Combo 1

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What translocation and affected genes responsible for Mantle cell lymphoma?

(11;14)(q13;q32) CCND1: 11q13 IGH: 14q32

What translocation and affected genes responsible for Ewings sarcoma?

(11;22)(q24;q12) FLI1: 11q24 EWSR1: 22q12

What translocation and affected genes responsible for Follicular lymphoma?

(14;18)(q32;q21) IGH: 14q32 BCL2 18q21

What translocation and affected genes responsible for Prostatic adenocarcinoma?

(7;21) (p22;q22) (17;21) (p21;q22) TMPRSS2 (21q22.3) ETV1 (7p21.2) ETV4 (17q21)

What translocation and affected genes responsible for Burkitt lymphoma?

(8;14)(q24;q32) MYC: 8q24 IGH: 14q32

What translocation and affected genes responsible for Acute myeloid leukemia (AML)

(8;21)(q22;q22) (15;17)(q22;q21) AML: 8q22 ETO: 21q22 PML: 15q22 RARA: 17q21

What translocation and affected genes responsible for Chronic Myelogenous Leukemia (CML)

(9;22)(q34;q11) ABL: 9q34 BCR: 22q11

Class I HLA characteristics?

(A, B, and C) Expressed on all nucleated cells. Present endogenous antigens (viral) to Cytotoxic T cells. Highly polymorphic Composed of an alpha chain and B2 microglobulin (coded outsided of MHC) * B2 microglobulin is required for class I HLA to work, if missing then the HLA would just fold over itself* A1 and A2 domains form a cleft and bind to short peptides approximately 8-10 aa in length. Hydrophobic transmembrane region

Lactase-glucosylceramidase breaks down what?

(B-glycosidase complex (lactase) breaks down lactose) Low activity Rate-limiting enzyme for lactose absorption Hydrolyzes B-1,4 bond (found in lactose) Hydrolyzes B bond in glycolipids.

Sucrase-isomaltase breaks down what?

(Sucrase = sucrose, isomaltase-maltase = branch chains a-1,6 bonds like isomaltase, etc) Sucrase part breaks down sucrose. Isomaltase-maltase part breaks down a-1,6 branches (isomaltose)

What does glucoamylase break down?

(breaks down maltose, maltotriose, etc. to monosaccharides) Exoglucosidase: Specific for a-1,4 glycosidic bonds Hydrolyzes sequentially from nonreducing (the o between sugars) end to form monosaccharides Breaks down maltose, maltotriose Is heavily glycosylated to protect from digestion.

Trehalase breaks down what?

(trahalose) Cleaves trehalose (found in mushrooms, honey, and shrimp) Only enzyme that can cleave trahalose (a-1,1 bond) Trehalase deficiency has symptoms similar to a-amanitin poisoning (diarrhea, liver and kidney failure, death - this is that poisonous mushroom) Cleaves a-1,1 bond

Adaptive immunity characteristics

*B and T lymphocytes* - Highly specific - Extensive diversity - Memory - Self limiting

Clinical importance of stem cells (3)

*Bone marrow transplants* - Must carefully match MHC (major histocompatibility complex) to prevent graft rejection. *Graft vs host disease* (GVHD) *Gene therapy* - SCID (severe combined immunodeficiency - bubble boy) - ADA deficiency (Adenosine deaminase deficiency), replace the gene in HSC's (hematopoietic stem cells)

B lymphocytes

*Bone marrow* Membrane bound Ig (immunoglobulin), serves as receptor for antigen Develop into plasma cells and memory cells All clonal progeny from a given B cell secrete Ab (antibody) molecules with the same Ag (antigen) binding specificity. B cells can bind to anything; sugars, lipids, or proteins. Responsible for generating antibodies, plasma cells are terminally differentiated B cells. b cells become plasma cells whose job is to just secrete antibodies and then die.

T helper cells (TH cells)

*CD4+* Recognize antigen in associated with class II MHC (exogenous antigen) Activated following recognition of Ag-class II MHC on antigen presenting cells (APC's) Activated TH cells divide and give rise to clones of effector cells which secrete various cytokines and play a major role in B cell and TC cell activation and the inflammatory response - TH1- activates Tc, MØ (macrophage), drives isotype switching to IgG. - TH2- activates B cells, drives isotype switching to IgE - TH17- inflammation, extracellular bacterial and fungal infections.

Cytotoxic T cells (Tc cells)

*CD8+* Recognize antigen in association with class I MHC (endogenous antigens) Activated following recognition with Ag-class I MHC complex Secretes few cytokines Directly recognizes and kills target cells (virus infected and intracellular bacteria)

IgG

*Class switching occurs via TH1 cells and IFN-γ* IgG can participate in many immune functions including: - Opsonization - Antibody dependent cellular cytotoxicity (ADCC) - Activation of classical complement - Only antibody that can cross the placenta It is the predominant antibody in the serum It is a high affinity antibody and predominates during the secondary immune response 4 subisotypes IgG1, IgG2, IgG3 and IgG4

IgE

*Class switching occurs via secretion of IL-4 and IL-13.* Low levels in plasma Binds to mast cells and basophils and causes them to degranulate. Used to kill parasites. Responsible for type I hypersensitivity.

IgA

*Class switching occurs via secretion of TGF-β* and to a lesser extent IL-4, IL-10, iNOS, and retinoic acid. This occurs predominantly in the mucosa. Predominant antibody in the secretions: mucosal surfaces, saliva, tears, nasal fluids, sweat, colostrum (first form of milk produced in mammary glands) and breast milk In secretions present as a dimer, so it can bind 4 antigens. Protected in secretion by secretory piece

*Fixation* is usually done by a chemical or mixture of chemicals, permanently preserves the tissue structure for subsequent treatments. Specimens should be fixated immediately after removal from body. Fixation is used to: -Terminate cell metabolism - Prevent enzymatic degradation of cells and tissues by autolysis (self-digestion). - Kill pathogenic microorganisms such as bacteria, fungi, and viruses. - Harden the tissue as a result of either cross-linking or denaturing protein molecules.

*Fixation*

Activation of Macrophages induces what?

*Inflammation* 1. Phagocytosis 2. Production of cytokines 3. Recruitment of neutrophils 4. Diapedesis (the passage of blood cells through the intact walls of the capillaries, typically accompanying inflammation.) All 4 of these actions leads to *inflammation*.

Immune system cells

*Lymphoid* - B cells, T cells, Null cells (NK cells) *Mononuclear cells* - Macrophages (MØ) - Granulocytes -- Neutrophils, Eosinophils, Basophils, Mast cells - Dendritic cells

IL-2 characteristics

*Made by T cells.* Autocrine regulation Main function is activating cytotoxic T cells.

What does Il-4 do?

*Made predominantly by Th2 cells.* Essential for class switching (along with IL-13) to IgE. Activates Th2 pathway and inhibits Th0 and IFN-y (and therefore macrophage activation). Main function is B cell activation and lass switching to IgE. IL-4 can also induce eosinophil development and differentiation.

Natural killer cells (NK cells)

*No B/T cell markers* No specific receptor for antigen (Ig/TCR) Cytotoxic activity against a wide array of tumors Receptor for antibody (CD16)-ADCC Chediak-Higashi (autosomal recessive) No NK cells- increased incidence in lymphomas.

T lymphocytes

*Thymus* Membrane receptors for Ag (antigen), similar to Ig (TCR (T-cell receptor)) TCR (T-cell receptor) only recognizes Ag (antigen) in association with MHC (Major histocompatability complex) 2 major subsets (2:1) - TH (T- helper cells (high maintenance)) (CD4+) - TC (T- cytotoxic cells) (CD8+) These are the most important cells of the immune response. Can only recognize protein. Don't just go out and recognize antigen, every single antigen has to be handed to them called MHC (major histocompatability complex). Much more high maintenance to B cell. All T cells have CD3. CD4 found in TH. CD8 found in TC.

Nonessential amino acids are synthesized from four common metabolites, what are they?

- *Pyruvate* (alanine) - *Oxaloacetate* (aspartate, asparagine) - *a-Ketoglutarate* (glutamate, glutamine, proline, arginine*) - *3-phosphoglycerate* (serine, glycine, cysteine) *arginine essential only during growth (phenylalanine -> tyrosine) (Tyrosine and Cysteine conditional nonessential because phenylalanine and methionine needed to synthesis in the body respectively)

Liver's role in central receiving, recycling

- Compounds entering blood via digestive tract must go through liver 1st (enterohepatic circulation) - Retrieves usable portions - Removes toxic compounds - Can make many different molecules from many different precursors (e.g. cen convert all protein amino acids to glucose, FA, or KB)

Maple syrup urine disease symptoms

- Distinct sweet odor of urine - Poor feeding, vomiting - Lethargy - Abnormal movements - Delayed development - Seizures, coma, and death possible without treatment.

Affinity maturation

- In the course of a humoral response, the average affinity of the antibodies produced increases by 100-10,000 fold - This is the result of somatic hypermutation and the Ag selection of high affinity clones - Somatic mutation - point mutations, deletions, or insertions into the V,D, or J region of rearranged Ig genes - The majority of mutations occur in the variable regions - Higher affinity antibodies are positively selected, lower affinity antibodies are signaled to die by apoptosis So the reason IgG, IgA, and IgE have higher affinity than IgM is because of affinity maturation. During T cell dependent B cell response, B cells start proliferating in the germinal centers, dividing quickly and acquiring somatic mutations (point mutations, deletions, or insertions) in the variable region. The mutations that are good and increase binding affinity to antigen stay and those B cells divide and make copies of itself. Those that bind not so well, or just okay, get killed by apoptosis. When we get these high affinity antibodies the B cells class switch so that only the IgG, IgE, IgA ones have these high affinity antibodies.

Management of patient with liver cirrhosis

- Irreversible in later stages - Alcohol abstinence - Avoiding superimposed insults to live (up-to-date with vaccinations, avoiding hepatotoxins) -Management of symptoms and prevention of complications.

How are amino acids transported into cells from the blood

- Primarily by Na+ dependent cotransporters. - Different genes and amino acid composition, specificities similar to transporters in intestinal cells.

Mild to moderate intensity long-term exercise

- Release of lactate decreases over the course of the exercise due to aerobic use of glucose and fatty acid becoming predominant. - Liver maintains blood glucose via liver glycogenolysis and gluconeogenesis. Both glycogenolysis and gluconeogenesis stimulated by epinephrine (and glucagon in liver). -Muscle AMPK stimulates GLUT4 translocation (increase glucose uptake). After ~40 min, increased dependence on FA. - Liver glucose output decreases - FA dependence becomes greater w/ increasing exercise duration - Type I slow-twitch oxidative fibers Hormonal signals include decreased insulin and elevated glucagon, epinephrine, and norepinephrine. GH, cortisol, and TSH may also contribute.

