general role of P-glycoproteins?

a multidrug transmembrane transporter protein responsible for transporting various molecules, including drugs, ouf of the cells- after phase 1 and phase 2 rxns, drug may be too polar to leave hepatocytes (phase 1 occurs in er and phase 2 in er or cyto) - in areas of high expression, reduces drug absorption (cancer takes advantage of this) -transporters MAY be needed to pump drugs into the cell (OATP or OCT - importatn in statins) fxns: - USED TO PUMP STUFF OUT liver: transporting drugs out of ht eliver cell into bile for elimination kidney: pumping drugs into urine for excretion placenta: transporting drugs back into maternal blood (reducing fetal exposure to drugs) intestines: transporting drugs intot he intestinal lumen and reducing drug absorption into the blood brain capillaries: pumping drugs back into the blood, limiting acces to teh brain

a) Is there tumor in the lymph node? (Bonus question: What is the black material in the tissue, and how did it get there?) b) What is the diagnosis? Be as specific as you can. c) Is there tumor at the bronchial resection margin?

a) The "black stuff" is coal or soot from air pollution. It is likely that macrophages collected the soot and then drained into the lymph nodes, bringing the soot with them. The soot could also be there because the lymph node now has lung tissue where it is normal for this soot to accumulate. I believe that there is tumor in the lymph node, primarily because there seems to be lung tissue (large empty holes) present in the lymph node, which should not exist. I also noted increased angiogenesis (more venules than are common) and loss of architecture around the germinal centers. Though this is a lymph node where there are a lot of leukocytes, there did seem to be signs on inflammation as well. b) I believe that this patient has adenocarcinoma with a decently high grade. Her lung tissue seems to have a significant glandular cells that have a high chromatin to cytoplasm ratio with multiple mitoses and unclear cellular boundaries. The cells have lost their architecture and seem to be overproducing mucus, such that some cells are suspended in this mucus, which would suggest that the glandular cells are not functioning properly. There are also neutrophils, which suggests inflammation. Furthermore, she is a non-smoker, and adenocarcinomas are more common in non-smokers. c) I think that the margins look clear. Tissue architecture is maintained (good muscle and cartilage and blood vessel distinctions). And the presence of the same dysplastic (almost anaplastic?) cell type is not visible.

How do antibodies protect against infection by intracellular microbes and what considerations are important for determining whether a normal humoral immune response or vaccination is sufficient for protection?

a. Antibodies bind to microbes during the extracellular portion of their life cycle thereby preventing infection of additional cells and interrupting the infectious disease process. b. Antibody binding to the microbe surface can also activate complement leading to enhanced phagocytosis and the formation of MACs followed by lysis of the microbe. c. To be effective antibodies must be present at sufficient concentrations at or prior to the extracellular phase of the microbe's life cycle and in the same location (blood, CNS, etc.) as the extracellular microbe. if you get infected with somethine like a virus (intracell rabies) that you might need passive immunization since you will not make antibodies at first (need time for T cell response) - at first you will make IgM (without T cells) so you need passive IgG first - always make IgM first but takes time for IgG which is more effective in terms of opsonization and ADCC

What are the manifestations of infections by C. trachomatis? How are genital chlamydia infections detected and treated?

a. Genital chlamydia is caused by serovars (serotypes) D to K. The symptoms of genital infection cause pelvic inflammatory disease, risk of infertility in women and epididymitis and prostatitis in men. Eye infection (conjunctivitis) can also occur as result of autoinoculation by someone with genital infection. Reactive arthritis can also occur. The triad of urethritis, conjunctivitis and reactive arthritis is called "Reiter's syndrome". Lymphogranuloma venereum (infection of the lymph nodes or lymphatics) is also caused by C. trachomatis. b. PCR and molecular tests diagnose genital chlamydia. c. Genital infection is treated with azithromycin or doxycycline.

How do monoclonal antibodies (mAb) function as therapeutic agents and how has fundamental knowledge of antibody structure, function and immunogenicity led to new and enhanced existing classes of therapeutics?

a.mAb bind and mask their targets to block normal functional interactions with other molecules and cells. b. Binding to soluble targets, like inflammatory mediators and growth factors, blocks inflammation and cell growth and homeostasis, respectively. c. Binding to cell surface targets blocks interactions with other cells that normally bind to that target. Cell surface binding can also deliver inhibitory or activating signals to the target-bearing cell to achieve the desired result. d. Chimeric molecules consisting of the binding portions of cell surface receptors coupled to the Fc region of IgG show prolonged stability in the circulation and improved efficacy. "Humanizing" mAb and Fc fusion proteins is necessary to minimize the host immune responses to these "foreign" molecules. Otherwise you might initiate an autoimmune response (most monoclonal antibodes are made in animals) Examples include mAb recognizing TNFα to treat inflammation, VEGF to treat cancer and ocular disease, T cell surface inhibitory molecules PD-1 and CTLA-4 to treat cancer and alpha 4 integrin to treat multiple sclerosis. - key here is neutralization M is for monoclonal spike (multiple myeloma has large M spike)

What factors can influence the amount of absorbed drug that makes it into the circulation?

absorption = transfer of a drug from site of administration to the bloodstream rate and efficiency of absorption depend on 1)factors in environ where drug is absorbed 2) drug's chemical characterisitcs and route of administration (IV has 100% bioavailbaility) mechanism of absorption can effect: most are lipid soluble and move thru passive diffusion across membranes driven by a gradient; proteins can be transported by receptor-mediated endocytosis except for the GI tract stie of absorption (blood flow and surface area greater to intestine than stomach so intestines preferred) how fast moves thru site (low absorption with diarrhea) Delays of transport (delays the rate of absorption in teh intestine) protonation (ionization of weak acids and bases)

carnitine

acetyl coa cannot move into the mito by itself because it is charged so it hooks up to this transporter molecule Carnitine receives the fatty acid group from the acyl CoA molecule in a reaction catalyzed by carnitine acyltransferase I. The acyl carnitine molecule can then be moved into the matrix via a specific transporter in exchange for carnitine coming out. -This movement of the fatty acid into the mitochondria is the rate limiting step for beta-oxidation.

What are the products of beta oxidation? How does this explain the ability of beta oxidation to supply all of the energy needs of the liver in the fasting state? How is CoA regenerated during extensive beta oxidation?

acetyl coa, FADH2, NADH FAs coming to the liver fully support the hepatocytes' energy needs thru beta ox and TCA but as fasting progresses, OAA gets used up by gluconeo (TCA slows) This isn't a problem for the hepatocytes because they get all the NADH and FADH2 that they need from Beta ox which allows OAA to be diverted to glucose production rather than for the TCA -but still need coa beta ox and ketone body formation are a coupled oxidation-reduction system and CoA-recycling system permetting beta ox to continue in the liver beyond the rate requried to support the liver's energy needs. the mitochondrial form of HMG CoA synthase (the cytosolic version is involved in syn of cholesterol) releases a CoASH (free CoA) by putting two acetyl coAs together to make the ketone bodies. This is how the coA is recycled

How would increasing or decreasing the pH affect the absorption of a drug that is a weak acid or a weak base?

acidic drugs will tend to be absorbed better at a lower pH; basic drugs will tend to be absorbed better at a higher pH pKa is a measure of the strength of the interaction of a compound with a proton; lower the pKa, the more acidic it is, the higher the pKa the more basic the distribution of the srug in its ionized and non-ionized forms depends on ambient pH and pKa of hte drug

mature DC

activaed that function as APCs for naive T cells and ar eimportant for initiation of adaptive immune responses to protein antigen

ApoC

activates lipoprotein lipase not found on any initial VLDL or chylomicron but must be picked up in the bloodstream (allowing for wider distribution) Once tags have been deposited, IDLs and chylomicrons lose the ApoC -II (no longer necessary)

What are the two types of signals required for naive T cell activation, and what happens to a T cell that receives one or other type alone or both together?

activation of naive T cells requires an antigen specific signal and a costimulation which is augmented by danger signals interpreseted by the innate immune system (DCs) - in our example we gave the non-protein LPS to the macrophages so they would produce the B7 secondary signal antibody was given as crosslink to bring Cd3s together

cell mediated immnity

adaptive immunity that is mediated by T lymphocytes and serves as the defence mechanism against microbes that survive within the phagocytes or infect nonphagocytic cells. CMI responses include CD4 T cell mediated activation of macrophages that have phagocytosed microbes and CD8 CTL-mediated killing of infected cells

What are the levels of lipoprotein lipase expression in the adipose and muscle tissues in the fed state?

adipose: levels high in fed state (carb diet), low in fasted state -promotes storage of fat in adipose -production stimulated by insulin (which lowers levels of hormone sensitive lipase) Muscle: levels lower in fed state (carb diet), higher in fasted state -promotes oxidation of fat in fasted state -producetion inhibited by insulin

familial hypercholesterolemia

autosomal dominant (haploinsufficient) characterized by high LDL leading to severe atherosclerosis and heart attacks (even in children), high blodd cholesterol; the issue is with the patient's ability to internalize the LDL particles bc they have issues with their LDL receptors (see image) -> caused by mutations in the LDL receptor gene: 1) no receptors produced -about 50% of cases have class 1 (issue with synthesis) 2)defective in transport from ER to golgi (likely receptors are degraded by ERAD so don't make it to cell surface) 3) receptors that traffic normally to surface but fail to bind LDL 4) receptors that bind to LDL but fail to internalize w/o LDL receptors, FH cells maintain normallevels of cholesterol by increasing syntehsis of cholesterol, leaving excess LDL in teh culture medum

CD62L ( L selectin) is an adhesion molecule expressed on naïve T cells which binds to high endothelial venules allowing for migration of T cells to lymph nodes. Most T cells stop expressing L selectin (CD62L) after they are activated by TCR signaling and differentiate into effector cells. How does this promote immune defense against infections in tissues? What other molecule expressed on naïve T cells is also not expressed on effector T cells, and also contributes to immune defense against infections in tissues in the same way?

after the naive T cells are activated and differentiate into expanded clones of effector T cells, these T cells must migrate back to the sites of infection, where they function to kill microbes. The migration of naive and effector T cells are controlled by three families of proteins—selectins, integrins, and chemokines—which regulate the migration of all leukocytes. The routes of migration of naive and effector T cells differ significantly because of selective expression of different adhesion molecules and chemokine receptors on naive T cells versus effector T cells, together with the selective expression of endothelial adhesion molecules and chemokines in lymphoid tissues and sites of inflammation. Naive T lymphocytes home to lymph nodes as a result of L-selectin and integrin binding to their ligands on high endothelial venules (HEVs). Chemokines expressed in lymph nodes bind to receptors on naive T cells, enhancing integrin-dependent adhesion and migration through the HEV. The phospholipid, sphingosine 1-phosphate (S1P), plays a role in the exit of T cells from lymph nodes, by binding to the receptor, called S1PR1 (type 1 sphingosine 1-phosphate receptor). Activated T lymphocytes, including effector cells, home to sites of infection in peripheral tissues, and this migration is mediated by E-selectin and P-selectin, integrins, and chemokines secreted at inflammatory sites.

what are the AA that carry ammonia thru the bloodstream

alanine and glutamine

For each of the following amino acids, how would its amino groups end up in urea? Trace the steps involved (including transamination steps that might be required). Branched chain amino acid (leucine, valine, isoleucine) Non-branched chain amino acid (eg, glycine, proline,...etc) Aspartate

an intermediate of the urea cycle 1. glutamate may undergo transamination to donate its amino group to oxaloacetate to generate aspartic acid, which enters the urea cycle 2. Aspartate gives its amino to the carbonyl group of citrulline by a condensation reaction to form argininosuccinate. This enzyme also utilizes ATP. 4. 3.The enzyme argininosuccinate lyase cleaves this molecule to form arginine and fumarate. The fumarate then enters the TCA cycle to be converted to oxaloacetate, which can then accept an amino group from glutamate to yield aspartate again. Notes: - this reaction is analogous to what we observed in muscle, where glutamate donated its amino group to pyruvate to generate alanine— the concept is that glutamate "collects" the amino groups and the redistributes them to a limited number of key components). The transamination of oxaloacetate to produce aspartate is a key reaction that helps balance the input of amino groups into the urea cycle. Once aspartic acid is consumed by the urea cycle, the product is fumarate and thus requires the action of the TCA cycle to regenerate oxaloacetic acid. Therefore the net result is that only the amino group from aspartic acid is consumed by the urea cycle and carbon skeleton is recycled. This is the key link between the urea cycle and TCA cycle.