Alcaptonuria symptoms

- Urine turns black when exposed to air. - Ochronosis, a buildup of dark pigment in connective tissues such as cartilage and skin, as well as in sclera of eyes. (Blue-black pigmentation usually appears after age 30.) - Often develop arthritis (spine and large joints) (early adulthood)

Free energy change of ATP-> ADP

-31 kJ/mol, occurs via hydrolysis

Cystinuria

-Defect in transport of amino acids, decreased resorption of amino acids in kidneys ( means more in urine). - Kidney stone formation due to insolubility of cystine.

Problems with amino acid metabolism: Phenylalanine and tyrosine (3)

-Inborn errors of metabolism - States required to test for these PKU, Alcaptonuria, and Tyrosinemia I PKU: defective phenylalanine hydroxylase (PAH) leads to hyperphenylalaninemia, irreversible mental retardation, delayed psychomotor skills, tremors, seizures, hyperactivity. lifelong dietary modification needed. Alcaptonuria: Homogentisate oxidase is defective, homogentisate accumulates, auto-oxidizes to a dark pigment that is excreted in urine. Tyrosinemia I: Genetic deficiency in fumarylacetoacetate hydrolase; fatal within first year of life. Phenylalanine + *Phenylalanine hydroxylase* (causes PKU) -> Tyrosine + PLP + *Tyrosine aminotransferase* (causes tyrosinemia II) -> p-hydroxyphenylpyruvate -> Homogentisate + *homogentisate oxidase* (causes alcaptonuria) -> -> *fumarylacetoacetate hydrolase* (causes tyrosinemia I) -> fumarate and acetoacetate

Monosaccharides

-fructose (some fruit, "soda pop") -Ribose (from DNA & RNA) - Glycerol (from triglycerides)

Lipases are regulated by?

-insulin (to allow FA uptake by tissues; LPL) -insulin counter-regulatory (lipolysis to release FA; HSL) Glucagon, epinephrine, cortisol HSL = hormone-sensitive lipase fed state = LPL fasting state = HSL exercise (HSL)

DIsaccharides

-lactose -sucrose -maltose

1. A-band (dark band): Everything that includes all the myosin. 2. H band: Contains myosin but no actin. 3. I band (light band): Contains actin but no myosin. 4. M band: Bunch of proteins that hold myosin in place. 5. Z disk or z line: Helps hold actin in place. 1 sarcomere is Z line to z line. 6. Connects cytoskeleton & extracellular matrix.

1. A-band 2. H band 3. I band 4. M band 5. Z disk or z line 6. Dystrophin protein

Assessing liver function via? (6)

1. ALT (alanine aminotransferase) and AST (aspartate aminotransferase) 2. Amino acids in serum 3. Urea 4. Bilirubin 5. Alkaline phosphatase (ALP) & y-glutamyl transferase (GGT) 6. Lipid profile, fasting blood glucose are also informative. - Cirrhosis patients tend to have higher fasting and postprandial (after a meal) blood glucose

6 different fates of glucose

1. Acetyl-CoA 2. Pentose Phosphate 3. Amino sugars (->glycosaminoglycans) 4. Glycogen 5. Lactate 6. Fructose, lactose.

T helper cell- Macrophage interaction

1. Antigen/MHC/T cell receptor complex formed. 2. Co-stimulatory molecules bind CD28 (on T cell) and B7 on (APC, macrophage in this case). 3. Cytokines are released by macrophage, specifically IL-1 or IL-12. 4. Upregulate IL-2 receptor after IL-1 or IL-12 received by T cell. Increase affinity of the IL-2 receptor for IL-2 molecules. 5. Make their own IL-2 molecules. IL-2 is by T cells for T-cells, T cells make it and T cells use it. T cells release IL-2 molecules to bind to the IL-2 receptor on its own surface. 6. When IL-2 molecules bind to IL-2 receptors it stimulates production of Interferon gamma (IFN-y). INF-y is a major cytokine that turns on macrophages and makes them upregulate everything. Also causes class switching to IgG. IL-2 is also essential for activating cytotoxic T cells (CD8). IgCAM and Integrin bind to each other (adhesion molecules) to facilitate this interaction. CTLA-4 is the downregulator of CD28. At the end of this process when we need to shut down CD28/B7 interaction we increase expression of of CTLA-4. TH1 response is equivalent to a type 4 hypersensitivity or delayed type sensitivity reaction.

5 roles of liver

1. Blood glucose homeostasis 2. Metabolism 3. Synthesis of proteins 4. Synthesis of N-containing molecules 5. Detoxification

What are the enzymes in urea cycle found in mitochondria

1. Carbamoyl Phosphate synthetase I (CPSI) 2. Ornithine transcarbamoylase

11 functions of the liver

1. Central receiving and recycling. 2. Synthesis/recycling of blood 3. Regulation of blood glucose 4. Synthesis, export of cholesterol and TG 5. Ketone body formation 6. Synthesis of nitrogen containing compounds 7. Detoxification 8. Ammonia depot, urea cycle 9. Nucleotide biosynthesis 10. Synthesis of glycoproteins, proteoglycans 11. Pentose phosphate pathway

What are some of the minor regulators of stimulating insulin release (3)

1. Certain amino acids 2. gastric inhibitory peptide 3. glucagon-like peptide (GLP-1) (epinephrin is minor inhibitor) (Glucose is major regulator- insulin release proportional to BG level)

What kind of peptides cleaved by chymotrypsin? Trypsin? Elastase?

1. Chymotrypsin- cleaves bulky, aromatic amino acids. 2. Trypsin- cleaves (+) charged amino acids. 3. Elastase- cleaves small, non-charged amino acids.

TCA intermediates used in other pathways? 1. Citrate 2. a-ketoglutarate 3. succinyl coa 4. malate 5. oxaloacetate

1. Citrate can be used in fatty acid synthesis. 2. a-ketoglutarate can be used in amino acid synthesis (or as neurotransmitter) 3. succinyl coa can be used in heme synthesis 4. malate can be used in gluconeogenesis 5. oxaloacetate can be used in amino acid synthesis.

What are the 7 nitrogen-containing compounds produced by the liver and what is their function

1. Creatine- Forms creatine phosphate in muscles (form of energy storage) 2. Glutathione- Protects against free radical injury (reduces peroxides) 3. Purines & Pyrimidines- Found in nucleotides 4. Sphingosine- Precursor of sphingolipids found in myelin (and other membranes) 5. Heme- Incorporated into hemoglobin. 6. Niacin - NAD, NADP coenzymes for oxidation reactions. 7. Glycine conjugates of xenobiotic compounds- Inactivation, target for urinary excretion.

Purines and pyrimidines uses (7)

1. DNA and RNA 2. Cofactors (NAD+, FAD, CoA) 3. Energy (ATP/GTP) 4. Activated intermediates in biosynthesis 5. SAM for methyl transfer 6. 2nd messengers (cAMP) 7. Allosteric regulators in metabolism. Purines and pyrimidines can be made from scratch or salvaged from existing bases.

Epinephrine pathway in muscle during glycogenolysis

1. Epinephrine stimulates adenylate cyclase which converts ATP to cAMP. 2. cAMP activates PKA. 3. PKA Activates phosphorylase kinase (glycogenolysis) via phosphorylation with ATP and inhibits glycogen synthase (glycogenesis) via phosphorylation with ATP. (Ca2+-calmodulin also activates phosphorylase kinase) 4, Phosphorylase kinase turns/activates phosphorylase b (inactive) to phosphorylase a (active) by phosphorylating it with ATP. (AMP also stimulates phosphorylase b to phosphorylase a activation) 5. Phosphorylase A turns glycogen into glucose 1-phosphase which then goes -> glucose 6- phosphate -> lactate or CO2 + H2O in muscle.

Sources that can produce Acetyl-CoA

1. Fatty acid, palmitate 2. Ketone body, acetoacetate. 3. Pyruvate (from glucose or alanine) 4. Ethanol

What 4 factors influence immunogenicity (illicit immune response)

1. Foreignness- the more different it is to us the better. 2. Molecular size- the bigger the immunogen (antigen) the better. 3. Chemical complexity- The more amino acids, etc. the better. 4. Susceptibility to Ag processing and presentation- Large, insoluble molecules are better.

Fasting state and glycogen degradation steps

1. Glucagon (liver) or epinephrine (muscle) signal G-protein. 2. Gas -> adenylate cyclase -> cAMP-> PKA. 3. PKA phosphorylates glycogen phosphorylase activating it. 4. Glycogenolysis is stimulated- glucose is released from the liver.

What can these glycolysis intermediates also produce: 1. Glucose 6-p 2. 1,3-bis-phosphoglycerate. 3. 3-phosphoglycerate. 4. Pyruvate. 5. Acetyl CoA

1. Glucose 6-p can produce five-carbon sugars or glycerol-P 2. 1,3-bis-phosphoglycerate can produce 2,3-bis-phosphoglycerate 3. 3-phosphoglycerate can produce 2,3-bis-phosphoglycerate or serine 4. Pyruvate can produce alanine. 5. Acetyl CoA can also produce fatty acids.

Glycogen metabolism start

1. Glucose enters cell. 2. Glucose converted to glucose-6-phosphate (via glucokinase in liver). 3. Glucose 6-phosphate -> glucose 1 phosphate via phosphoglucomutase (reversible). 4. Glucose 1-phosphate + UTP -> UDP-glucose (intermediate only used in synthesis pathway) 5. Glycogen synthesis.

Pancreatic B-cells and insulin release steps

1. Glucose in blood, taken up by B-cells via GLUT 2 transporters. 2. Metabolized which makes intracellular ATP levels rise. 3. Increased ATP/ADP ratio shuts down K+ channel 4. Membrane depolarizes. 5. Activates Ca2+ channels. 6. Increase Ca2+ stimulates fusion of vesicles and insulin release.

What are the only 3 enzymes that can fix nitrogen atoms onto an organic molecule?

1. Glutamate dehydrogenase 2. Glutamine synthetase 3. CPSI (Carbamoyl phosphate synthetase I, involved in production of urea)

2 main enzymes involved in glycogen degradation

1. Glycogen phosphorylase- cleaves nonreducing ends making glucose-1-phosphate. 2. Debrancher enzyme- cleaves the remaining branch (transferase) and attaches to primer glycogen (amylo-1,6 glucosidase) to be degraded by glycogen phosphorylase.

Glycogen synthesis steps

1. Glycogenin glycosylates itself using UDP-glucose to create primer. (reducing end attached to glucogenin) 2. Glycogen core + UDP glucose + glycogen synthase -> increasing glycogen core. (a-1,4 glycosidic bonds link glucosyl residues in long chain, lengthening glycogen primer) 3. Glycogen core + branching enzyme -> adding branches to glycogen core (a-1,6 branches every 8 to 10 residues). 4. Continued glycogen synthesis at all nonreducing ends. ======= -glucosyl units added from UDP-G to nonreducing ends by glycogen synthase -Glycogen synthase is regulated - Anomeric carbon of each glucose is attached via a-1,4-glycosidic bond to the hydroxyl on carbon 4 on terminal residue. -After 11 residues added, 6-8 cleaved by amylo-4,6-transferase (branching enzyme) and reattached by an a-1,6 bond). -Branching allows for increased sites for synthesis and degradation and enhances solubility

5 fat deposit sites in the human body.