ABO antigens Are they naturally occuring?

antigenic similarity to bacteria that colonize GI tract and induce natural immunity (which is why we develop antibodies to them without exposure) -we don't expect baby to make antibodies before 4 months, mostly igM response anyway, and those do not cross the placenta so she isn't getting them from mom -they don't get T cell help because the antigens are sugars similarly, in the man with a transplant from A to B, endothelial cells and epithelial cells are not being replaced and they still express antigen A so now he would be functionally AB (A in tissues, B in blood) so wouldn't make antibodies to etiher

What are the risk factors for symptomatic secondary tuberculosis?

any impairment of the cellular immune system can render a person vulnerable to reactivation of latent mycobacteria. 1. Subtle depression of the immune system resulting from stress or hormonal factors may go undetected. 2. Other factors include malnutrition, therapy with corticosteroids or other immunosuppressive drugs, malignancy, and endstage renal disease. 3. Worldwide, the most important cause of reactivation is coinfection with HIV. 4. The higher frequency of certain histocompatibility types (i.e., human leukocyte antigen or HLA) in persons who develop active TB suggests a genetic predisposition. 5. The disease may reactivate in the elderly because of a poorly understood loss of immune competence that can occur with aging. 6. In addition, local physical disturbances at the site of a latent focus can alter the balance between host and pathogen. For example, lung surgery can disturb quiescent pulmonary foci and cause active TB at that site.

small cell lung cancer (carcinoma)

arises from neuroendocrine cells of the lung (can arise in any organ where neuroendocrine cells are prsent but most common is lung) tends to metastasize early in course so not surgically treated (presumed metastic at presentation) frequently associated with paraneoplastic phenomena and has dismal prognosis (very aggressive- "rapid release") sensitive to chemotherapy/radiotherapy largely confined to heavy smokers

Granuloma

associated with chronic inflammation aka tubercles The pathologic features of TB are the result of hypersensitivity to mycobacterial antigens. The classic tissue response involves organization of macrophages, Langhans giant cells, and lymphocytes resulting in formation of granulomas. This pattern constitutes a successful tissue reaction with containment of infection, healing with eventual fibrosis, encapsulation, and scar formation. However, with time, the centers of the tubercles may become necrotic. Necrosis in TB tends to be incomplete, resulting in semisolid caseous material. Caseous necrosis is unstable, especially in the lungs, where it tends to liquefy and discharge through the bronchial tree, producing a cavity and providing conditions in which bacteria multiply to very high numbers.

what are the major differences between autophagy and the ubiquitin-proteasome system?

autophagy: lysosome mediated protein degradation; can degrade entire organelles and large aggregates; sometimes will phagocytose things that are too big for the proteasome u-p system: ubiquitin system ubiquitinates proteins essentially targeting them for destruction by the proteasome; rapid, selective protein turnover - remember that antigen presentation (MHC I and MHC II) build off of these two pathways: MHC I builds off of proteasome; MHC II builds off lysosome/endosome/autophagy

Why is carnitine deficiency associated with hypoglycemia?

beta oxidation is critically linked to fasting to provide the energy needs of liver and muscle cells so that AA and OAA can go to making glucose (high acetyl coa will lower PDH and increase PC) if you don't have beta ox (no carnitine carriers), all the glucose will be used up for energy

What are the ATP dependent steps in proteasome function

bind ubiquitinated proteins unfold substrates (gate is very small 14A so protein has to be unfolded) open the gate in the 20S (conformational change allowing gate opening) promote translocation into the 20S

What would it mean if the bioavailability is 1?

bioavailability is the fraction of administered drug that reaches the systemic circulation a bioavailability of 1 means that 100% of the drug reached the systemic circulation which is what happens for a drug delivered intravenously

In Microbiology, you have heard about Staphylococcal superantigens. These toxins are capable of binding to MHC (outside the peptide binding groove) and also binding to framework regions in a subset of TCR beta chain variable regions (outside the CDR). This results in polyclonal activation of T cells bearing one or a few Vbeta chains (e.g Vb5+ T cells). What is the consequence of such a large and anatomically widespread T cell response?

biochemical signals that lead to T cell activation are triggered by a set of proteins linked to the TCR that are part of the TCR complex and by the CD4 or CD8 coreceptor. In lymphocytes, antigen recognition and subsequent signaling are performed by different sets of molecules. The TCR αβ heterodimer recognizes antigens, but it is not able to transmit biochemical signals to the interior of the cell. The TCR is noncovalently associated with a complex of transmembrane signaling molecules including three CD3 proteins and a protein called the ζ chain. The TCR, CD3, and ζ chain make up the TCR complex. Although the α and β TCRs must vary among T cell clones to recognize diverse antigens, the signaling functions of TCRs are the same in all clones, and therefore the CD3 and ζ proteins are invariant among different T cells. polyclonal activation sidesteps all of this... Microbial superantigens may cause systemic inflammatory disease by inducing excessive cytokine release from many T cells (nonspecific now).

How do phase I and phase II reactions change the properties of drugs? How are these reactions distinct from one another?

biotransformation may 1. may convert an active drug into an active or toxic metabolite 2. inactive prodrug may be converted to an active drug 3. may convert an active drug into an inactive drug 4. an unexcretable drug may be converted into an excretable metabolite (to enhance renal or biliary clearance) phase 1: oxidation/reduction reactions (expose polar groups through oxidase in hepatocytes) phase: conjugation/hydrolysis (for esters and amides) - biochemistry more closely related

two major sources of amino acids

breakdown of body tissue and diet (body can also synthesize non-essential amino acids from carbon skeletons produced by various metabolic pathways

How can the diet affect drug metabolism?

by inducing or inhibi%ng enzymes of the P450 system. An interes%ng example is grapefruit juice. The psoralen deriva%ves and flavonoids in grapefruit juice inhibit both P450 3A4 and MDR1 in the small intes%ne. Inhibi%on of P450 3A4 significantly decreases the first-pass metabolism of co-administered drugs that are also metabolized by this enzyme, and inhibi%on of MDR1 significantly increases the absorp%on of co-administered drugs that are substrates for export (efflux) by this enzyme. The grapefruit juice effect is important when grapefruit juice is ingested together with drugs that are acted upon by these enzymes.Such drugs include some protease inhibitors, macrolide an%bio%cs, HMG-CoA reductase inhibitors (sta%ns), and calcium channel blockers. Saquinavir is one of the protease inhibitors that is both metabolized by P450 3A4 and exported by MDR1. St. John's wort can induce P450 expression and thereby decrease the efficacy of other drugs Because many endogenous substances used in the conjuga%on reac%ons are ul%mately derived from the diet (and also require energy for the produc%on of the appropriate cofactors), nutri%on can affect drug metabolism by altering the pool of such substances available to the conjuga%ng enzymes.

ammonia

byproduct of amino acid breakdown and purine catabolism and degradation of pyrimidine toxic so body needs urea cycle to convert it into nontoxic, water soluble form liver is main site in teh body forgeneration of urea

What reaction is catalyzed by acetyl CoA carboxylase?

catalyzes the rate limiting step of FA syn acetyl coA has to be activated (turned into higher ENRG intermediate that will drive FA syn) so ACC converts acetyl coA to malonyl coA extra energy in malonyl coa required for cabon cabon bond forming rxn in FA syn this step is activated by insulin and inhibited by glucagon or epinephrine

How do superantigens cause disease and how does this differ from ordinary antigens?

cause TSS (associated with S. aureus); they are exotoxins (not the bacteria themselves) Superantigens cross-link one chain (β-chain) of the T-cell antigen receptor with major histocompatibility complex class II molecules on macrophages. The effect of this interaction is a massive release of cytokines from macrophages and T cells that mediate TSS. These antigens cause a cell to cell interaction that is unique and causes over-expression of cytokines that leads to disease interleukin 1 (endogenous pyrogen) released from macrophages causes the fever of TSS. Tumor necrosis factor-α released from macrophages and tumor necrosis factor-β released from T cells cause capillary leak and therefore hypotension. Finally, interferon-γ and interleukin 2 release from T cells accounts for the rash of TSS patients. It is also important to remember that the massive release of interferon-γ in TSS appears to prevent formation of protective neutralizing antibodies against the superantigens. Thus, TSS patients mostly remain susceptible to recurrent TSS, particularly women who continue to use tampons after TSS episodes. In addition, superantigens appear to subvert the formation of inflammation through an undefined mechanism when the organism is in abscesses. Thus, for example, surgical incision sites may not show the characteristic inflammation associated with staphylococcal infections. The staphylococcal superantigens are structurally related to the streptococcal scarlet fever toxins, which also cause TSS. streptococcal bacteria also make superantigens: In addition to causing the rash seen in scarlet fever, SPE-A and SPE-C are also bacterial superantigens that can nonspecifically activate a large subset of T cells.The resulting massive release of proinflammatory cytokines by the activated T cells results in a sepsis-like clinical picture with shock and multiorgan failure. This streptococcal toxic shock syndrome (STSS) is very similar to the toxic shock syndrome (TSS) caused by Staphylococcus aureus

toxic shock syndrome (TSS)

caused by exotoxins of S. aureus characterized by fever, skin rash, hypotension, peeling of the skin on recovery, and the dysfunction of several essential systems The disease was originally associated with the use of highly absorbent tampons, which appear to introduce oxygen into the vagina and stimulate toxin production by the organisms. Oxygen is absolutely essential to the production of TSS-inducing toxins, and the vagina in the absence of tampons is anaerobic. The exotoxins involved in TSS include toxic shock syndrome toxin-1, the cause of all menstrual TSS cases and one-half of nonmenstrual cases, and staphylococcal enterotoxins, particularly enterotoxin serotypes B and C. These three exotoxins are produced by the bacteria in high concentrations

Fc receptor

cell surface receptor specific for the carboxyl terminal constant region of an Ig molecule. Fc receptors are typically multichain protein complexes that include signaling components and Ig-binding components. several types of Fc receptors exist, including those specific for dif IgG isotypes, IgE, and IgA. mediate many of the cell-dependent effector functions of antibodies, including phagocytosis of antibody-bound antigens, antigen-induced activation of mast cells, and targeting and activation of NK cells

How is LDL is taken up by the cell, and how is its cholesterol delivered to the cell?