1. Greater omentum- omental adipose tissue 2. Mesentery- mesenteric adipose tissue 3. Retroperitonea adipose tissue 4. Deep subcutaneous adipose tissue. 5. Superficial subcutaneous adipose tissue Both deep subcutaneous (visceral) and superficial adipose tissue increase when gaining weight. Subcutaneous doesn't keep up in vascularization as more fat deposited.

Urea cycle pathway

1. HCO3- (from CO2 + H2O) + NH4+ + 2 ATP + *carbamoyl phosphate synthetase I (CPSI)* --> Carbamoyl phosphate. (In mitochondria) 2. Carbamoyl phosphate + ornithine + *ornithine transcarbamoylase* --> citrulline (the amine group from carbamoyl phosphate is added to ornithine and the phosphate part is removed) (In the mitochondria). 3. Citrulline (moves into the cytosol) + Aspartate + ATP + *argininosuccinate synthetase* --> argininosuccinate. (cytosol) 4. Argininosuccinate + *argininosuccinate lyase* --> arginine removing fumarate in the process. (cytosol) 5. Arginine + H2O + *arginase* --> urea (excreted in urine) + ornithine (ornithine crosses into mitochondria to be used in step 2 and continue cycle).

Preparative phase of glycolysis enzymes

1. Hexokinase (glucose to glucose 6-phosphate, uses ATP) 2. Phosphoglucoisomerase. (glucose 6-phosphate to fructose 6-phosphate) 3. Phosphoglucokinase (F-6-phosphate to fructose 1,6 bisphosphate, uses ATP) 4. Aldolase (F-1,6-bis to dihydroxyacetone phosphate and glyceraldehyde 3- phosphate) 5. Isomerase (Dihydroxyacteone phosphate to glyceraldehyde 3-phosphate)

6 signs of liver damage

1. Increase in ALT, AST; may have increased Amino Acids in serum. 2. Jaundice (inefficient bilirubin glucuronidation) 3. Prolonged clotting times (liver not producing enough clotting factors) 4. Edema (liver not producing enough albumin) 5. Hepatic encephalopathy (less urea, excess ammonia) 6. Increased ALP and GGT may indicate some liver diseases

What do the complement pathways do?

1. Induce inflammation. Anaphylatoxins. 2. Lyse certain infectious agents (mainly neisseria because it has oligopolysaccharide instead of LPS via the MAC (membrane attack complex) which is C5-C9.) 3. Opsonize infectious agents (only complement that does this is C3b). 4. Clear immune complexes!! All of these pathways converge at C3 and result in a membrane attack complex (MAC). The larger proteins, B fragments (except for C2b) acquire enzyme activity- bind to surface. The smaller proteins (a fragments) have biological activity and are known as anaphylatoxins (degranulate basophils and mast cells releasing histamine, etc. and responsible for the anaphylactic response. Complements are also really good at lysing red blood cells, can cause massive hemolytic anemia if there are too much of them.

What are the 5 oxygen independent killing methods?

1. Inducible nitric oxide synthetase (iNOS) generates nitric oxide (NO) in both phagocytic cells and non-phagocytic cells. 2. Cathepsin G, a neutral protease (breaks down protein). 3. Lactoferrin (steals iron). 4. Lysozyme (breaks down peptidoglycan) 5. Defensins (punch holes) Not really strong enough to kill the bacteria, not enough to compensate if you have a defect in oxygen dependent killing.

Timeline of an immune response to an acute infection

1. Innate immune response 2. Induction of adaptive response 3. Adaptive immune response 4. Immunological memory

Insulin and glycogen synthesis pathway

1. Insulin allosteric inhibitor on glycogen phosphorylase a. 2. Inhibits cAMP therefore PKA inhibited. 3. Protein phosphatases are activated- dephosphorylate glycogen synthase (activate it) and glycogen phosphorylase (deactivate it) 4. Glycogenolysis inhibited, glycogen synthesis activated.

4 things fat tissue triggers

1. Insulin secretion from pancreas. 2. Heptatic glucose production in the liver 3. Glucose uptake and metabolism in the skeletal muscle 4. Leptin synthesis. Main functions of adipose tissue: glucose uptake, fat storage, and metabolism.

B cells vs T cells: 1. Interaction with antigen? 2. Binding of soluble antigen? 3. Involvement of MHC? 4. Chemical nature of Antigen? 5. Epitope properties?

1. Interaction with antigen? B cells: Binary complex of membrane antibody (mIg) and antigen. T cells: Ternary complex of TCR, antigen, and MHC. 2. Binding of soluble antigen? B cells: Yes T cells: No (has to be on MHC) 3. Involvement of MHC? B cells: No T cells: Yes 4. Chemical nature of Antigen? B cells: protein, polysaccharide, and lipid. T cells: protein only 5. Epitope properties? B cells: Accessible, hydrophilic, mobile peptides containing sequential or nonsequential aa. T cells: Internal linear peptides produced by antigen processing and capable of binding to MHC molecules.

Isotype vs allotypes vs ideotypes?

1. Isotype: also called classes includes IgG, IgA, IgE, IgM, and IgD. 2. Ideotypes: Variable region binding specificity (hypervariable regions). 3. Allotypes: Small allelic differences in the constant region genes (subtle differences within species). My IgG won't be the same as someone else's IgG because of this.

What are the 3 precursors for gluconeogenesis

1. Lactate (RBCs) 2. Amino acids (alanine) 3. Glycerol (adipose)

What are the location/function of the following lipases: 1. Lipoprotein lipase (LPL): 2. Hormone-sensitive lipase (HSL): 3. Pancreatic lipase:

1. Lipoprotein lipase (LPL): muscle and adipose tissue. Releases fatty acids from lipoproteins (chylomicron, VLDL, etc.) to allow tissue uptake. 2. Hormone-sensitive lipase (HSL): Inside adipose tissue. Allows fatty acid release from adipose tissue. 3. Pancreatic lipase: Duodenum of small intestine. Breaks down triglycerides (dietary lipids) into FAs and 2-MG

Amino acids converted to what in the liver? (5)

1. Liver proteins 2. Tissue proteins (A.A travel through blood to tissues) 3. Nucleotides, hormones, porphyrins. 4. NH3, urea 5. Pyruvate and citric acid cycle intermediates (gluconeogenesis, ketone bodies, or stored as glycogen, triglycerides)

What are macrophages called in the lungs? Connective tissues? Liver? Kidney? and Brain?

1. Lungs: alveolar macrophages 2. CT: histiocytes 3. Liver: kupfer cells 4. Kidney: Mesangial cells 5. Brain: Microglial cells

Overview of transport of carbohydrates (3 steps)

1. Monosaccharides are taken up by cells of the small intestine (apical side). 2. Pass through the cell and exit on the serosal/basal side and into the capillaries for distribution throughout the body. 3. Glucose is taken up by different tissues by different tissue-specific transporters (GLUT 1-5)

What are the 3 main pathways for glycogen metabolism in skeletal muscle? The 3 main stimulators for glycogenolysis in muscle?

1. Muscle contraction: ATP-> AMP-> glycogen phosphorylase b -> glycogen phosphorylase a 2. Nerve impulse ->Ca2+ -> Ca2+-calmodulin -> Phosphrylase kinase 3. Epinephrine -> cAMP-> PKA -> phosphorylase kinase Glycogenolysis in muscle stimulated by: AMP, Ca2+, or epi.

Glycogen break down in muscle vs liver

1. Muscle- glycogen -> glucose 6-phosphate -> glycolysis. (stimulated in anaerobic glycolysis) 2. Liver- Glycogen -> glucose 6- phosphate -> glucose -> blood glucose. (stimulated by glucagon)

Mutations in innate immune receptors (5)

1. Mutation in signaling molecules effecting TLRs (Toll-like receptors) - Recurrent, severe bacterial infections (pneumonia) 2. Gain of function mutations in inflammasome - Gout - Atherosclerosis - Type II diabetes 3. NOD-2 mutations - IBD (irritable bowel disease) 4. IL-12 receptor deficiency - Recurrent infections with intracelluar bacteria (mycobacterium (like tuberculosis)) 5. IFN-y receptor deficiency - Recurrent infections with intracelluar bacteria (mycobacterium (like tuberculosis))

How can you treat hyperammonemia?

1. N-removing compounds. 2. Low protein diet. 3. Arginine supplementation (if block is afer argininosuccinate).

How much of every WBC type in human body?

1. Neutrophils the most ~50-70% 2. Lymphocytes at 20-40% 3. Monocytes at 1-6% 4. Eosinophils at 1-3% 5. Basophils at <1%

Liver cirrhosis symptoms

1. Portal hypertension - FIbrosis, reduced fenestrations 2. Thin-walled varices - From obstruction (shunting) of portal blood from liver, returns to heart via esophageal veins, makes the esophageal veins bigger. 3. Varices may rupture and cause bleeding into abdominal/thoracic cavity. 4. Increased ammonia in blood as bacteria metabolize blood proteins. 5. Hapatic encephalopathy (worsening of brain function due to liver not filtering toxins) 6. Jaundice and edema in abdomen

Regulation of the urea cycle? (3)

1. Regulated by substrate availability. Increase in arginine stimulates urea cycle. (feedforward regulation) 2. Allosteric activation of CPSI by N-Acetyl-glutamate (NAG). (as Arginine increases more NAG is formed). 3. Regulation of urea cycle enzyme synthesis. - Induced by high protein diet, fasting. Higher rate of ammonia production = higher rate of urea formation.

Summary of electron transport chain

1. Reoxidation of reduced coenzymes. 2. Consumption of O2 3. Formation of H2O 4. Stepwise release of free energy upon coenzyme oxidation 5. Coupled unidirectional pumping of H+ across membrane.

Effects of high protein meal (4)

1. Stimulate glucagon release 2. Stimulate insulin release to lesser extent. - stimulates AA uptake in tissues - increases protein synthesis 3. Gluconeogenesis enhanced 4. Reduced glycogen and TG synthesis

Enzymes can be regulated by> (4)

1. Substrate availability 2. Enzymes 3. Covalent modification of enzyme 4. Allosteric regulation (molecule binds to enzyme somewhere other than active site.)

What are the 3 major steps in urea cycle?

1. Synthesis of carbamoyl phosphate (in mitochondria) 2. Productin of arginine by urea cycle (cytosol) 3. Cleavage of arginine to produce urea. (cytosol).