cells use the LDL receptor to take up LDL (via ApoB100) by receptor-mediated endocytosis 1. in the endosome, the acidic pH causes the receptor to release LDL and is recycled to the surface 2. cholesterol is released from the endosome THEN 2 OPTIONS: storage or use it 3. If enough C is present in the cell, it will stimulate cholesterol storage as cholesterol esters (IT'S STORAGE FORM, like TAGs) by increasing expression of ACAT 4. a lot of C will downregulate the production of HMG CoA reductase (RLS of cholesterol syn) and expression of LDL receptors (both mediated by SREBO TF)

Caseous necrosis

cheesy appearance of the lesions in the apex of the lung in TB infections The most common site of reactivation is the apex of the lung (see Fig. 231). Lesions slowly become necrotic, undergo caseous necrosis (named for its cheesy appearance), and eventually merge into larger lesions. With time, the caseous lesions liquefy and discharge their contents into bronchi. This event has several major consequences. It creates a wellaerated cavity in which the organisms proliferate. The discharge of caseous material also distributes the organisms to other sites in the lung, which can lead to a rapidly progressive tuberculous pneumonia. In addition, the bacterialaden contents of caseous lesions are coughed up and become infectious droplet nuclei. Although the reason for the apical pulmonary localization is not known with certainty, it is likely that deficient lymphatic flow at the apices, where the pumping effect of respiratory motion is minimal, favors retention of organisms. When hypersensitivity develops, tissue damage creates apical cavities characteristic of pulmonary TB in adults.

cholesterol ester

cholesterol storage particle - VERY hydrophobic so must be packaged in lipoproteins to travel thru the blood enzyme that produces is is called ACAT (acyl-enzyme A: cholesterol acyltransferase) and is located in the ER if cells didn't store cholesterol as CE, it would go back to the surface of the plasma membrane because of alcohol group - ester makes it hydrophobic so good for packing

How do triglyceride and cholesterol contents differ between chylomicrons, VLDL, LDL, HDL?

chylomicrons - TAG 86%, CE 3%, C 1% VLDL - TAG 52%, CE 14%, C 7% LDL - TAG 10%, CE 38%, C 8% HDL - TAG 5-10%, CE 14-21%, C 3-7%

How can drug metabolism enzymes be involved in the activation of a drug?

clopidogrel, an an%platelet drug that promotes blood vessel patency aJer strokes or coronary angioplasty. The loss of efficacy of this medica%on may lead to re-stenosis or re-thrombosis of a vessel or stent, oJen with severe consequences. Clopidogrel is a prodrug that is metabolized to its ac%ve form via P450 enzymes, including P450 2C19, and polymorphisms of P450 2C19 have recently been associated with both decreased an%platelet effect and increased cardiovascular morbidity. In addi%on, because many proton pump inhibitors are also metabolized by P450 2C19, co-administra%on of clopidogrel with one of these commonly prescribed medica%ons may lead to a decrease in the plasma levels of ac%ve clopidogrel.

What is MHC polymorphism and how is it different from T cell antigen receptor diversity?

co-dominance (alleles inherited from both parents are expressed equally) one T cell will not recognize both an MHC I HLA A and MHC I HLA B molecule even if it is a CD8 (looking for class 1) MHC polymorphism means that many different alleles are present among the different individuals in the population. The total number of HLA alleles in the population is estimated to be more than 5000, with about 2500 for the HLA-B locus alone, making MHC genes the most polymorphic of all genes in mammals. The polymorphism of MHC genes is so great that any two individuals in an outbred population are extremely unlikely to have exactly the same MHC genes and molecules. These different polymorphic variants are inherited and not generated de novo in individuals by somatic gene recombination, as are antigen receptor genes. Because the polymorphic residues determine which peptides are presented by which MHC molecules, the existence of multiple alleles ensures that there are always some members of the population who will be able to present any particular microbial protein antigen. MHC polymorphism may have evolved because it ensures that a population will be able to deal with the diversity of microbes and at least some individuals will be able to mount effective immune responses to the peptide antigens of these microbes. Thus, everyone will not succumb to a newly encountered or mutated microbe.

Why are adjuvants necessary for effective immune responses to purified proteins?

co-stimulation requirement for T cell activation The key is that these adjuvants will stimulate the APCs to make costimulator B7 receptors necessary for the costimulation of T cells (CD28 receptor) bc otherwise T cells will have no response or tolerance (die) off (think that they are seeing self molecules) Protein antigens, such as those used in vaccines, fail to elicit T cell-dependent immune responses unless these antigens are administered with substances that activate APCs, especially dendritic cells. Such substances are called adjuvants, and they function mainly by inducing the expression of costimulators on APCs and by stimulating the APCs to secrete cytokines that activate T cells. Most adjuvants are products of microbes (e.g., killed mycobacteria) or substances that mimic microbes, and they bind to pattern recognition receptors of the innate immune system, such as Toll-like receptors. Thus, adjuvants trick the immune system into responding to purified protein antigens in a vaccine as if they were parts of infectious microbes. These issues are of practical importance because enhancing the expression of costimulators may be useful for stimulating T cell responses (e.g., against tumors), and blocking costimulators may be a strategy for inhibiting unwanted responses. Agents that block B7:CD28 are used in the treatment of rheumatoid arthritis, other inflammatory diseases, and graft rejection, and antibodies to block CD40:CD40L interactions are being tested in inflammatory diseases and in transplant recipients to reduce or prevent graft rejection.

statins

competitive inhibitor of HMG-CoA reductase so that cells upregulate the production of LDL receptors i order to bring more cholesterol intothe cell (helps reduce blood levels of LDL) -effect is especially important in the liver recall that with broken LDL receptors, the cells are making a lot of Cholesterol because they aren't sensing the endogenous cholesterol so the HMG CoA reductase is on overdrive

hallmarks of targeted therapy in terms of side effects and treatment regimen

continuous dosing; fewer side effects because they tend to target much more selectively; side effects can include difficulty with wound healing (anti-VEGF), early menopause (hormone antagonists) - not quite targeted but more selective than chemo

How have the two types of signals been targeted for therapy?

costimulation can be blocked by CTL4-Ig and there is ongoing research to study blockage of antigen specific signals from immunodominant self peptides involved in autoimmunity CTL4-Ig (recombinant soluble) has higher affinity for B7 than CD28 so it will prevent interaction of second signal and therefore prevent T cell differentiation also talked about isolating patient's T cells and transfecting them with recombinant fusion gene encoding a membrane protein with extracellular anti-Cd19 antibody binding site (attacking CD19+ B cell tumors) and cytoplasmic tail with severla intracellulat zeta chain ITAM motifs plus the cytoplasmic domain of CD28 - they will then target B cells wihtout needing second signal

calcineurin

cytoplasmic serine/threonine phosphatase that dephosphorylates and thereby activates the transcription factor NFAT. activated by calcium signals generated thru TCR signaling in response to antigen recognition immunosuppressive drugs cyclosporine and FK506 work by blocking clacineurin activity

TAGs

triglycerides/triacylglycerols storage form of fatty acids (fatty acid + glycerol) highly hydrophobic due to the akyl chain of the fatty acids; do not mix well with water so forms a lipid droplet that must be surrounded by a protein coat.

what is the basis for ethnicity

defined based on social, linguistic, and cultural features self-identified ethnicity - what ppl call themselves (some correlate well iwth continental ancetry) but doens't imply causation

What determines if OAA made by pyruvate carbozylase goes to the TCA cycle to support energy needs or exit mito into gluconeo?

depends on availability of ATP and NADH, if levels are low then energy needs of the cell are great and will move into the TCA if, in the fasting state, beta ox is high and supplying the NADH and acetul coa, the NADH will slow the TCA cycle (at pyruvate dehydrogenase) and acetyl coa levels will rise, stimulatin gproduction of OAA by pyruvate carbozylase to exit cell and become glucose Key: cell will prioritize its own ATP generation until levels are sufficient and then will channel the OAA into glucose production

Volume of distribution

describes the extent to which a drug partitions btwn plasma and tissue compartments. Quantitatively, Vd represents the fluid volume that would be required to contain the total amount of absorbed drug in the body at a concentration equivalent to that in the plasma at steady state extrapolated volume based on teh concentration of drug in the plasma, NOT a physical volume low for durgs that are retained primarily within the vascular compartment and high for durgs that are highly distributed into muscle, adipoase, and other nonvascular compartments useful parameter for claculating the loading dose of a drug required to achieve a particular plasma concentration fact that drug clearance is usually a first order process allows calculation of Vd (constant fraction of drug eliminated/ unit time) in order to extrapolate Co on the Y axis Vd= administered dose/ Co note picture is for a 70 kilo person

Absorption

drug absorption from the site of administration permits entry to teh therapeutic agent (directly or indirectly) into the plasma the duration of action and peak plasma concentration of a drug can be affected markedly by the drug's absorption rate three drugs have the same bioavailability, volume of distribution, and clearance in identical doses but different rates of absorption. Drug A reaches the highest peak plasma concentration, since all of the drug is absorbed before significant elimination can take place. Drug C is absorbed slowly and never achieves a high plasma concentration, but it persists in the plasma for longer than drugs A or B because absorption continues during the elimination phase. It should be noted that the hypothetical drugs A, B, and C could all be the same drug administered by three different routes. For example, curve A could represent intravenous glucocorticoid administration, curve B could be a depot intramuscular injection, and curve C could be an ultraslow-release subcutaneous formulation of the same drug. Effect of protonation (pH) on absorption: The take home point is that acidic drugs will tend to be absorbed better at a lower pH, whereas basic drugs will tend to be absorbed better at a higher pH.

pyogenic infection

infection characterized by severe local inflammation, usually with pus formation, generally caused by one of the pyogenic bacteria ex. absesses of S. aureus

What are some of the hallmarks of cancer?

em- emerging en-enabling H-hallmarks Sustaining proliferating signaling (EGFR inhibitors) -BCR-ABl -Her2 -estrogen/progesterone receptors -Ras/Raf/Map -P13k -PTEN (can't turn a pathway off; PI3k inhibitor) -Mtor Evading Growth Suppressors -P53: guardian of the genome (G2) - also resisting cell death- reg Tf stabilized in presence of DNA damage (upregulates P21 inihibts cyclin B) -Rb (G1 inhibitor of E2F for Cyclin E so you skip D requirement or need for GFs) -APC- more an EMT thing -BCL-1 (translocation, lymphomas - anti-apoptotic) telomerase- enabling replicative immortality activating invasion and mets EMT transition (VEGF importance) - not a broken part of the cell but using old machinery to a new end Enabling: genome instability an dmutation, avoiding immune destruction, tumor promoting inflammation (acute inflammation can have tumor promoting effects) - thoughts ot add "I" to TMN, deregulating cell energetics

PLCgamma1

enzyme that catalyzes hydrolysis of the plasma membrane phospholipid PIP-2 to geneate IP3 and DAG becomes activated in lymphocytes by antigen binding to the antigen receptor

glutamine synthase

enzyme that makes glutamine from glutamate and free ammonia

bacterial capsule

esp. strep pneumoniae (but also GAS and some straings of S. aureus) defenses against opsonization and phagocytosis One of the main host defense mechanisms against bacterial infection involves the complement system, which can be directly bactericidal through the generation of the lytic membrane attack complex. The complement system is highly efficient in eliminating most extracellular bacteria. Other organisms, like the pneumococcus, are not killed by complement alone but require phagocytosis by neutrophils or macrophages, the professional phagocytes. Recognition by professional phagocytic cells, however, requires signaling through opsonization, a process whereby complement components with or without antibodies are activated on the bacterial cell surface. A successful pathogen circumvents these mechanisms by completely enveloping its cell surface in a thick layer of hydrophilic polysaccharide, or capsule. The polysaccharide does not activate complement efficiently in the absence of a specific antibody and thus serves to protect the underlying components of the bacterial cell surface. In other words, the capsule provides the pneumococcus with "stealthlike" capability.

Why is statistical correction for certain factors (like matching for socioeconomic status") not a good way to interpret genetics as a causal agent?

ex. Bjorn tennis player Looking at likelihood of first name Bjorn correlates with Swedish ancestry after controling for socioeconomic statis, still diff in genetic ancesty that would correlate well with person's first name is Bjorn instead cultural and geo separation of Swedes led to differences in ancesty and it is these diff that lead to name Bjorn

bottleneck

ex. founder effect decrease in size occurs when there is a marked or prolonged reduction in the # of ppl in a pop (will affect effect of drift) 2 effects: 1 particular disease caused by the mutation may become more commo if the number of founders is relatively small relative to carrier rate in teh original population 2 most ppl who have the disease will have this particular allele (rather than allelic heterogeneity) - this is the founder effect - everyone who has this allele will traec back to one ancestor in the founder population so allele will be on one long haplotype (young and useful for GWAS (ex. Fdel506 and Ashkenazis and Finns) - 35 diseases more common in Finladnd with a predominant allele while some diseases are basically absent yet disease burden is the same (WE ARE ALL CARRIERS)

alpha-keto acid

ex. pyruvate (post deamination of alanine) a carbon skeleton (without the ammonia) that is one of the products of transamination transamination reaction convert amino acids to alpha-keto acids by transferring the amion group from the AA to alpha-ketoglutarate (forming glutamate)

Out of Africa theory

explains major features of human genetic varitaion that we observe when we compare populations vast majority of genetic variatns exicst in African populations while pop further removed from Africa show successive reductions in the fraction of genetic variatns observed in Africa vast majority of common (hence old) genetic variation that is seen outside of Africa also seen inside of Africa (but only a subset of African in seen in the rest of the world) common variants are typically old; lower frequency tend to be more recent in origin support: at initial split, West African population was small, so rare variants didn't make it out of africa at all (exit was a founding event) - why there is more genetic variation in this older population (rare variants in other populations are newer) routes of migration inferred from DNA studies but match the archeological record more diversity within africa than outside of africa

Th2

functional subset of CD4 cells that secrete a particular set on inflammatory cytokines, including IL4, IL5, and IL13 whose principal function is to stimulate IgE and eosinophil/mast cell mediated immune reactions Unlike T H 1-mediated activation, which enhances the ability of macrophages to kill microbes, T H 2-mediated macrophage activation enhances other functions, such as synthesis of extracellular matrix proteins involved in tissue repair. This type of response is called alternative macrophage activation (see Fig. 2-10 ). Some of the cytokines produced by T H 2 cells, such as IL-4, IL-10, and IL-13, inhibit the microbicidal activities of macrophages and thus suppress T H 1 cell-mediated immunity. Therefore, the efficacy of cell-mediated immune responses against a microbe may be determined by a balance between the activation of T H 1 and T H 2 cells in response to that microbe.

Th17

functional subset of CD4 helper T cells that secrete a particular set of inflammatory cytokines, including IL-17 (and Il-22) that are prtoective against bacterial and fungal infections and alsom mediate inflammatory reactions in autoimmune and other inflammatory diseases. Therefore, these cells are important in defense against extracellular bacterial and fungal infections. Mutations in genes involved in the development and functions of these cells result in increased susceptibility to bacterial and fungal infections, particularly mucocutaneous candidiasis. This subset, which secretes IL-17 and IL-22, was discovered because of its role in animal models of immunologic diseases (multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis) and is increasingly being implicated in these diseases in humans. T H 17 cells secrete cytokines that recruit leukocytes, mainly neutrophils but also monocytes, to sites of antigen recognition.

why do properties differ across human populations and how can this cause a problem in genetics?

geographic and/or cultural separation -> separation leads to: 1. genetic variants (some selection, mainly random drift) - huge population growth has contributed to this 2. environmental exposures (will also cause selective pressure) 3. cultural practices 4. self-identified/externally labeled ethnicities all of these can be correlated to the fact that they arose with the separation - problem bc genes are often looked at as being causal leading to misconception that genetic differences are the causes of differences between groups (when it could be any of the above) THEREFORE these correlations are FUNDAMENTALLY CONFOUNDED and can lead to mistakes of causation fallacy ex. disease risk and name "Bjorn" with Swedish ancestry

What is the role of alanine in amino acid transport from muscle to the liver?

glucose-alanine cycle set the stage: branched AA cannot be synthesized in the liver (lack the enzymes) so they are catabolized in skeletal muscle but you have to get the urea and you have a lot of pyruvate hanging around Transamination reactions! 1. Amino acid gives amino group to alpha ketoglutarate which yields glutamate and alpha ketoacid. 2. glutamate gives amino group to pyruvate which becomes alanine alanine then goes to the liver, where the amino group will be processed into urea and pyrvate is funneled into gluconeo note pyruvate is an alpha ketoacid!

For each of the following amino acids, how would its amino groups end up in urea? Trace the steps involved (including transamination steps that might be required). Glutamine

glutamine yields glutamate and NH3 thru GLUTAMINASE NH3 can go straight to the urea cycle glumate then can lose its NH3 to become alpha ketogluterate thru glutamate dehydrogenase

From the sesssion, why does propofol have a short duration but a long elimination half-life?

half-life describes elimination but drug is driven by DISTRIBUTION drug goes to highly vascularized regions first then reversibly will re-enter the blood due to gradients and move onto the tissues - distribution is the key here - threshold to get them asleep must be somewhere above equilibrium between the two compartments (to prevent elimination) graph C!

What is the half-life of a drug? How is this related to the clearance of the drug?

half-life describes the amount of time required to reduce the plasma drug concentration by one half. The drug with a shorter half-life will have a larger clearance clearance depends on the half-life by inverse relationship (see equation)

non-small cell lung cancer (carcinoma)

historical classification - no longer standard of care term includes all primary lung carcinomas other than small cell carinoma ; two most common types (now distinguished) adenocarcinoma and squamous cell carcinoma; clumped together bc tend to metastasize late in course and surgical resection is initial treatment of choice for both Both have better prognonsis than small cell and surgery for early stage disease adenocarcinoma most common in nonsmokers; squamous cell more common in smokers Adenocarcinomas have unique chemosensitivty profie and around 60% have a defined oncogenic driver (usually EGFR)- making it targetable squamous cell is associated with pulmonary hemorrhage if used with antiangiogenic agents (ex. VEGF inhibitor) and is rarely defined with an oncogenic driver. THerefore has limited targetability for therapy.

How is VLDL metabolized?

like chylomicrons, particles contain mostly TAGs, with relatively small amount of CEs 1. VLDLs exit liver with only ApoB100 2. In bloodstream, pick up ApoC-II and ApoE from HDL (ensuring they are widely circulated before LPL can be used to release lipids 3. ApoE increases ApoB100 affinity for LDL receptors (and functions as a liver signal), But ApoC II increases affinity for lipoprotein lipase allows for TAG release into the tissues via lipoprotein lipase as it circulates and picks up the appropriate lipoproteins 4. particle is now IDL, some of this (with ApoE) taken back up by the liver 5. ApoC II and Apo E eventually removed and given back to HDL 6. leaves only low affinity ApoB100 which slows the rate that the liver takes it back up which allows other tissues to use their LDL receptors to take up the cholesterol rich particle, enabling delivery of cholesterol to other tissues, eventually remaining LDL particles are taken up by the liver

What are the sources of the Gram-positive bacteria that cause infection and how are these bacteria transmitted?

human resevoir- Person-to-person spread is mediated by respiratory droplets or by direct contact in the case of skin transmission. People with nasal colonization are able to transmit the organisms more efficiently than are people with skin or pharyngeal colonization. Streptococci are transmitted by contact between humans who carry the organism or have disease. Staphylococcus aureus: Humans are the major reservoir for S. aureus. The organisms frequently colonize the anterior nares and are found in approximately 30% of healthy individuals. However, studies of individuals over time have found that up to 90% of people are eventually colonized in the nares with S. aureus at some point in their lives. Carriage of staphylococci usually occurs after direct, skin-to-skin contact with another carrier. Infection may also occur after penetration of a contaminated object through the skin. Virulent staphylococci (i.e., S. aureus) may cause skin infections, from which organisms may disseminate to almost any organ or tissue. Staphylococci spread from person to person, usually through direct contact or aerosols associated with upper respiratory viral or bacterial infections. It is important to remember that S. aureus is an important secondary pathogen associated with patients recovering from influenza and parainfluenza (croup) infections. S. aureus and most other bacteria do not usually penetrate into deep tissues unless the skin or the mucous membranes are damaged or actually cut. Skin damage may be caused by burns, accidental wounds, lacerations, insect bites, surgical intervention, or associated skin diseases. If present in very large numbers, some bacteria, including S. aureus, are able to enter spontaneously and cause disease.

ITAM

immunoreceptor tyrosine-based activation motif conserved morif composed of 2 copies of the sequence tyrosime-x-x-leucine found in cytoplasmic tails of various membrane proteins in teh immune cytoplasmic tails of various membrane proteins in the immune system that are involved in signal transduction. ITAMS are present in teh zeta and CD3 proteins of the TCR complex, in Igalpha and Igbeta proteins in the BCR complex, and in several Ig Fc receptors. When these receptors bind their ligands, the tyrosine residues of the ITAMS become phosphorylated and form docking sites for other molecules involved in propagating cell-activating signal transduction pathways

ITIM

immunoreceptor tyrosine-based inhibition motif six-amino acid (isoleucine-x-tyrosine-x-x-leucine) motif found in teh cytoplasmic tails of various inhibitory receptors in the immune system, including FcgammaRIIB on B cells and killer cell Ig-like receptors (KIRs) on NK cells When these receptors bind their ligands, the ITIMs become phosphorylated on their tyrosine residues and form a docking site for protein tyrosine phosphatases which in turn function to inhibit other signal transduction pathways

Alpha-, beta-, and gamma- hemolysis

in S. aureas: The α-, γ-, and δ-toxins have been traditionally referred to as hemolysins (cytolysins) because they lyse red blood cells contained in blood agar plates. However, this effect on red cells does not appear to play a role in human infection. α-Toxin, γ-toxin, and a related toxin called Panton-Valentine leukocidin are particularly effective in damaging neutrophils. Another non-pore-forming hemolysin is called β-toxin; this protein toxin is a sphingomyelinase (also called hot-cold hemolysin) that prepares red blood cells at 37°C for lysis at 4°C. The role of β-toxin in human disease is unclear but appears to be important in biofilm formation, sometimes called biofilm ligase, especially during endocarditis

What is the role of glucose 6-phosphatase in glycogenolysis and gluconeogenesis?

in the liver, converts glucose-6-phosphate to glucose for transport out of the cell (same enzyme for when the liver is producing glucose from glycogen) Basically the opposite enzyme of glucokinase/hexokinase down the pathway of gluconeogenesis - used in glycogen breakdown and gluconeogenesis

Why can patients with FH not be treated with statins?