Essential amino acids are required in the diet because generally humans are not capable of? (3)

1. Synthesizing branch chain amino acids. 2. Synthesizing aromatic amino acids 3. Incorporating sulfur into compounds.

Endogenous antigen processing and presentation. 1. How are viruses converted into 8-10 amino acids to fit inside class I HLA? 2. HLA molecules are in the ER and peptides are in the cytoplsm, how do the HLA molecules get loaded? 3. HLA class I + antigen are in the ER, how do they make it to the cell surface to present antigen to T cytotoxic cells?

1. Viral peptides are large, get degraded within proteosomes to fit inside the class I HLA. 2. TAP I and TAP 2 (transporters of antigen process) 3. Vesicular transport through the golgi to the surface.

Structure of glycogen (3)

1. a-1,4 glycosidic bonds with a-1,6 branches every 8-10 units. 2. Only one anomeric carbon per molecule of glycogen. 3. May be simultaneously degraded from all nonreducing ends.

Glucose 6 phosphate precursor of what (3)

1. glycolysis 2. pentose phosphate pathway 3. other pathways for synthesis of other sugars.

Lactose intolerance possible causes (4)

1. natural loss of lactose > age 7. 2. Injury to the intestinal mucosal cells 3. Gastroenteritis 4. Excess alcohol consumption.

How much acetyl coa, nadh, fadh2 from 16 carbon palmitoyl. How much ATP.

16/2 = 8 Acetyl Coa 1 NADH per cleave 1 FADH2 per cleave so 7 NADH and 7 FADH2 ATP produced: 2.5 ATP per NADH 1.5 ATP per FADH2 10 atp per acetyl coa So 7(2.5) + 7(1.5) + 8(10) = 108 ATP 110 - 2 ATP (FA activation) = 106 ATP total

How much ATP is used in FA activation by fatty acyl-CoA synthetase

2 ATP

Pyruvate dehydrogenase produces (energy)

2 NADH

How many NADH and FADH are produced in glycolysis and TCA cycle

2 NADH in glycolysis another 2 NADH in the PDC (linker step) and 6 in TCA cycle for a total of 10. FADH2 only made in TCA cycle and only 2 made.

Triglycerides first digested to what

2-Monoacylglycerol and FA

Micelle is what

2-monoglycerides + fatty acid + biles salts = micelles

1. Osteogenesis Imperfecta: - Affects Type I collagen - "Brittle bone disease"- risk factor for rheumatoid arthritis and osteoporosis. - Ligament and tendon weakness - Blue sclerae, progressive hearing loss. 2. Achondrogenesis Type 2: - Affects Type II collagen - Short stature, bone and joint - Typically lethal 3. Vascular Ehlers-Danlos syndrome - Affects Type III collagen - Fragile, thin skin and easily bruised. - Risk of arterial rupture.

3 common collagenopathies

1. *Mucous (ex, sub-lingual + stomach glands)* a. Secretions are viscous and slimy; extensive glycosylation of proteins (PAS +) b. Cells stain pale with H&E (secretions lost in prep) 2. *Serous (ex. Parotid gland + pancreas)* a. Secretions are watery; little to no glycosylation on proteins b. Apical cytoplasm is eosinophilic; perinuclear cytoplasm is basophilic (rER). 3. *Mixed* a. Submandibular gland b. Contain both mucous and serous cells c. Processing artifact: serous demilune (half-moons).

3 secretions of multicellular glands

What are the enzymes in urea cycle found in cytosol

3. Argininosuccinate synthetase. 4. Argininosuccinate lyase 5. Arginase

Antibody gene rearrangement

5 heavy chain classes (μ,δ,γ,α, and ε) 2 light chain classes (κ and λ) The heavy and light chains are encoded by multiple gene segments Variable (V), Diversity (D) and joining (J) segments compose the variable region of the heavy chain while only V and J segments are used to generate the light chains, No *D segment in the light chain*. Generates an incredible amount of diversity

Net reaction of TCA cycle per glucose (2 turns)

6 NADH 2 FADH2 2 GTP 4 CO2

Pentose phosphate pathway overall reaction produces what from 3 glucose-6-phosphates?

6 NADPH 3 CO2 2 Fructose 6-P 1 Glyceraldehyde 3-P

1. Protection (skin) 2. Absorption (intestines, kidneys) 3. Transport of nutrients/waste (along or across an epithelium) 4. Secretion (glands) 5. Excretion (kidneys) 6. Gas exchange (airway) 7. Selective barrier 8. Sensory receptors for special senses: -Olfactory epithelium, hair cells, taste buds, retina

8 functions of epithelial tissue

Normal level of blood glucose

80-100

Suffering from Rickets. Caused by vitamin D deficiency. Causes soft bones.

A 4-year old male presents to the clinic with a history of malnourishment. See images below for presentation. 1. What do you suspect the child suffering from? 2. What causes this disease?

White adipose tissue mass-- Lipoma

A 54 year old male presents with a soft, painless mass. Physical exam reveals the image below (left). The mass is excised and a biopsy reveals the histological specimen below (right). What is the most likely diagnosis?

(Left picture is normal, right picture is patient's bone biopsy) Osteoporosis caused the broken hip. Osteoporosis evident on the patient's bone biopsy. Treatment: Inhibit osteoclasts or activate osteoblasts via drugs.

A 72-year-old female presents to the emergency department following a recent fall. She fell off a curb at a local grocery store. 1. You suspect a hip fracture 2. What is going to be one of your main concerns? 3. Treatment?

Osteoarthritis. Most commonly affected are areas of weight bearing including hips, knees, lower lumbar, vertebrae, hands, and feet. Affects articular cartilage. Forms bone when trying to repair the articular fibers.

A 75 year old female presents to the clinic with complaints of chronic joint pain. Physical examination reveals joint deformity. What do you suspect? What are the most commonly affected areas? What is the disease *progression*?

Antibody dependent cellular cytotoxicity (ADCC)

A pathogen (virus) enters a cell and before it leaves the cell it will put its virus specific ligoproteins in/on the cell membrane. Then an antibody (IgG) attaches to the antigen (virus proteins) and then bring it to NK cells, macrophages, neutrophils, eosinophils, anybody with a receptor for IgG (aka CD16). The target cell is then killed, NK cells punch holes in it. It's mainly NK cells that do this but other cells can do it too, anyone with CD16 (receptor for IgG). Some viruses don't have to leave a cell to infect other cells like herpes, HIV, etc because they have cell fusion protein which will fuse cells together so the virus can travel between cells. These cells need to be killed by T cells.

What is any allosteric activator of muscle glycogen phosphorylase?

AMP

What does AMP activate/stimulate?

AMP activates glycogenolysis and glycolysis. Increase in AMP stimulates Phosphorylase b and PFK-1 in glycogenolysis pathway.

Exogenous antigen processing and presentation

APC phagocytosis a protein antigen. The phagocyte binds with a lysosome to create a phagolysosome which breaks apart the antigen into the appropriate length. The class II MHC can't bind while it is in the ER because there is a invarient chain attached to it which is a good thing because the class I MHC can bind in the ER so when infected with viruses the class I MHC would be expressed rather than class II MHC. So instead, the class II MHC will eventually fuses with the phagolysosome and the acidic lysosomal compartment chews up most of the invariant chain so that you are just left with a little clip molecule still blocking the chain. Then HLA-DM, a helper molecule, takes out that little clip and the class II MHC can finally bind to the antigen and express it on the cell surface, present it to T helper cells.

Which epigenomic regulatory gene mutation in 60% of ovarian clear cell carcinoma, and 30-40% endometrial carcinoma?

ARID1A: Nucleosome positioning/chromatin remodeling

Fuels used in skeletal muscle (6)

ATP by any means possible including: 1. Creatine phosphate (rapid) 2. Muscle glycogen (rapid) 3. Fatty acids (preferred) 4. Glucose 5. Ketone bodies 6. Some amino acids (including BCAAs)

How much do ATP, ADP, and AMP concentrations change during exercise?

ATP decreases 20% while ADP and AMP increase (AMP increases the most). Concentration of AMP, produced by adenylate kinase reaction, serves as a sensitive indication of decreasing ATP levels.

Steps in triacylglycerol resynthesis

ATP dependent. FA + ATP -> FA-AMP + CoASH (coenzyme A) -> FACoA + 2-Monoacylglycerol -> diacylglycerol + FACoA -> Triacylglycerol + ApoB-48 -> nascent chylomicrons

Mitchell hypothesis

ATP synthase + H+ gradient = oxidative phosphorylation

Oligomycin (interfere oxidative phosphorylation)

ATP synthase inhibitor Inhibits proton flow through the F0 component of the ATP synthase.

Where are monosaccharides absorbed?

Absorbed through intestinal epithelial cells into blood for distribution.

What can undergo spontaneous decarboxylation to make acetone?

Acetoacetate

Rate limiting step in synthesis of fatty acids

Acetyl CoA carboxylase

Fed vs fasting state and acetyl-CoA

Acetyl Coa= acetate + oxaloacetate. Fed: Acetyl CoA -> TCA cycle because you have enough oxaloacetate. Fasting: Acetly-CoA -> ketone bodies because not enough oxaloacetate for TCA.

MCAD (acetyl-coa dehydrogenase) deficiency

Acetyl-CoA dehydrogenase is the first enzyme to cleave in B-oxidation. Causes: reduced gluconeogensis (hypoglycemia) reduced ketone body production (hypoketotic) Reduced ureagenesis (Hyperammonemia) Overall causes neurological damage/hepatic encephalopathy Jamaican vomiting also affects this enzyme, hypoglycin is the compound in unripe fruit of ackee tree.

Acidic dye: *Eosin*, carries _net negative charge_ on its colored portion and is described by the general formula Na+dye-. Basic dye: Carries a _net positive charge_ on its colored portion and is described by the general formula dye+Cl-. *Hematoxylin* does not meet the definition of a strict basic dye but has properties that closely resemble those of a basic dye. The color of the dye is not related to whether it is basic or acidic. Basic dyes: Methyl green (green), methylene blue (blue), Pyronin G (red), and Toluidine blue (blue). Acidic dyes: Acid fuschsin (red), Aniline blue (blue), Eosin (red), and Orange G (orange). ================================ Basic dyes react with anionic components of cells and tissue (components that carry a net negative charge) such as the phosphate groups of nucleic acids, the sulfate groups of glycosaminoglycans, and the carboxyl groups of proteins. (Basophilia) At high pH (about 10) all 3 groups (phosphate, sulfate, and carboxyl) are ionized and seen. At slightly acidic/neutral pH (5 to 7) sulfate and phosphate groups seen. At low pH (below 4), only sulfate groups seen. ================================= Acidic dyes react with cationic groups in cells and tissues (components that carry a net positive charge), particularly with the ionized amino groups of proteins. (Acidophilia) Not as specific nor as precise as reactions with basic dyes. Acidic dyes sometimes used in combinations to color different tissue constituents like the Mallory staining technique:aniline blue (collagen), acid fuschsin (ordinary cytoplasm), and orange G (red blood cells). =============================== Basic dyes (basophilia) shows: 1. Heterochromatin and nucleoli of the nucleous. 2. Cytoplasmic components such as the ergastoplasm. 3. Extracellular materials such as the complex carbohydrates of the matrix of cartillage. Acidic dyes (acidophilia) shows: 1. Most cytoplasmic filaments, especially those of muscle cells. 2. Most intracellular membranous components and much of the otherwise unspecialized cytoplasm 3. Most extracellular fibers.