increased expression of LDL receptor is essential for hte ability of statins to lower LDL from the blood stream. Bc this step does not work effectively in patients wtih FH, statins do not lower blood LDL levels as efficiently (particularly for homozygous individuals because they do not have any functional genes that can be stimulated) LDL has low clearance- even normal ppl take about 2 weeks; homozygotes for FH do eventually get clearance but it is bc it is taken up in macrophages (no by the tissues- remember macrophages have scavenger receptors that are not specific for ApoB) - if LDL receptors on the liver don't work, the body won't be able to make bile and won't be able to get rid of excess cholesterol (will instead make high levels of intracellular cholesterol in all cell types and high levels of VLDL by liver)

how does del508 relate to genetic drift?

increased frequency and detection rate in Caucasion because of founder effect in out of Africa bottleneck there are more dramatic effects for traditional founder populations such that allelic heterogeneity is lower (larger fraction of the mutations in the pop like Ashkenazis or Finns so even better for screening panels)

roles of AKT

induces glycogen synthesis by inhibiting GSK3 induces glucose transporter expression by blocking GAPs promote cell survival by blocking caspase 9 decreases skeletal muscle degradation by blocking FOXO, which normally allows E3s to ubiquinate muscle protein increases mTOR (translation) by blocking TSC2 downstream on insulin receptor

When a pathogen or a vaccine-antigen breeches the skin, where and when does the initial activation of the adaptive immune response occur? How does the antigen get there?

induction of response occurs in the secondary lymphoid organs when the APC (normally the mature DC with activated CCR7 receptors) comes to the lymphoid organ and presents to the naive T cell gets there by following CCR7 signaling

How can one drug increase the metabolism of another drug?

induction: second drug increases the expression of a P450 enxumes that metabolizes the first drug -second drug induces the expression of the P450 enzymes primary mechanism: transcription, tho augmented translation and decreased degradation also have minor roles (xenobiotic receptors are typically nuclear receptors)

How does M. tuberculosis damage the host?

infection may elicit a host immune response responsible for the pathologic features of the disease. The pathologic features of TB are the result of hypersensitivity to mycobacterial antigens. The classic tissue response involves organization of macrophages, Langhans giant cells, and lymphocytes resulting in formation of granulomas (sometimes called tubercles). Active tuberculosis (TB) most often causes pulmonary disease associated with fever, weight loss, and drenching night sweats. The involvement of macrophages in the containment of M. tuberculosis comes at a price. Two cytokines produced by these cells, IL1 and TNFα, contribute to symptoms of the disease. Among their various activities, these cytokines mediate fever, weight loss, and night sweats. In response to the carbohydrates, lipids, and proteins of the tubercle (granuloma) bacilli, macrophages also produce many other cytokines that modulate the immune response. In particular, increased production of IL10 may suppress the immune response and promote disease progression. The net effects of these complex events are the local pathological manifestations of TB, including caseous necrosis and fibrosis with calcification

How can one drug decrease the metabolism of another drug?

inhibition: addition of a second drug may inhibit the metabolism of the first drug ex. second srug inhibits the P450 enzyme that normally metabolise the first drug - -can allow drug levesl to reach toxic conc. and prolong the presence of an active drug in the body How it happens: 1. ex. Ketoconazole (antifungal) has N moiety that binds ot ht eheme iron in teh active site of P450 enzymes which prevent the metabolism of other drugs by competitive inhibition 2. irreversible inhibition ex. secobarbital (barbituate) which alkylates and permanently inactives the p450 complex

why are proteasome inhibitors well tolerated (in some cases) even though proteasome function is so essential in the cell?

inhibitors primarily only target one of the three different protease functions of the proteasome (chymotrypsin like). as such, they only reduce degradation by 20-30%. Normal cells can survive this but cancer cells can overcome it (ex. 17pdel)

What are the effects of insulin signaling on protein synthesis and glucose uptake in muscle cells?

insulin increases the expression of GLUT4 in muscle cells which increases glucose uptake into the cells. Glucose is stored in teh msucle cells as glycogen (but cannot be released back into circulation because it does not have glucose phosphatase) insulin also favors protein synthesis: the acUvaUon of insulin signaling increases the rate of protein synthesis in skeletal muscle and to some extent also in the liver. This makes sense, as the presence of insulin signals adequate nutrients, so it is a time for the body to rebuild tissue. If insulin falls low enough, the muscle starts to degrade its own protein, and releases the amino acids into the circulaUon, where they travel to the liver. The carbon skeletons are used to synthesize glucose for the brain. Note that although glucagon levels are higher, it has liTle direct effect on skeletal muscle, because muscle does not express the glucagon receptor. The effects of glucagon are important in the liver, because it helps the liver turn the carbon skeletons into glucose which is then released into the circulaUon. However, there is another hormone that can help the skeletal muscle break down its proteins into amino acids. This is a hormone called corUsol, which is a steroid hormone produced by the adrenal cortex (the region surrounding the adrenal medulla). CorUsol acUvates the expression of genes that promote skeletal muscle breakdown. These include E3s of the ubiquiUn system that recognize components of the sarcomere and degrade them. Insulin signaling will activate AKT in the muscle cell inhibiting FOXO which transcibes the above E3s

How do cortisol and insulin control the breakdown of skeletal muscle to amino acids?

insulin: promotes AA uptake by the muscle and muscle protein synthesis and inhibit muscle breakdown (the liver will make glucose to prevent hypoglycemia from lack of carbs in a high protein meal) ** insulin RTK leads to Akt activation which will inhibit FOXO, the reg TF that promotes the expresssion of E3s that recognize and ubiquitinate skeletal muscle protein (also IGF-1) glucocorticoid hormone cortisol (binds receptors in lever as well as muscle): in muscle, changes gene expression at level of transcription (receptor for cortisol is a regulatory TF) which increases the expression of genes that help degrade muscle protein into amino acids and suppresses genes that promote protein synthesis

What are the immune evasion mechanisms of STIs?

intracellular growth- Chlamydia pilus variation- Neisseria capsule production- meningococcus

endosome

intracellular membrane-bound vesicle into which extracellular proteins are internalized during antigen processing have acididc pH and contain proteolytic enzymes that degrade proteins into peptides that bind to class II MHC molecules A subset of class II MHC rich endosomes called MIIC play a special role in antigen processing and presentation by class II pathway

Parenteral

intravenous, intramusclar, subcutaneous deliveries introduces drugs DIRECTLY across the body's barrier defense into the systemic circulation used for drugs that are POORLY absorbed from teh GI tract (like proteins, heparin) and for agents that are unstable in teh GI tract (ex. insulin) also used for treatment of unconscious patients and under circumstances that require a rapid onset of action

S. aureus spread

invasion originates endogneous source and spreads hematogenously

In which ways do lipoprotein lipase and hormone-sensitive lipase regulate fatty acid uptake and release?

lipoprotein lipases (produced in adipocyte but expressed in capillary walls) promotes the uptake of fatty acids from VLDL and chylomicrons to be made into triacylglycerides for storage in adipocytes. hormone sensitive lipase responds to glucogon and epinephrine by metabolizing the triacylglycerides which increases fatty acid circulation (carried away by albumin rafts and picked up thru FFA transporters) (this is inhibited by insulin)

what are the fates of glutamate?

liver: free ammonia or give amino group to OAA to make aspartic acid peripheral: take an ammonia to make glutamine muscle: give ammonia to pyruvate to make alanine (branched AA that don't go to the liver)

How many drugs are typically used to treat symptomatic tuberculosis? How long does treatment take?

isoniazid (INH), rifampin, pyrazinamide (PZA), and ethambutol. Persons with pulmonary TB usually become noncontagious within 2 weeks of therapy if the organisms are sensitive to the drugs administered. Unlike most bacterial infections that can be cured with a single drug, active TB requires multiple drugs for cure because of the remarkable propensity of the organism to develop resistance. Chromosomal mutations associated with resistance to any single drug are already present in about one of every 10^6 to 10^7 bacteria, even though the organisms have never been exposed to the drug. Because tuberculous cavities can contain in excess of 10^11 organisms, many of the bacteria present will be resistant to any single drug, even before treatment is begun.Fortunately, the chance that one organism will become resistant to two drugs simultaneously is small. Therefore, prescribing multiple drugs in combination prevents resistance.Prescribing multiple drugs also allows for a shorter duration of therapy.In the 1970s, it was discovered that including rifampin in the regimen allowed therapy to be shortened to 9 months. Later, it was discovered that adding PZA allowed cure in 6 months.

What does cross-presentation mean and discuss its significance to CD8+ T cell responses.

it is the delivery of proteins from the phagosome or endosome into the cytosol and then proteasomal processing of these proteins special process of DC cells Many viruses do not infect DCs (which are the only cells that can activated CD4 and CD8 cells). Therefore, DCS have to phagocytose or endocytose th virus, viral molecules or virally infected cells. This will put the viral proteins in the endo/lysosomal pathway which is how you activate MHC II for CD4 activation. BUT we need naive viral specific CD8 cells to deal with the virally infected cells. So cross presentation in the dendritic cell allows it to activate both types of cells even if it is not infected and has to get the viral protein from the outside world.

Describe the different functions of Th1, Th2, and Th17 cells, using the cytokines they produce as the organizing principal.

it should be noted that many activated CD4 + T cells may produce various mixtures of cytokines and therefore cannot be readily classified into these subsets, and there may be considerable plasticity in these populations so that one subset may convert into another under some conditions Th1 T H 1 cells stimulate phagocyte-mediated ingestion and killing of microbes, a key component of cell-mediated immunity. The most important cytokine produced by T H 1 cells is interferon-γ (IFN-γ), so called because it was discovered as a cytokine that inhibited (or interfered with) viral infection. IFN-γ is a potent activator of macrophages, especially the ability of macrophages to kill ingested microbes (classical macrophage activation). IFN-γ also stimulates the production of antibody isotypes that promote the phagocytosis of microbes, because these antibodies bind directly to phagocyte Fc receptors and they activate complement, generating products that bind to phagocyte complement receptors Th2 T H 2 cells stimulate phagocyte-independent, eosinophil-mediated immunity, which is especially effective against helminthic parasites ( Fig. 5-16 ). T H 2 cells produce interleukin-4, which stimulates the production of IgE antibodies, and interleukin-5, which activates eosinophils. IgE activates mast cells and binds to eosinophils. These IgE-dependent, mast cell- and eosinophil-mediated reactions are important in killing helminthic parasites. IgE coats the heminths, eosinophils bind to the IgE, eosinophils are activated to release their granule contents, and granule enzymes kill the parasites. In addition, some of the cytokines produced by T H 2 cells, such as IL-4 and IL-13, promote the expulsion of parasites from mucosal organs and inhibit the entry of microbes by stimulating mucus secretion. The cytokines of T H 2 cells also activate macrophages. Unlike T H 1-mediated activation, which enhances the ability of macrophages to kill microbes, T H 2-mediated macrophage activation enhances other functions, such as synthesis of extracellular matrix proteins involved in tissue repair. This type of response is called alternative macrophage activation Th17 T H 17 cells induce inflammation, which functions to destroy extracellular bacteria and fungi and may contribute to several inflammatory diseases. This subset, which secretes IL-17 and IL-22, was discovered because of its role in animal models of immunologic diseases (multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis) and is increasingly being implicated in these diseases in humans. T H 17 cells secrete cytokines that recruit leukocytes, mainly neutrophils but also monocytes, to sites of antigen recognition. Therefore, these cells are important in defense against extracellular bacterial and fungal infections. Innate immune system influence

Major Histocompatability Complex

large genetic locus on human chromosome 6 that includes the highly polymorphic genes encoding the peptide-binding molecules regozniged by T cels. Also includes genes encoding cytokines, molesulces inolved in antigen processing, and complement proteins

what factors influence genetic drift

largest influence on genetic variation size of population, number of generations - "a long time" is relative to size of population large pop- only minor changes in drift; small pop- large changes major continental populations were medium sized so only a few genes drifted out of the genome -mostly we have chared genetics

What does the uptaek of fat from a lipoportein particle depend on?

level of lipoprotein lipase present in the capillary director of fat delivery

What determines the rate of citrate synthase of the TCA cycle?

levels of OAA determine the rate - BUT pyruvate to OAA can go two ways: 1) to make glucose (has to exit mito) 2) to replenish the TCA The simple key to remembering all this is that the cell will prioritize ATP generation. Once ATP levels are sufficient, it will then channel OAA into glucose produce. **If the levels of ATP and NADH are low, it means the cell is energy depleted, and therefore the OAA will enter the TCA cycle to support energy generation- this will generate ATP and NADH. ++HOWEVER, in the fasting state, there is a lot of beta oxidation that is supplying NADH and acetyl CoA. Because the liver is getting a lot of NADH from beta oxidation, it needs less from the TCA cycle. The high levels of NADH will slow the TCA cycle, and acetyl coA will rise, stimulating production of OAA. But in this case, the OAA will exit the mitochondrion to be used for gluconeogenesis. So the liver will rely on B ox while sending glucose out for the brain

β2 microglobulin

light chain of a class I MHC molecule that is extracellular protein encoded by a nonpolymorphic gene outside of the MHC, is structurally homologous to an Ig domain, and is invariant among all class I molecules

apoB100

longer version of the apoB gene (100%) made in the liver and acts as scaffold for VLDL also found on IDL and LDL major binding site for LDL receptor (responsible for uptaek of particle by the liver)

LDL

low density lipoprotein with just apoB100, job is to distribute cholesterol to teh cells (chylomicrons can't do this)

coreceptor

lymphocyte surface receptor that binds to an antigen complex at the same time that membrane Ig or TCR binds the antigen and delivers signals required for optimal lymphocyte activation CD4 and CD8 are T cell co-receptors that bind nonpolymorphic parts of an MHC molecule concurrently with the RCR binding to polymorphic residues and the bound peptide CD2 is a co-receptor in B cells that binds to complement-opsonized antigens at the same time that membrane Ig binds another part of the antigen

Alternative macrophage activation (M2 macrophage)

macrophage activation be IL-4 and IL-13 leading to an ANTIINFLAMMATORY and tissue reparative phenotype in contract to classical macrophage acitvation by IFN-gamma and TLR ligands

Classical macrophage activation (M1 macrophage)

macrophage activation by IFNgamma , Th1 cells, and TLR ligands, leading to a proinflammatory and mircrobicidal phenotype. Classically activated macrophages are called M1

The major function of Th1 cells in immune defense is activation of which of the following types of cells? Eosinophils Neutrophils Mast cells Macrophages

macrophages

cortisol

made by the adrenal cortex (glucocorticoid hormone) - released in the fasted state circulates in the blood and binds to receptors in skeletal muscle as well asliver In skeletal muscle, works by changing gene expression at the level of transcription (receptor for cortisol is a reg TF) of genes that help degrade muscle protein into AA and suppresses genes that promote protein syn

!l-17

main cytokine of Th17 (named for it) T H 17 cells induce inflammation, which functions to destroy extracellular bacteria and fungi and may contribute to several inflammatory diseases ( Fig. 5-17 ). This subset, which secretes IL-17 and IL-22, was discovered because of its role in animal models of immunologic diseases (multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis) and is increasingly being implicated in these diseases in humans. T H 17 cells secrete cytokines that recruit leukocytes, mainly neutrophils but also monocytes, to sites of antigen recognition. Therefore, these cells are important in defense against extracellular bacterial and fungal infections.

cytochrome p450 (CYP)

main type of Phase 1 reaction oxidase enzymes name defines the class which includes the heme protein mono-oxygenases AKA microsomal mixed-function oxidases involved in metabolism of ~75% of all drugs used today have broad substrate specificity due to activated O of the complex (pwerful and less specific)

phase II reaction

major form of biotransformation conjugation/hydrolysis reactions lumped together becuz biochem is more relatated (ester and amide hydrolysis use to be considered phase 1) Substrates for these reac%ons include both metabolites of oxida%on reac%ons (e.g., epoxides) and compounds that already contain chemical groups appropriate for conjuga%on, such as hydroxyl (-OH), amine (-NH2), or carboxyl (-COOH) moie%es.These substrates are coupled by transfer enzymes to endogenous metabolites (e.g., glucuronic acid and its deriva%ves, sulfuric acid, ace%c acid, amino acids, and the tripep%de glutathione) in reac%ons that oJen involve high-energy intermediates

phase I reaction

major form of biotransformation oxidation/reduction reactions typically transform the drug into more hydrophilic metabolites (so can be excreted by the kidneys in aqueous urine) by adding or exposing polar func%onal groups such as hydroxyl (-OH) or amine (-NH2) groups. Such metabolites are often pharmacologically inac%ve and, without further modifica%on, may be excreted involve membrane-associated enxymes expressed in teh ER of hepatocytes (and some in other tissues) called OXIDASES

strongest evidence of selective pressure in humans

malaria belt - you don't have balanced pressures elsewhere so you don't see sickle cell carriers variants for sickle cell correlate with malaria selection can lead to differences in allele frequencies across populations another example is lactase persistence (arose many time in many different places- convergent evolution) - correlates well with milke production in cows- co-evolution

Why is malonyl CoA required for fatty acid synthesis? How does it affect the rate of beta oxidation?

malonyl coA is a reciprocal regulator of beta ox in that it is an allosteric inhibitor of CAT 1/CPT1 which inhibits B ex since the substrate is not available in the mito this way once FA biosyn is stimulated, you inhibit B ox to prevent a futile cycle activated acetyl coA in form of malonyl coa functions in the second step of FA syn. After acetyl CoA is attached to the condensing enzyme, malonyl group of malonyl coA is attached to the sulfur at the end of a phospanetheine chain attached to the acyl carrier protein on the other subunit of synthase. The COOH of hte malonyl is released as CO2 which generates a carbanion that attackes the carbonyl atom of the bearby acetyl group and the CE site is not empty and there is a 4C group on teh A - so malonyl coA basically acts as the initial nucelophile and the base of the chain and will always be on the ACP (after oxidation steps, teh chain ends up on teh CE site)

What is the function of reverse cholesterol transport and the role of HDL in this process?

mature HDL removes cholesterol from the cells, facillitated by ABCG1. How this happens (maturation of HDL): 1. Liver makes and secreted the A1 lipoprotein w/o lipids (stage 1 of HDL) 2. when extrahepatic cholesterol levels get too high, expression of cholesterol and phospholipid transporters ABCA1 and ABCG1 are increased-> efflux of cholesterol and phosphlipids 3. A1 lipoprotein gets togehter with these effluxed cholesterols and phospholipids to form nascent HDL 4. LCAT (lecithin:cholesterol acyltransferase), an enzyme in the plasma uses phospholipids and cholesterol in teh nascent HDL to esterify cholesterol and produce mature, globular shaped HDL 5. Mature HDl removes cholesterol from cells facillitated by ABCG1(ABCA1 expressed in a lot of tissues; ABCG1 highly expressed in macrophages to help them get rid of cholesterol and prevent foam cells) 6. scavenger receptors on liver cell or other cells that consume a lot of cholesterol (steroid producting cells) then pick up the HDL cholesterol is removed from the HDL by direct: receptors on liver or steriod hungry cells directly remove the cholesterol and send it thru the membrane, releasing teh protein HDL indirect: cholesterol ester transfer proteins allows exchange of 1/3 of cholesterol in the HDL to move to apoB100 particles to be delivered to cells

glutamate dehydrogenase

mediates the removal of ammonia from glutamate, which prepares the ammonia for disposal occurs in the mito of the liver but also in most other cells of the body -one source of free ammonia in the peripheral tissues that must be disposed of in the liver (can be picked up by glutamine synthesis) uses process of oxidative deamination (of glutamate = major pathway for generating ammonia in the liver); requires NAD+ or NADP+ as an e- accpetor reversible (so can synthesize glutamate from alpha-ketoglutarate and free ammonia)- direction proceeds determined by concentraions of hte reactants as well as allosteric regulators of the glutamate dehydrogenase enzyme

costimulation/ costimulator

molecule on the surface of or secreted by an antigen-presenting cell that provides a stimulus (or second signal) required for the activation of naive T cells, in addition to antigen The best defined costimulators are the B7 molecules (CD80 and CD86) on APCs that bind to the CD28 molecule of T cells

Il-2

molecule that is transcribed by NFAT (as well as IL-2 receptor in activated T cells) The first cytokine to be produced by CD4 + T cells, within 1 to 2 hours after activation, is interleukin-2 (IL-2). Activation also rapidly enhances the ability of T cells to bind and respond to IL-2, by increasing the expression of the high-affinity IL-2 receptor ( Fig. 5-11 ). The receptor for IL-2 is a three-chain molecule. Naive T cells express two signaling chains but do not express the chain that enables the receptor to bind IL-2 with high affinity. Within hours after activation by antigens and costimulators, the T cells produce the third chain of the receptor, and now the complete IL-2 receptor is able to bind IL-2 strongly. Thus, IL-2 produced by antigen-stimulated T cells preferentially binds to and acts on the same T cells, an example of autocrine cytokine action. The principal functions of IL-2 are to stimulate the survival and proliferation of T cells, resulting in an increase in the number of the antigen-specific T cells; IL-2 was originally called T cell growth factor. (IL-2 also is essential for the maintenance of regulatory T cells and thus for controlling immune responses,

Elimination

more general term that excretion that refers to any process that inactivates a drug - encompasses drug metabolism which inactivates teh drug by modifying its structure so that it can no longer affect the target as well as teh idea of extretion which inactivates the drug's ability to interact with the target by physically removing the drug from teh body Fourth major process of pharmacokinetics after metabolism AKA excretion; very general term The drug and its metabolites are eliminated from teh body in urine, bile, or feces Clearance = elimination plus metabolism

cis vs. trans fatty acid

most unsaturated FAs syntehsized by living systems are cis trans are made chemically (reduction- hydrogenation) leading to elongated, not kinked structure that looks more liek a saturated FA trans double bond fixes a FA in extended conformtaiton similar to how a cis fixes a FA in a kinked conformation

How do mutations in the LDL receptor lead to FH?

mutations prevent the uptake of LDL cholesterol by the liver, thereby leading to an increase in circulating LDL levels. Bc the liver does not take up LDL from the blood efficiently (high Km of ApoB100), the liver also continues to produce cholesterol at an elevated rate

amino acids synthesized in the body

nonessential amino acids alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine

NFAT

nuclear factor of activated T cells transcription factor required for the expression of IL-2, IL-2 TNF, and other cytokine genes 4 diff NFATS are each encoded by separate genes; NFATp and NFATc are found in T cells Cytoplasmic NFAT is activated by calcium/calmodulin-dependent, calcineurin-mediated dephosphorylation that permits the TF to translocate into the nucleus and bind to consensus binding sequences in the regulatory regions of IL-2, IL-4, and other cytokine genes, usually in association withoother TFs such as AP-1