Acidic and Basic Dyes

What does Th2 activate and drive

Activates B cells, mast cells, and eosinophil, drives isotype switching to IgE

What does Th1 activate and drive?

Activates T cytotoxic cells and macrophages, drives isotype switching to IgG

Epinephrine does what in the muscles? Alpha and beta receptors?

Activates glycogenolysis and inhibits glycogen synthesis. Enhances the effects of glucagon in liver. Alpha receptors -> PLC -> IP3 and DAG-> Ca2+ and PKC Beta receptors -> cAMP -> PKA

FA import and oxidation steps

Activation of FA: ATP + CoA + fatty acid -> fatty acyl CoA. (enzymes for FA oxidation in mitochondrial matrix) Carnitine shuttle (intermembrane): Fatty acyl CoA transferred from outer mitochondrial membrane to mitochondrial matrix via Carnitine. Carinitine is exchanged for CoA to make Fatty Acyl carnitine which then can cross into matrix. FA Oxidation: Fatty acyl carnitine -> fatty acyl CoA in mitochondrial matrix. Beta oxidation of fatty acyl CoA produces FADH2, NADH, and acetyl-CoA

1. Attachment 2. Release 3. Bending 4. Force generation 5. Reattachment (same cycle for all muscles but duration of stages alters)

Actomyosin cross-bridge cycle

What are the linked human cancers to this product and where is this product found? Benzene

Acute myeloid leukemia Principal component of light oil; despite known risk, many applications exist in printing and lithography, paint, rubber, dry cleaning, adhesives and coatings, and detergents; formerly widely used as solvent and fumigant.

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome disseminated intravascular coagulation?

Acute promyelocytic leukemia and prostatic carcinoma Tumor products that activate clotting

What is somatic hypermutation

Adds to the diversity of the variable region. Allows immune system response to get better because after you bind to an antigen it refines the affinity of the antibody molecule.

What is one cause of SCID and how do you treat it?

Adenosine deaminase deficiency (ADA), treat it by replacing the gene in hematopoietic stem cells.

Adenylate kinase and atp production

Adenylate kinase turns 2 ADP to 1 ATP releasing 1 AMP in the process which then signals to AMPK, K-ATP, AMP-sensitive metabolic enzymes, and adenosine to decrease ATP consumption and stimulate ATP production.

Which adipokine decreases free FA

Adiponectin

Which 2 tissues increase GLUT 4 transporters on their surface in response to insulin?

Adipose and muscle

Adipose vs muscle in regards to LPL Km

Adipose has higher Km for Lipoprotein lipase- will require alot in blood in order for it to be absorbed by adipose tissue. Muscle has lower Km for LPL.

Adipokines

Adipose tissue produces hormones called adipokines. Different functions: - Help regulate appetite - Regulate adipocyte cell size - Act on cells of the immune system (promote inflammation) Few examples: - Adiponectin: decreases free FA, improves lipid and glycemic profile. Is an insulin sensitizing hormone- elevated levels is good. Those with obesity have lower levels of this hormone. -Leptin: Decreases food intake. Suppresses appetite. - Interleukin-6: pro-inflammatory

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome nonbacterial thrombotic endocarditis?

Advanced cancers Hypercoagulability

Fuel use during exercise

Aerobic fuel oxidation preferred Anaerobic glycolysis: - Initiation of exercise (few min) - Prior to increased blood flow. - Type IIB fast-twitch glycolytic fibers - Lowoxidative capacity - Strenuous activity - ATP demands exceed oxidative capacity.

Effects of training on muscle metabolism: aerobic vs resistance

Aerobic training: - Increase glycogen stores - Possibly use glycogen more efficiently with training - Increase mitochondrial size, numbers. Resistance training - Muscle hypertrophy to increase max force production - Strength, power, and endurance.

Pyruvate kinase deficiency

Affects RBC the most due to their reliance on glycolysis- causes hemolytic anemia. Believed to affect the Na+/k+ ATPase pump and other ATP dependent processes.

Deficiency in C3 causes what?

Affects both complement pathways. Causes recurrent bacteria infections, immune complex disease.

Deficiency in C5, C6, C7, C8, or C9 causes what?

Affects the MAC attack. Causes recurrent meningococcal and gonococcal infections.

Deficiency in C1q, C1r, C1s, C4, and C2 causes what?

Affects the classical pathway. Causes increase in immune complex diseases and increase in infections with pyogenic bacteria.

What is the major gluconeogenic amino acid

Alanine

What are the major N carriers in blood?

Alanine and glutamine (gln/Q). They transport amino acid nitrogen to liver via blood. Wouldn't want NH4+ to travel freely in your blood.

How are alanine, lactate, and glycerol used in gluconeogenesis pathway

Alanine and lactate form pyruvate. Glycerol forms Dihydroxyacetone phosphate (DHAP)

Liver's role in synthesizing blood proteins

Albumin: -55-60% total protein in blood (major blood protein) -Contributes to osmotic pressure and helps prevent edema. - Nonspecific transporter (e.g. steroid hormones, xenobiotic compounds, fatty acids, hydrophobic vitamins and drugs) - Hypoproteinemia can lead to edema due to decreased protein-mediated osmotic pressure in blood (examples of causes: Kwashiorkor syndrome, cirrhotic liver damage). Low levels of protein in blood and water seeps out of blood into surrounding tissues due to osmotic pressure. Clotting factors: If you have decrease in liver synthesizing proteins you will have less clotting factors. Glycoproteins: - Roles include protease inhibition, acute phase proteins in immune response, secretogogues for hormone release.

Treatment of gout

Allopurinol (inhibitor of xanthine oxidase) to decrease production of uric acid. Avoid diet rich in meat, seafood, fructose-sweetened drinks, alcohol.

Hepatocytes characteristics

Almost all metabolic pathways in the liver occur in hepatocytes. Long lifespan, low turnover Maintain constant liver mass (proportional to total body mass)

Tissue Macrophages

Alveolar macrophages - found in lung Histiocytes - found in connective tissues Kupfer cells - found in the liver Mesangial cells - found in the kidney Microglial cells- found in the brain

Glycolysis intermediates can be used to make?

Amino acids and fatty acids

Fate of amino acid carbon and nitrogen?

Amino acids containing carbon skeleton are used as fuel source. Nitrogen group is removed and excreted (waste).

What does ketogenic amino acids mean?

Amino acids that produce acetyl-CoA or acetoacetate (ketone bodies). Some amino acids are both glucogenic and ketogenic. Lysine and leucine are strictly ketogenic.

What are the intestinal cell enzymes

Aminopeptidases (close to N-terminus) Turns peptides into di- and tri- peptides + amino acids. Found in intestinal epithelial cell. Amino acids are then excreted into the blood.

Ornithine transcarbamylase deficiency (OTC) leads to accumulation of what?

Ammonia, glutamine, and carbamoyl phosphate.

i. *Cell body* - Nucleus - Cytoplasm ii. *Dendrites* - Periphery -> cell body - *Dendritic spines* iii. *Axon* - Cell body -> synapse - *Axon Hillock* - *Initial Segment of Axon* - *Myelin*

Anatomy of a Neuron

Zonula Adherens and Macula Adherens/Desmosomes -Serve to anchor cytoskeleton of adjacent epithelial cells - interact with actin (z.a) and intermediate filaments (m.a) -Provide structural and mechanical integrity

Anchoring junctions

Opsonization

Another way to recognize and respond to pathogens - May involve adaptive immune components such as IgG Phagocytes have membrane receptors for IgG and C3b - CD16 Enhance phagocytosis up to 4,000-fold. (Know IgG and C3b)

B cell development and activation stages/steps.

Antigen independent stage - occurs in the bone marrow - Involves the development of B cells from Hematopoietic stem cells through a series of defined intermediates Antigen dependent stage - Occurs in the periphery - Involves the development of mature B cells to memory and plasma cells. 1. Lymphoid stem cell can be a T cell, B cell, or NK cell. Once it commits to B cell, it goes into the Pro-B cell stage (progenitor). 2. At the Pro-B cell stage start Ig heavy chain gene rearrangement with RAG expression, Tdt, MHC II, and CD19, CD20, CD21, CD40. 3. After the heavy chain rearranges good it goes into the Pre-B cell stage which has characteristic *cytoplasmic Mu* (because its the first to be made). Light chain start rearranging in this stage, tdt isn't expressed here. 4. After light chain rearrangement, it enters the immature B cell stage which is characterized by *surface IgM*. RAG expression stops after the light chain rearrangement finishes in this stage. This is where selection happens, if it binds to itself it gets killed right in the bone marrow. If not then it moves into the periphery and onto the next stage. 5. Next it enters the mature B cell stage which is characterized by surface *IgM and IgD*. This is in the periphery. This is where it will test its antigen binding, if it binds antigen then goes to the next stage. It is naive until it binds to an antigen, has 1 month to find an antigen. 6. Becomes an activated/ blast B cell. Depending on which antigen it binds it either turns into a plasma cell which is characterized by *cytoplasmic Ig* or memory B cell which is characterized by surface IgG, IgA, or IgE.

Long cytoplasmic processes Core of microtubules (axoneme), anchored to basal bodies. *Specialized for: Motility (motile) and response to environment (primary)* Located on _respiratory epithelium_ , uterine tubes, etc.

Apical Modifications: Cilia characteristics

Short cytoplasmic processes Core of actin filaments, anchored to terminal web *Specialized for: absorption*, increases surface area. Located on epithelial cells of intestine, kidney, etc. "Brush border" (means it has microvili)

Apical Modifications: Microvilli characteristics

Also known as sterovilli Long, immotile microvilli (actin core) Limited to epididymis (absorptive) and hair cells of inner ear (mechanoreceptors)

Apical modifications: Stereocilia characteristics

What protein is essential component of chylomicrons?

ApoB-48

Superantigens

Are bacterial or viral proteins that bind outside of the peptide binding cleft on the TCR and MHC. This causes less specificity among the T cells so way more T cells are activated. From 1% normally to up to 25% with superantigens. With T cells you also get the B cells activated, cytokines, macrophages, etc all this combined to make the person go into shock. Toxic shock syndrome.