ABO antigens What types of antigens are they?

oligosaccharide

glutamine

one of the sources of ammonia for the urea cycle cells use enzyme glutamine synthase to capture any free ammonia that gets produced and incorporates it into glutamate to generate glutamine that can be transported safely in the blood stream back to thel iver where gluatminase regenerates ammonia (captured by the urea cycle) and gluatmate

Ig heavy chain

one of two types of polypeptide chains in an antibody molecule. the basic structural unit of an antibody includes 2 identical disulfide linked heavy chains and two identical light chains each heavy chain is composed of a vraible Ig domain and 3 or 4 contant C Ig domains. the different antibody isotypes are distinguished by structural differences in their heavy-chain constant regions The heavy-chain constant regions also mediate effector functions, such as complement activation or engagement of phagocytes

Excretion

one type of elimination (other type is metabolism) inactivates teh ability of hte drug to interact with the target by physcially removing the drug from the body. principal site is the kidney, although excretion into the bile is important too

Why is glutamine synthase a key enzyme in protecting peripheral tissues from the effects of ammonia? What is the role of glutaminase in the liver? How are these two ideas connected?

only the liver has the ability to convert ammonia to urea but you can't just send ammonia into the blood stream (incredibly toxic to the brain) glutamine synthase is used to capture any ammonia that gets produced which is then incorporated into glutamate to generate glutamine which is transported safely in the blood stream back to the liver. In liver, enzyme glutaminase regenerates ammonia and glutamate where the free ammonia can be directly captured by a reaction in the urea cycle Basically, you gotta get ammonia out of hte muscle and into the liver where the urea cycle is without sending toxic ammonia thru the blood

essential fatty acid

out bodies can directly synthesize "mon-unsaturated" fatty acids (one double bond) but don't have the machinery to introduce a second double bond so we can't make polyunsaturated fatty acids and have to consume them in teh diet linoleic acid and alpha-linolenic acid are considered essential (seeds, nuts, oils) - once ingested, they can be elongated or desaturated. Not that linoleic acid is the precursor to arachidonic acid DHA made from alpha-linolenic acid (and found in fish oils) composes 50% of the total lipid content of the brain

avidity

overall strength of interaction between two molecules such as an antibody and an antigen depends on both the affinity and valency of interactions, therefore the avidity of a pentameric IgM antibody, with 10 antigen-binding sites, for a multivalent antigen may be much greater than the avidity of a dimeric igG molecule for the same antigen. can also be used to describe the strength of cell-cell interactions, which are mediated by many binding interactions betwen cell surface molecules

What is the role of glutamate dehydrogenase in the liver?

oxidative deamination of glutamate require NAD+ or NADP+ as an electron acceptor REVERSIBLE REACTION (can also be used for synthesis of glutamate from a-ketoglutarate and free ammonia In the liver, occurs in the mito but can also be an important source of free ammonia in peripheral tissues that must be disposed of in the liver

neonatal immunity

passive humoral immunity to infections in mammals in teh first month of life, before full development of the immune system mediated by maternally produced antibodies transported across the placenta into the fetal circulation before birth or derived from ingested milk and transported across gut epithelium

conjugation reactions

phase 2 biotransformation - modify compounds thru attachment of hydrophilic groups to create more polar conjugates -occur independently of O/R rxns, which often competes for substrates with O/R rxns -virtually all drug products are inactive -often require transport out of the cell (since they are now polar) Some products of oxida%on and reduc%on reac%ons, however, require further modifica%ons prior to excre%on. In these reac%ons, a drug (represented by D) or drug metabolite (represented by D-OH and D-NH2) is conjugated to an endogenous moiety. Glucuronic acid, a sugar, is the most common group that is conjugated to drugs, but conjuga%ons of acetate, glycine, sulfate, glutathione, and methyl groups are also common. The addi%on of one of these moie%es makes the resul%ng drug metabolite more hydrophilic and oJen enhances drug excre%on. (Methyla%on, an important excep%on, does not increase drug hydrophilicity.) ex. drug A activates a nuclear receptor called pregnane X receptor that heterodimerizes with the retinoid X receptor to form a complex that initiates transcription of P450 enzyme

Describe the regulation of cholesterol synthesis and uptake in the extrahepatic cells/ regulated expression of LDLRs?

point of regulation: SREBP TF When cell cholesterol levels are low... increased expression of LDL receptor and expression of HMG CoA reductase absence of cholesterol at SCAP to attach to COP II (ER to golgi vesicle transport protein) to take attached SREBP to golgi once in golgi, a serine protease cleaves SREBP, making it sensitive to another protease (metalloprotease) which releases the basic helix-loop-helix (bHLH) domain of SREBP from teh membraen so it can move to the nucleus where it binds and activates teh tsterol response element (SRE)

polyunsaturated fatty acid

polyunsaturated FA may bind and activate receptors that inhibit the expression of genes invovled in cholesterol and fat syn, or stimulate expression of genes that break down fat so diets with high amounts of sat and trans fats may promote fat syn

Peptide binding groove/cleft

portion of an mhc mol that binds peptides for display to T cells. the cleft is composed of paired alpha helices resting on a floor made up of an eight stranded B pleated sheet (the protein binding motif) the polymorphic residues which are AAs that vary among diff MHC alleles are located in and around this cleft

How can genetic differences affect drug metabolism?

ppl exhibit polymorphisms or mutations in one or more enzymes of drug metabolism, changing the rate of some of these reactions and eliminating others altogether some diff may be more frequent in some races ex. how affecting pharmaceuticals: most companies avoid developing a drug that is metabolized by a highly polymorphic enzyme bc may lead to wide inter-individual variablity in a response (ex. P450 2D6)

When we eat sugar it can be used in our body to synthesize fatty acids, but fatty acids cannot be made into sugar. Why?

pyruvate dehydrogenase converts pyruvate into acetyl coa ( a precursor for fatty acids) but there is no reverse pathway. Sugars can be converted to pyruvate through TCA which can go on to become acetyl coa (first precursor step to the TCA) which can then make fatty acids

Consider the relationship between patterns of genetic variation and self-described ethnicity/ancestry

race is not a biological constract (race does not equal ethnicity) ethnicity is self-defined race/ethnicity labels may have a role in assisting in diagnosis because of correlations with genetic variants, disease rates, environmental exposures, and socioeconomic factors but they are prone to misinterpretation

Rh antigens Do they cause hemolytic disease of the newborn? why or why not?

readily crosses placenta and can cause hemolytic disease of the newborn Rh is a protein so creates IgG that readily crosses the placenta (needs T cell help to cause class switch) therefore, at 28 weeks gestation, we test moms for RH+ with an agglutination test on her serum (for anti +) and her RBCs for presence of RH+

What is the difference between first-order and zero-order kinetics?

refers to whether the drug enzymes are saturated or not 1st order: [D] <<<< Km so rate of drug metabolism and elimination is directly proportional to the concentration of free dutg and a constant fraction of drug is metabolized per unit ot time- linear kinetics because plot of drug concentration v time on semi-log scale is linear 0 order: [D] >>>>> Km so enzymes are saturated (aspirin, ethanol, phenytoin) so Vmax = V and a constant amount of drug is metabolized per unit of time, the rate of elimination is constant and does not depend on the drug concentration

immature dendritic cell

resting DCs that are important for induction of tolerance to self antigens

electron transport chain

results in the pumping of H+ into the intermembrane space and oxidizes NADH and FADH2 -creates an electrochemical gradient (- charge across the inner mito membrane on the matrix side) which is used by ATP synthase to drive the unfavorable synthesis of ATP by coupline it to favorable passage of protons down their electrochemical gradient into matrix -the larger the proton gradient, the slower the rate of electron transport because complex 1 is moving protns against the electrochemical gradient so electron transport will occur at higher rates when ATP synthase is also active in making ATP and dissipating the proton gradient consists of 5 major protein complexes

Distribution

second key process in pharmacokinetics After absorption, the drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids

How is Lyme disease diagnosed using laboratory tests?

serology is currently the only type of diagnostic approved by the FDA designed to detect antibodies made by the body against certain antigens patients with early lyme test may not yet make antibodies (less than 4 weeks); longer than 4 weeks will likely have anitbodies 2 steps 1. serum highly sensitive but not specific immunoassay such as analysa- neg. no further testing 2. serum tested by immunoblotting (IgM and IgG antibodies) - important issue is number of bands as all patients will likely have at least 1 reactive band (5/10 in IgG and 2/3 bands in IgM assay) caveats: don't skip steps -increases false positive results IgM is likely false positive if greater than 6 weeks from infection

Zero order kinetics

some drugs have VERY Large doses (so C is much larger than Km) and velocity simplifies in another way enzyme is saturated by a high free-drug concentration and rate of metabolism REMAINS CONSTANT OVER TIME AKA nonlinear kinetics a constant amount of drug is metabolized per unit of time and the rate of elimination is constant and does not depend on teh drug concentration

Il-4

some of the cytokines produced by T H 2 cells, such as IL-4 and IL-13, promote the expulsion of parasites from mucosal organs and inhibit the entry of microbes by stimulating mucus secretion Some of the cytokines produced by T H 2 cells, such as IL-4, IL-10, and IL-13, inhibit the microbicidal activities of macrophages and thus suppress T H 1 cell-mediated immunity. Therefore, the efficacy of cell-mediated immune responses against a microbe may be determined by a balance between the activation of T H 1 and T H 2 cells in response to that microbe. Il-4 also amplifies the TH2 subset and inhibits others

Spirochete

spiral-shaped bacterium such as the Borrelia burgdorferi that is the pathogen for Lyme disease Borrelia species, along with the leptospires and treponemes, are spirochetes. Like all spirochetes, Borrelia structure consists of a long, thin corkscrewshaped cell surrounded first by an inner (cytoplasmic) membrane, then by a thin peptidoglycan layer, and finally by an outer membrane that is only loosely associated with the underlying structures. Flagella, which provide spirochetes with the ability to swim rapidly through viscous environments, such as host tissues, are contained between the two membranes and determine the corkscrew shape of the cell. The Borrelia species are fastidious, lacking the ability to synthesize amino acids, fatty acids, nucleotides, and enzyme cofactors, and need to scavenge numerous metabolic components from the host.

How does poliovirus damage the host?

stong inhibition of host cell macromolecular synthesis leads to cell death and lysis tissue damage largely from immune system response (CPE)

affinity

strength of the binding between a single binding site of a molecule (eg an antibody) and a ligand (eg an antigen). The affinity of a molecule X for a ligand Y is represented by the dissociation constant (Kd) which is teh conc of Y that is required to occupy the combining site of half the X molecules present in solution. Most antibodies produced in a primary immune response have a K d in the range of 10 −6 to 10 −9 M, but with repeated stimulation (e.g., in a secondary immune response), the affinity increases to a K d of 10 −8 to 10 −11 M. This increase in antigen-binding strength is called affinity maturation

For each of the following amino acids, how would its amino groups end up in urea? Trace the steps involved (including transamination steps that might be required). Non-branched chain amino acid (eg, glycine, proline,...etc)

transaminase is not oxidative! These AA give their amino groups to glutamate which can then donate NH3 directly to the urea cycle OR give the NH3 to aspartate which will enter the urea cycle glutamine, glutamate, and aspartate are the three amino acids that can directly produce ammonia or donate to the urea cycle

TH1

subset of T helpers that secrete a particular set of cytokines including IFN-gamma principal function is to stimulate phagocyte-mediated defense against infections, especially with intracellular microbes. IFN-γ also stimulates the production of antibody isotypes that promote the phagocytosis of microbes, because these antibodies bind directly to phagocyte Fc receptors and they activate complement, generating products that bind to phagocyte complement receptors (see Chapter 8 ). Because of these actions of IFN-γ, T H 1 cells are critical for ingestion and killing of intracellular microbes in phagocytes. Individuals with mutations affecting the generation or function of T H 1 cells are extremely susceptible to infections by such organisms, especially atypical mycobacteria, which are common in the environment and usually not pathogenic in healthy people. IFN-γ also stimulates the expression of class II MHC molecules and B7 costimulators on macrophages and dendritic cells, which may serve to amplify T cell responses.

What are the substrates and products of a cytochrome P450 enzyme?

substrates: Drug (75% of current drugs), O2, NADPH, H+ products: Drug-OH, H2O, NADP+ can use electron carriers to transfer e- from NADPH to O2 (ex. iron moiety) 5 of human P450s account for ~95% of oxidative metabolism of drugs

What are the substrates and products of alpha ketoglutarate dehydrogenase? How is the regulation of this enzyme similar to pyruvate dehydrogenase?

substrates: alpha-ketoglutarate, NAD+, CoA products: succinyl coA, CO2, NADH This reaction is chemically similar to that catalyzed by pyruvate dehydrogenase, and the enzyme is regulated in a similar fashion, as it is inhibited by its products succinyl-CoA and NADH and also by ATP.

What are the substrates and products of a transaminase? What role do these enzymes play in amino acid catabolism?

substrates: amino acid and alpha ketoglutarate products: glutamate and alpha-keto acid coenzyme PLP from vitamin B6 is bound to the enzyme muscle has high levels of amintransferases for branched chain AA whereas liver does not but liver will also have high levels of these enzymes during fasting to shuffle pyuvate thru gluconeo

What are the substrates and products of citrate synthase?

substrates: oxaloacetate and acetyl coa products: citryl coa -> citrate levels of OAA are generally low so pathway can be stimulated by adding more OAA (via pyruvate carboxylase which is activated when acteyl coa levels rise)

What is the role of lipoprotein lipase-mediated lipolysis and how it is regulated?

synthesized by most tissues but especially important in muscles and adipose (remember that the muscles use the FA for energy in the fasting state) LPL is secreted into the space surrounding the cell where it is transported across teh endothelium to the lumen of the capillary (made in the tissues, used in teh capillary) Once at capillary endothelium (EC), proteoglycans and protein GPIHBP1 bind LPL to faciliate chylmicron and VLDL interactions . FAs then diffuse out of hte capillaries and are taken up by surrounding tissues TAGS in larger lipoproteins are hydrolyzed at a faster rate taht TAG in smaller particles size of hte particle determines its chance of contacting the vascular wall - REGULATION

Would you consider a proteasome inhibitor to be a conventional chemotherapeutic agent or a targeted agent?

targeted b/c they are highly selective in that they target the 26s proteasome complex (chymostripsin-like protease part of the 20s subunit) bortezomib works blocks proteasome function in cells, which subsequently down regulates NFkappaB activation (doesn't degrade its inhibitor) and triggers apoptosis (jnk pathway) -specificity is in the difference of hte physiology of the cancer cells that makes them more dependent on the proteasome

What is an example of a conventional chemotherapeutic agent that we discussed in the course? What cellular processes do conventional agents typically target? What is the basis for their "selectivity" (such as it is) for cancer cells vs. normal cells?

temozolomide (requires MMR): damages DNA such that alkylated bases are added during DNA replication and causes a mismatch that the MMR does not notice... enters into a futile cycle (because recognizes older strand)... and this leads to cell death. Temozolomide takes advantage of the fact that certain cancer cells have unstable DNA (how it hits cancer cells less than normal cells) - you have a mismatch from a chemical modification which creates a lot of ss breaks by making the pathway work like crazy but not really fixing the damage. Overtime damage accumulates (cannot fix the error) normally targets rapidly dividing cells

zeta chain

transmembrane protein expressedin T cells as part ofht eTCR complex that contaims ITAMS in its cytoplasmic tail and binds the zap-70 protein tyrosine kinase during T cell activation

What is the difference between the distribution phase and the elimination phase?

the initial phase, from immediately after administration thru rapid fall in concentration is the distribution phase during which a drug rapidly isappears from the circulation and enters the tissues (drug distribution is the process by which drug reversible leaves teh bloodstream and enters the interstitium) elimination phase: when drug in teh plasma is in equilibrium with drug in the tissues; in first order kinetics, the plot will show a straight line during the eliminiation phase and is used to determine the half-life delivery of drug from plasma to the interstitium primarily depends on cardiac output, regional blood flow, capillary permeability, tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity of the drug

apolioprotein

the isolated protein of the lipoprotein

IL-2 is produced by CD4 T cells in response to antigen specific stimulation, and is a major driver of T cell proliferation. Despite the fact that only a few T cells in a given lymph node are specific for a particular antigen, the IL-2 produced causes preferential proliferation of antigen specific clones. What is responsible for minimizing so called "bystander" proliferation?

this enormous expansion of T cells specific for a microbe is not accompanied by a detectable increase in bystander cells that do not recognize that microbe. The first cytokine to be produced by CD4 + T cells, within 1 to 2 hours after activation, is interleukin-2 (IL-2). Activation also rapidly enhances the ability of T cells to bind and respond to IL-2, by increasing the expression of the high-affinity IL-2 receptor.Naive T cells express two signaling chains but do not express the chain that enables the receptor to bind IL-2 with high affinity. Within hours after activation by antigens and costimulators, the T cells produce the third chain of the receptor, and now the complete IL-2 receptor is able to bind IL-2 strongly. Thus, IL-2 produced by antigen-stimulated T cells preferentially binds to and acts on the same T cells, an example of autocrine cytokine action. Bystander T cells will not produce the autocrine cytokine IL-2 and thus will never produce the high affinity receptor IL-2 even though they will always have the 2 chain, low affinity version

How the body can get rid of excess cholesterol?

thru bile acids or thru direct excretion into the intestines

urea cycle

to drive the urea cycle faster, increase any of the components of the cycle - beauty of having arginine as an intermediate because rate of UC linked to amount of available AA NH4 in the mito can come from glutamine (glutaminase), oxidative deamination of glutamate by glutamate dehydrogenase, or bacterial oxidation of AA in the gut

Why is it important to bind the right peptide to the right MHC molecule?

to mount the T cell mediated response appropriate to infection... bacteria will be endocytosed and go thru lysosomal pathway to activate CD4 which is important to activate macrophages to engulf the bacteria. Endosomal phagocytosis of toxins will initiate CD4 to activate B cells that will neutralize the toxins infected cells with a virus will initiate the proteasomal pathway (MHC 1) which will activate CD8 to kill the infected cells

how is proteolysis by trypsin different than proteolysis by the proteasome?

trypsin: serine protease that cleaves peptide chains at carboxyl side of lysine or arginine...specificity is regulated by its ability to bind to those amino acids on a protein proteasom: multiprotein complex that can degrade sundry proteins...specificity based on presence of ubiquitin chain on target protein -proteasomes need ATP and do not need to be cleaved themselves (do not come in a zymogen form) and are much larger than proteases like trypsin Protesaomes, unlike conventional proteases, degrade proteins processively to small peptides (processing goes all the way to small pieces) whereas conventional protease just makes like 1 cut

ABo antigens Do they cause hemolytic disease of the newborn? why or why not?

unlikely to cross the placenta and cause severe hemolytic disease of the newborn create IgM (t cell indendpendent due to sugar nature) so can't cross the placenta and cause blood type problems

alpha ketoglutarate dehydrogenase

very similar to PDH converts alpha-ketoglutarate into succinyl coA chemically similar to that catalyzed by PDH and the enzyme is regulated in a similat fashion -inhibited by products (succinyl coA and Nadh) and by ATP

bile acids and salts

ways to get rid of cholesterol in the body have detergent-like properties to help solubilize dietary fat

Why not kill off all of the carriers?

we are all carriers of recessive disease alleles each person has greater than 50 recessive lethal or severely deleterious variants Also pleiotropy- genes influence more than one trait, you don't know what you are taking out that might be protective Also they might become NBD (glasses)

vaccines in s. pneumoniae

we don't make vaccines against staph because not a lot of immunogenics againsthte capsule and we normally make the vaccine against the capsule; even without the capsule S. aureus is virulent GAS is great at evading (M protein) and we share an antigen (HA)

How was the possible effectiveness of bortezomib in treatment of multiple myeloma originally discovered? Was it easily predicted based on the biology that was known at the time?

were bortezomib's effects on myeloma expected? hell no. it was a serendipitous discovery that this drug worked well for myelomas. there just happened to be someone with a myeloma in the clinical trial, which included a large array of cancer types, who responded extremely well to the drug. myelomas make an abnormal immunoglobin which is why they are a good target

what are they two major pathways that degrade cellular proteins?

what are they two major pathways that degrade cellular proteins? autophagy and ubiquitin-proteasome system

Elimination phase

when drug in the plasma is in equilibrium with drug in the tissues (two compartment model) and then the drug and its metabolites are eliminated from the body in urine, bile, or feces

prodrug

when metabolite is active such that the administered agent is acting as the "prodrug" - doesn't actually do the intended effect, metabolite does inactive compounds that are metabolized by the body into their active, therapeutic forms ex. selective estrogen receptor modulator tamoxifen (must be hydroxylated) or angiotensin II receptor antagonist losaratan (needs oxidation of alcohol group to a carboxylic acid by P450 2c9) -can be used for therapeutic benefit in cancer chemotherapy (ex. mitomycin C, activated to powerful DNA alkylating agent after reduced by several enzymes and selectively kills hypoxic cancer cells in the core of solid tumors bc 1) these cells have increased levels of the cytochrome P450 reductase that activates it 2)reoxidation of hte drug is inhbited under hypoxic conditions

If you double the dose what do you expect to happen to the half life?

you expect it to last for 1 additional half-life as long as you are under first order linear kinetics if you saturate teh enzymes, then you will see weird things in teh half life

Given that a patient receives the same total dose of drug, what is the effect of increasing dosing frequency?

you would decrease the individual doses of the drug Using smaller doses at shorter intervals reduces the amplitude of the swings in drug concentra%on. However, the steady-state concentra%on of the drug, and the rate at which the steady state is approached, are not affected by the frequency of dosing (assuming the total dose remains the same). In the graph above, curves B and C represent administra%on of the same total dose of drug, and this the levels oscillate around the same mean steady state concentra%on that would be achieved by con%nuous infusion (curve A, black). However, curve B (blue), in which half the dose is given twice as frequently shows smaller fluctua%ons than if the full dose is given once per day (curve C, red).

ZAP-70

zeta-association protein of 70kD cytoplasmic protein tyrosine kinase, similar to Syk in B cells, that is critical for early signaling steps in antigen-induced T cell activation binds to phosphotylated tyrosines in teh cytoplasmic tails fo the zeta and CD3 chains ofthe TCR complex an din turn phosphorylates adaptor proteins that recruit other components of the signaling cascade