1. Multipolar neurons: have 1 axon and 2 or more dendrites (picture on the right) - Motor & interneurons 2. Bipolar neurons have 1 axon and 1 dendrite. (rare, middle picture) - Retina & CN VIII 3. Pseudounipolar (unipolar) neurons have one process, the axon divides close to the cell body into 2 long axonal branches. No dendrites. (left most picture) - Sensory neurons

Arrangements of neurons

*Superficial zone*- Is closest to the articular surface and contains elongated chondrocytes. *Intermediate zone*- Lies below the superficial zone and contains rounded chondrocytes. *Deep zone*- Characterized by small, round, chondrocytes that are arranged into columns. *Calcified zone*- Separated from the deep zone by a calcified line called the tidemark characterized by a calcified matrix and the presence of small chondrocytes. *No perichondrium*

Articular cartilage is divided into 4 zones

How does N enter urea cycle?

As NH4+ (released from glutamate in glutamate dehydrogenase with NAD+/NADP+ cofactors) and Aspartate (purine nucleotide cycle in brain and muscles)

In what form does pyruvate from glycolysis enter the TCA cycle in the mitochondria?

As acetyl-CoA

B. sublingual gland

As you are examining a 64 year old woman, you discover a mass in her mouth. A biopsy is taken and at the edges of the abnormal cells you see the image below. The mass is most likely located in: a. Buccinator muscle (in cheek) b. Sublingual Gland c. Tooth d. Cheek Mucosa e. Hard Palate

How is oxaloacetate synthesized

Aspartate + PLP in transamination reaction -> Oxaloacetate and vice versa. (NH3+ group removed from aspartate (transferred to a-ketoglutarate and makes glutamate) to make oxaloacetate) Oxaloacetate + PLP in transamination reaction -> Aspartate. (NH3+ group added to oxaloacetate (NH3+ group comes from glutamate to a-ketoglutarate reaction) to make aspartate) Oxaloacetate is part of TCA cycle

Largest & most populated neuroglial cell Communicate of neurons & blood vessels - Microenvironment (extracellular K+) Provide support to CNS neurons: 1. Mobilize waste and metabolites 2. Confine or metabolize NT's at synapse 3. Contribute to *Blood-brain barrier* Types: a. *Protoplasmic* b. *Fibrous*

Astrocytes

What converts disaccharides and oligosaccharides to monosaccharides and where does this occur?

At the brush border, glycosidases digest disaccharides and oligosaccharides to monosaccharides. 4 glycoproteins: 1. Glucoamylase 2. Sucrase-isomaltase 3. Trehalase 4. Lactase-glucosylceramidase

Purine biosynthesis (A, G)

Atoms are donated from Aspartate, glutamine, glycine, N10-formyl-FH4, and CO2. Energy required (ATP and GTP) N10-formyl-FH4 is molecule that transfers single C groups - Derived from folate (folate is needed for purine (and therefore DNA) synthesis). Aspartate, glutamine, Glycine provide the amide N to form purines, N10-formyl-FH4 adds single carbons to complete the rings. CO2 provides 1 carbon.

Pyrimidine biosynthesis (C, T, U)

Atoms are donated from aspartate, CO2, and glutamine. Base made first, then attached to R5P (ribose-5 phosphate)

Effector processes Transmit stimuli Cell body -> other neuron/cell Single axon per neuron - Branch to multiple targets *Axon hillock* *Initial segment of axon* - AP generates here Conduction velocity depends on axon size and *myelination* state

Axons

What does IL-7 do?

B and T cell development.

Which accessory molecules transduce the signals for B cell receptors? T cell receptors?

B cell receptors use Ig alpha and Ig beta to actually transduce the signal to initiate the activation process. T cell receptors use CD3 for the same purpose. Mutation in these accessory molecules would be that the B and T cells couldn't properly respond to antigens, differentiate them, etc.

B cell activation by a bacteria cell

B cell with its antibodies binds to the antigens on a bacterial cell. This initiates the Iga and Igb to signal to the SYK (B cell specific tyrosine kinase receptor) to phosphorylate which allows signals to reach the nucleus to change gene expression. Now CD19 role in this is receptor complex is that it is a coreceptor. When the coreceptors are ligated, you need less antigens to elicit a response (1000 vs 15 with coreceptor).

Clonal selection

B cells randomly made and only the ones that match the antigen will replicate itself and either become plasma cell or memory cells.

What are the lymphoid cells (lymphocytes)?

B cells, T cells, and NK cells B and T cells part of the adaptive response while NK cells part of the innate response.

Which ketone accumulated more in the blood as fasting continues?

B-hydroxybutyrate accumulates more than acetoacetate.

What are the 3 ketone bodies

B-hydroxybutyrate, Acetoacetate, and acetone (released in breath, fruity)

BG levels and hormone response

BG <80 mg/dL (4.4 mmol/L) - Reduction in insulin secretion BG <70 mg/dL (3.9 mmol/L) - Increased secretion of glucagon and epinephrine BG <67 mg/dL (3.7 mmol/L) - Secretion of norepinephrine and growth hormone (GH) BG <65 mg/dL (3.0 mmol/L) - Secretion of cortisol BG <55 mg/dL (3.0 mmol/L) - Autonomic symptoms develop BG <50 mg/dL (2.8 mmol/L) - Cognitive function is impaired

Cells adhered to basement membrane, composed of basal lamina and underlying reticular connective tissue. (Not made up of epithelial tissue) *Functions of basal lamina*: Cell attachment, compartmentalization, filtration, tissue scaffolding, regulation + signaling Cells anchored to underlying connective tissue via *junctions* (hemidesmosomes, focal adhesions) *Basal infoldings* increase cell surface area (transport, etc.) (Picture is of the basal portion of a kidney tubule cell showing basal infolding)

Basal domain characteristics

Antibody structure

Basic structure - 2 identical heavy chains - 2 identical light chains Heavy and Light Chains - variable and constant regions - disulfide bonds link the chains together - light chains have 2 domains, 1V and 1C - heavy chains have 4-5 domains, 1V and 3-4 C

1. Abundant, basophilic granules 2. Granules: - Azurophilic (primary)- lysosomes; myeloperoxidase, acid hydrolases, etc. - Specific (secondary) - heparin, histamine, heparin sulfate, leukotrienes, IL-4, IL-13 3. Bind IgE, secreted by mast cells.

Basophil key points

Why does the body excrete N as urea?

Because NH3 is toxic to the brain.

Why is the favored form in the body NH4+?

Because the pKa of ammonia (NH3) is 9.3, the favored form in the body at physiological pH is ammonium (NH4+).

What is bilirubin?

Bilirubin is one of the heme degradation products. When RBCs destroyed, bilirubin released and can be found in blood. Billirubin accumulation = jaundice (yellowing of skin and whites of eyes). Gallbladder can cause gallbladder to be obstructed which means bile salts can't be secreted into GI which gives stool a light clay-colored appearance (no bile salts in it). Often caused by liver and gallbladder disorders (elevated bilirubin)

Constant regions, antigen dependent vs antigen independent.

Biological function of antibodies comes from the constant region. Some biological functions mediated by the constant region are antigen independent like IgG crossing the placenta or IgE binding to mast cells. Some are antigen dependent. In antigen dependent functions, a cryptic site on the constant region is exposed after antigen binding and causes a conformation change in the antibody molecule after formation of the Ag-Ab complex.

This tumor marker is found in what tumor types? TP53 mutants in urine?

Bladder cancer

What is the associated neoplasm and etiologic agent in chronic cystitis

Bladder carcinoma Schistosomiasis

Disorders of the urea cycle

Blocks in urea cycle increase glutamine levels; alpha-ketogluterate levels become too low to fix more N, ammonia levels rise. -Accumulation of ammonia is very toxic to CNS. Extent of elevation in glutamine and NH4+ depends on the defective enzyme. High levels of ammonia and glutamine lead to brain swelling; elevated glutamine opens MPTP, leads to cell death; lower glutamate means less excitatory neurotransmitter synthesis resulting in lethargy and reduced CNS activity. Hyperammonemia- can cause irreversible brain damage and mental retardation. - Diagnose early, treat aggressively with N-removing compounds, low protein diet. -If block is after argininosuccinate, arginine supplementatin can help. Most common defect is Ornithine transcarbamylase deficiency (step 2).

This is a blood smear of a patient with homozygous sickle cell disease. There are several sickle cells, a nucleated RBC and Howell-Jolly body (nuclear material in RBC (appears purple) -> damaged spleen)

Blood smear from 16 year old female. What seems off?

The number of small lymphocytes is greatly increased, suggesting a B-cell or T-cell leukemia.

Blood smear from a 40 year old female with chronic fatigue. Observations?

Controls communication between blood & brain - Protecting CNS from toxins, immune cells, & fluctuating levels of circulating substances Specialized *endothelial cells* with continuous tight junctions Neuroglial cells associated: - Astrocytes -- Support barrier --- *Glial limitants* -- Buffer (K+) O2, CO2, some lipid-soluble molecules pass free (ethanol, steroids, etc. ) Transmembrane carrier proteins actively transport specific macromolecules (like glucose, amino acids, nucleosides, vitamins).

Blood-brain barrier

1. *Intramembranous*: simpler; no cartilage precursor - Flat bones of skull, face, mandible, and clavicle 2. *Endochondral*: cartilage precursor - Long bones and bones of the axial skeleton that bear weight (ie- vertebrae).

Bone formation is classified into 2 types

Derived from osteoblasts Similar to osteoprogenitor cells Flat cells seen on the surface of quiescent bone Considered Periosteal and endosteal cells

Bone lining cells

Cleaves proteins attaching synaptic vesicles to presynaptic membrane Less/No ACh release into cleft ↓ response to stimulus

Botox = *Botulinum Toxin*

Dendrites (D) Golgi cells (G) Gray matter - Granule cell layer (Gr) - Molecular layer (Mol) White matter(WM) Purkinje Cells are not the same as Purkinje Fibers

Brain

Leptin triggers the brain to release what and what do they do

Brain releases: Neuropeptide Y which causes: Decrease NPY secretion, decreased food intake, decreased body weight, increased sympathetic tone, increase energy expenditure. Normalization of glucose and insulin. Endocrine hormones: When leptin levels high, releases- glucocorticoids, insulin, and TNF-a/IL-1. When leptin levels low, releases catecholamines, T3/T4, cAMP, and androgens.

This tumor marker is found in what tumor types? CA-15-3

Breast cancer

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome "disorders of the central and peripheral nervous system"

Breast carcinoma- no mechanism listed

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome "hypertrophic osteoarthropathy and clubbing of the fingers"

Bronchogenic carcinoma and thymic neoplasms Unknown

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome myasthenia gravis

Bronchogenic carcinoma and thymic neoplasms immunologic

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome dermatomyositis?

Bronchogenic carcinoma, breast carcinoma. Immunologic

Functions in thermogenesis (newborn to 10 yo) Abundant mitochondria (cytochrome oxidase), blood vessels, and sympathetic innervation. Brown adipocytes are multilocular and smaller than white adipocytes *Locations:* a. Upper back b. Shoulder c. Thorax d. Abdomen

Brown adipose tissue

Thermogenin

Brown adipose tissue has thermogenin which is thermogenic- is an ETC uncoupler- allows protons to sneak back into matrix which decreases ATP production. Lose energy through heat. Helps to keep warm- most adipose tissue is white as we reach adulthood. Babies have brown fat.

How can macrophage function be enhanced?

By T helper cytokines which increase their phagocytic activity, give them higher levels of class II MHC on the cell surface, and in turn increased ability of macrophages to activate T helper cells.

How is fructose metabolized

By conversion to intermediates of glycolysis: Dihydroxyacetone-P and Glyceraldehyde-3-P Occurs mainly in liver. Rate limiting enzyme of fructose metabolism: Aldolase B (cleaves fructose 1-P) (in liver) (not rate limiting in glycolysis) Uses Aldolase A in muscle Fructose can also be converted to Fructose-6-P (in glycolysis intermediate) in muscle and adipose via hexokinase when glucose is low.

How does the body capture energy as ATP?

By oxidizing fuel, fatty acids in low oxidized state while ketone bodies are already in a high oxidized state therefore you get more energy out of fatty acids than ketone bodies (glucose in the middle).

What does a deficiency in C1-INH cause?

C1-INH (C1 inhibitor) normally inhibits the classical pathway of complement system. A C1-INH deficiency causes hereditary angioedema. You have overuse of C1, C4, and C2 which causes edema at mucosal surfaces so the most obvious sign is that the patients face is swollen but it happens everywhere.

What initiates the MAC attack?

C5 convertase

14-year-old male who had grand mal seizure at school Mild left-sided muscle weakness (face, arm, leg); CVA suspected; cleared spontaneously within a few days Slight mental retardation; downward partial dislocation of lenses of both eyes (corrected surgically); slight waddling gait last few years Increased length of long bones, slight scoliosis Diagnosis

CAT scan consistent with small infarct in right cerebral hemisphere. Decreased mineralization of skeleton (osteopenia) and high Met and HCy (homocystein), low Cys in blood

What stimulates gallbladder, pancreas secretions?

CCK (cholecystokinin)- Hormone produced by intestinal cells and secreted when stomach contents enter intestine.

What is the CD marker for macrophages?

CD14

NK cells characteristics

CD16 and 56 Responsible for killing viral infected and transformed cells (ADCC) Non-specific Activation of NK cells leads to degranulation - perforin (punch holes in membrane of target cells and fills it full of toxin components which makes the target cell die.) Apoptosis - Fas on the NK cell binds with Fas on the target cell and induces the target cell to commit suicide

What is the CD marker for NK cells?

CD16 and CD56

Which adhesion molecule is important in getting WBC into tissues from the blood?

CD18 which is activated by IL-8 (cytokine) and initiates tight binding of the WBC to the vascular endothelium.

What is the CD marker for B cells?

CD19, CD20, and CD21

What is the CD marker for all T cells?

CD3

What is the CD marker for stem cells?

CD34

What is the CD marker for T helper cells?

CD4

What is the CD marker for APC's (antigen presenting cells) and what are the APC's?

CD40 Macrophages, dendritic cells, and b cells.

What is the CD marker for activated T helper cells?

CD40L

What is the CD marker for T cytotoxic cells?

CD8

What is the INK4/ARF family and what are the main functions?

CDKN2A-C: P16/INK4a binds to cyclin D-CDK4 and promotes the inhibitory effects of RB. P14/ARF: Increases P53 levels by inhibiting MDM2 activity.

Overview of pyrimidine synthesis

CPS-II (first step in synthesis converts glutamine + CO2 + 2 ATP -> Carbamoyl phosphate) reaction similar to the CPSI reaction in the urea cycle. - Occurs in cytosol (not mitochondria) - Uses glutamine instead of NH4+ -Regulated step Note that orotate is an intermediate. Uses ATP

Regulation of pyrimidine synthesis

CPS-II is Inhibited by: UTP Stimulated by: PRPP

Location of the carnitine shuttle (3)

CPTI: outer mitochondrial membrane CPTII and translocase: inner mitochondrial membrane.

Which epigenomic regulatory gene mutation found in 40% of diffuse large B cell lymphoma?

CREBBP/EP300: histone acetylation

Effector cells in cell-mediated immunity

CTL = Cytotoxic T cell

T cell receptor

Can only bind one antigen, is always membrane bound and never secreted, and can only recognize things bound on MHC.

Pathway when OTC is defective, clinical diagnosis?

Carbamoyl -> orotate -> pyrimidines and urine. Pyrimidine synthesis pathway becomes flooded with OTC defect. Excess orotate is produced and excreted in the urine. This excess urinary orotate is indicative of a problem in the urea cycle.

What does glucogenic amino acids mean?

Carbon skeletons converted to some product of glucose breakdown. These amino acids produce pyruvate or intermediates of the TCA cycle. Considered glucogenic because they can lead to production of glucose in the liver. Some amino acids are both glucogenic and ketogenic. Lysine and leucine are strictly ketogenic.

What is the associated neoplasm and etiologic agent in osteomyelitis

Carcinoma in draining sinuses bacterial infection

This tumor marker is found in what tumor types? carcinoembryonic antigen

Carcinomas of the colon, pancreas, lung, stomach, and heart

Cells *DO NOT DIVIDE* little capacity for repair past childhood Fibroblasts in connective tissue form scar tissue - Replace dead cells -> release troponin Surrounding cells respond with *hypertrophy* (No satellite cells here)

Cardiac muscle repair

*Appositional* - Forms at the surface of existing cartilage - New cells derived from perichondrium *Interstitial* - Forms within an existing cartilage mass - New cells form from existing chondrocytes

Cartilage growth

Cartilage is composed of chondrocytes Chondrogenesis: - Aggregation of mesenchymal cells into a chondrogenic nodule - Differentiate into chondroblasts - Chondroblasts secrete cartilage matrix - Become chondrocytes - Surrounding mesenchymal tissue forms perichondrium

Cartilage is composed of?

Glucose and diabetes

Cataracts -Glucose increases rate of sorbitol, fructose formation. -Glucose & fructose increase nonenzymatic glycation of lens protein.

Glutamine synthetase role in cells around portal vein?

Catches NH3 that escaped from urea production and adds it to glutamate to form glutamine. *Uses ATP*

Dilated region of neuron Large, central *Nucleus - Nucleolus* *Perinuclear cytoplasm* - *Nissl bodies* -- rER & free ribosomes - Golgi apparatus - Mitochondria - Lysosomes - Microtubules - Neurofilaments - Transport vesicles - Inclusions

Cell body (soma)

Cell mediated immunity

Cell mediated immunity deals specifically with things that are intracellular like viruses and some bacteria. Cell mediated immunity goal is to always destroy the host cell that harbors the virus, etc. Intracellular bacteria and parasites or fungi induce delayed type hypersensitivity via Th1 and macrophage activation.

Osteoprogenitor cells Osteoblasts Bone lining cells (periosteal and endosteal cells) Osteocytes Osteoclasts

Cell types

Injury induces *axonal degeneration* CNS is unable to regenerate due to restrictions: - Inefficient clearance of myelin debris -- Restriction of sufficient number of macrophages by: --- *blood-brain barrier- macromolecule* ---- Disrupted at site of injury -- Inefficient phagocytic activity by: --- *Microglia cells* -- Clearance can take months-years - Formation of *astrocyte-derived scar* (plaques) -- Fills space left by degenerated axons.

Central Nerve Injury

I. Composition A. Brain & spinal cord B. White matter C. Gray matter II. Meninges A. Dura mater B. Arachnoid mater C. Pia mater III. Blood-brain barrier IV. Nerve injury

Central Nervous System

Often heavy metal staining or immunocytochemica methods necessary i. Oligodendrocytes ii. Astrocytes iii. Microglia iv. Ependymal cells

Central Neuroglia

What is the associated neoplasm and etiologic agent in chronic cervicitis

Cervical carcinoma Human papillomavirus

Location: Heart *Striated muscle* - Striated arrangement Involuntary muscle - *Autonomic* control Difference from skeletal muscle: - Individual *mononucleated* cells - Cells do not run length of muscle -- Attach linearly via *Intercalated discs* -- Cells branch

Characteristics and classifications of cardiac muscle

Composed of cells and extra-cellular matrix (ECM) ECM composed of fibers and ground substance Function is a reflection of composition *Locations:* Fascia, tendons, ligaments, supportive layers of vessels/nerves/muscles/organs

Characteristics of connective tissue

- Composed of cells and a basement membrane - Lines cavities and covers surfaces - Three distinct surface domains - Cells adhered to one another via cell junctions (form selective barrier) - Renewed continuously through mitosis. - *Avascular* *Absent from: articular cartilage, anterior surface of iris, enamel of teeth.*

Characteristics of epithelial tissue

*Pseudostratified Epithelium* Simple epithelium All cells attach to basement membrane (just 1 cell that stretches goes from apical to basement) *Locations*- Trachea, bronchi, ductus deferens, epididymis Secretion and conduit Absorption and conduit Will find cilia on these pseudostratified epithelium

Characteristics of this tissue type:

*Transitional Epithelium* (urothelium) Stratified epithelium Specialized for distention- cells flatten and "unfold" (cells at the top termed 'umbrella cells') *Locations*: Lower urinary tract (minor calyces, ureter, bladder, proximal urethra). (Barrier, distensible property)

Characteristics of this tissue type:

Release of chemical substance (*neurotransmitters*) from presynaptic cell into synaptic cleft Affect ion channels on postsynaptic cell -> transmit impulse

Chemical synapse

What are mitogens

Chemical/molecules that are capable of inducing cell division in a high % of B and T cells. Activate many clones, not just cells bearing specific receptors (polyclonal activators). Many are sugar binding proteins called lectins which bind to glycoproteins on cell surface. Some activate B cells, T cells, or both. Concanavalin A - T cell Phytohemaglutinin- T cells Pokeweed mitogens- B and T cells Non-lectin (2 most important mitogens) - LPS- B cells - EBV (epstein barr virus)- B cells

What is the associated neoplasm and etiologic agent in Opisthorchis, cholangitis

Cholangiocarcinoma, colon carcinoma Liver flukes (opisthorchis viverrini).

Chromogranin A marker for

Chromogranin A is a protein that is found in neuroendocrine cells, which are mainly present in the pancreas (i.e., islet cells), gastrointestinal tract, lungs, and adrenal glands. The biopsy of this patient's ileal mass shows numerous small cells of similar shape and size (monomorphic cells) arranged in a rosette pattern that is typical of a carcinoid tumor. Chromogranin A, synaptophysin, and neuron-specific enolase can be used as an immunostain to confirm the neuroendocrine origin of this tumor.

What does a deficiency in NADPH oxidase cause

Chronic granulomatous disease

Microtubules Kartagener's syndrome and Young's syndrome (bronchiectasis, rhinosinusitis and reduced fertility.)

Cilia made of? What diseases are characteristic of cilia disorder?

What are the 3 classes of HLA (MHC), which chromosome is it found in, and general characteristics.

Class I (A, B, and C) - Cytotoxic T cells. Class II (DP, DQ, and DR) - Helper T cells. Class III- Non-classical HLA (don't worry about). All 3 classes found on chromosome 6 They are highly polymorphic (high allelic differences and variability). Expression is co-dominant (one from mom and one from dad and they are coexpressed).

What is the difference between the classical, lectin, and alternative pathways?

Classical pathway: Antibody binds to specific antigen on pathogen surface. Need at least 1 IgM (which is pentameric) or 2 IgG (monomeric) to initiate. Needs antibody so this is adaptive immune system. Lectin pathway: mannose-binding lectin binds to pathogen surface. Initiates when a complement binds to carbohydrates on bacteria and initiates this pathway. Happens innately. Alternative pathway: Complement proteins coming from the liver, spleen, and macrophages spontaneously lyse (C3 to C3a and C3b) then if C3b binds to the pathogen surface because of attraction to it's (example) LPS, etc, this pathway is triggered. Happens innately.

- *Long bones* - Short bones - Flat bones - Irregular bones Compact vs spongy bones

Classification of bones

Based on: 1. Cell type 2. ECM/ground substance characteristics 3. Function Classifications: 1. *Embryonic Connective Tissue* a. Mesenchyme b. Mucous CT 2. *Connective Tissue Proper* a. Loose CT b. Dense CT (regular, irregular) 3. *Specialized Connective Tissue* - Bone - Cartilage - Adipose - Blood - Hemopoietic - Lymphatic

Classification of connective tissue

1. Number of cell layers: - Simple - Stratified 2. Cell morphology: - Squamous - Cuboidal - Columnar 3. Apical modifications: - Keratinized/ non-keratinized - Ciliated

Classification of epithelial tissue (3)

Simple columnar: -Small intestine and colon (absorption and secretion. -Stomach lining and gastric glands (secretion) -Gallbladder (Absorption)

Classify this epithelial tissue and its characteristics/location

Simple cuboidal: - Small ducts of exocrine glands (Absorption and conduit) -Surface of ovary (germinal epithelium) (Barrier) -Kidney tubules and Thyroid follicles (Absorption and secretion)

Classify this epithelial tissue and its characteristics/location

Simple squamous: - Vascular system (endothelium) and Body cavities (mesothelium) (exchange, barrier in central nervous system) - Bowman's capsule (kidney) and Respiratory spaces in lung (Exchange and lubrication)

Classify this epithelial tissue and its characteristics/location

Stratified columnar: - Largest ducts of exocrine glands, anorectal junction (Barrier, conduit)

Classify this epithelial tissue and its characteristics/location

Stratified cuboidal: - Sweat gland ducts, anorectal junction, large ducts of exocrine glands (Barrier, conduit)

Classify this epithelial tissue and its characteristics/location

Stratified squamous: - Epidermis, oral cavity and esophagus, vagina (barrier and protection)

Classify this epithelial tissue and its characteristics/location

What does a-amylase cleave

Cleaves a-1,4 glycosidic bonds. (to limit dextrin and maltose) via endoglucosidase

What is required for lipase to digest fat droplet

Colipase - allows interaction between lipase and fat droplet (made by bile salts).

This tumor marker is found in what tumor types? TP53, APC, RAS mutants in stool and serum

Colon cancer

This tumor marker is found in what tumor types? CA19-9

Colon cancer, pancreatic cancer

What is the associated neoplasm and etiologic agent in inflammatory bowel disease

Colorectal carcinoma

- Allow adjacent epithelial cells to communicate directly via passage of small molecules -Permits coordinated cell activity (ex. cardiac muscle, smooth muscle) Major link protein: Connexin Cytoskeleton component: None.

Communicating junctions (Gap Junctions)

Components: - Brain - Spinal cord Composed of: *Gray Matter* (Cortex & Nuclei) - Neuronal cell bodies - synapses - *Neuropil*: collection of dendritic, axonal, and glial cell processes. *White matter* (Medulla) - Myelinated axons

Composition of CNS

*Cells*: 1. Fibroblasts (related: osteoblasts, chondroblasts) form almost the entire ECM. 2. Immune cells (macrophages, lymphocytes, etc.) *Extra-cellular Matrix* 1. _Fibers_ a. Collagen b. Elastic fibers c. Reticular fibers 2. _Ground Substance_ a. Proteoglycans b. Glycoproteins c. Glycosaminoglycans

Composition of Connective tissue

Combination of fibers and ground substance Properties of ECM give each connective tissue specific characteristics *Ground substance*: - Proteoglycans, glycosaminoglycans (GAGs), multiadhesive glycoproteins - Provides structural support, biochemical barrier, and metabolic regulation of cells. - GAGs are negatively charged- bind water (responsible for the physical properties of ground substance)

Connective Tissue Extracellular Matrix

Consists of Type III collagen fibrils Typically require special staining (i.e. PAS, silver stain). Thin and branching, arranged in meshworks: - Between CT and epithelium - Around small blood vessels - Embryonic tissues - *Initial stages of wound healing* - *Hemopoietic and lymphatic tissues (support organ tissue)*

Connective Tissue Fibers: Reticular fibers

(Left: Dense regular connective tissue- found in tendon and ligaments to resist tensile force) (Right: Dense irregular connective tissue (collagen fibers arranged in parallel). Found in wall of gut tube or skin, places with lots of distention/movement. Collagen fibers look chunky) *Dense Connective Tissue*: Relatively few cells (mainly fibroblasts) and abundant fibers (mainly collagen) A. *Dense Irregular CT*: Bundles oriented in various directions; *strength and support (i.e. submucosa, deep skin (dermis), intestinal tract, places with lots of distention/movement)* B. *Dense Regular CT*: Densely-packed fibers arranged in parallel; *comprise ligaments, tendons, aponeuroses.*

Connective Tissue Proper: Dense connective tissue. (Identify)

*Loose Connective Tissue*: - "Areolar tissue" - Relatively cellular (many "wandering" cells) with thin, sparse fibers. - Abundant ground substance- *site of inflammatory/immune response, ideal for diffusion.* *Locations*: Under epithelium and mucous membranes, around vessels

Connective Tissue Proper: Loose connective tissue

Designed for stretch and distension Fibers of elastin and fibrillin Synthesized by fibroblasts and vascular smooth muscle cells. Stain well with resorcin-fuschsin or orcein.

Connective Tissue fibers: Elastic Fibers

*Resident cells* - Fibroblasts and myofibroblasts - Macrophages - Mast cells - Adult stem cells - Pericytes - Adipocytes *Wandering/Transient Cells* - Lymphocytes - Neutrophils - Eosinophils - Basophils - Monocytes - Plasma cells

Connective tissue cells

1. Collagen 2. Reticular fibers 3. Elastic fibers

Connective tissue fibers

Most abundant CT fiber, produced by fibroblasts Appear eosinophilic and of variable size - Collagen molecules comprised of three alpha chain polypetides -> collagen fibrils -> collagen fiber. Provide flexibility and tensile strength Numberous types: - *Type I*- in loose connective tissue, bone, tendon, ligaments, etc. - *Type II* - in cartilage - *Type III*- forms reticular fibers

Connective tissue fibers: Collagen

Contribution to the amino acid pool (2)

Constituted of both digested dietary and digested intracellular proteins. - Excess dietary protein (carbon skeleton) converted to glycogen and triglycerides for storage. Intracellular protein digestion - Lysosomes (proteases) - Ubiquitin-proteasome system (25% of intestinal epithelial cells lost each day, the protein components are digested and absorbed)

Lactate dehydrogenase

Converts pyruvate to lactate, is reversible. Regenerates NAD+ in the process.

How does creatine phosphate generate ATP

Creatine phosphate + ADP + creatine (phospho) kinase (CPK or CK) --> Creatine + ATP Creatine synthesis begins in kidney, completed in liver, and imported by muscle (and other tissues).

Creatinine

Creatinine forms spontaneously from creatine phosphate. Creatinine released from skeletal muscles at steady rate, proportional to muscle mass. Excreted in urine. Can be used to determine concentration of other molecules excreted in urine. Elevated in blood suggests impaired renal function.

Cross priming?

Cross priming is when a cell (APC) expresses both class I MHC and class II MHC at the same time. Example: Dendritic cells can engulf a whole virus infected cell and the virus antigens will be processed by both class I and class II MHC. This is a good thing because cytotoxic T cells need IL-2 to be effective killer and these cytokines don't like to travel long distances, instead travel via autocrine to neighboring cells. So this way, T helper cells are activated by class II MHC and send out IL-2, etc. and T cytotoxic cells would be right there to get the IL-2.

Cystic Fibrosis and effect on protein digestion?

Cystic Fibrosis causes thickening of exocrine secretions therefore reduced ability to digest proteins. Give pancreatic enzymes supplements to help.

Cytochrome P450 enzymes characteristics

CytP450- dependent monooxygenase enzymes. Broad spectrum of biological activity. *Essential for metabolism of medications. * *Introduce oxygen into compound* Intermediate is reactive free radical NADPH-cytP450 oxidoreductase, cytP450 key components Microsomal enzymes (found in smooth ER) Inducible by presence of substrate CytP450 family has 57 functional genes, 9 major subfamilies - CYP2E1 = CytP450 family, subfamily 2, E for EtOH detox, isozyme 1 -CYP3A4 accounts for 30-40% CYP450 enzymes in liver

Cytokeratin marker for

Cytokeratin is an intracytoplasmic protein found in cells of epithelial origin (i.e., lining cells of the gastrointestinal, respiratory, urinary, and reproductive tracts). Therefore, immunostaining with cytokeratin would be positive in epithelial tumors (e.g., squamous cell carcinoma (SCC), adenocarcinoma). On histology, well-differentiated SCC would show evidence of keratinization, while adenocarcinomas would show glandular architecture. This image shows monomorphic cells arranged in a rosette pattern characteristic of a carcinoid tumor. Since it does not originate from epithelial cells, it would not stain with cytokeratin.

Eosinophils

Cytoplasm stains with acidic dye (eosin) Bilobed nucleus Granulated Phagocytic, but less important than neutrophils Major role against *parasites* Secretion of eosinophilic granules results in damage to the parasite membrane Main job is to help eliminate parasites like worms. Also play a role in allergies

A 46 year-old patient presents with jaundice, severe abdominal distension and tenderness, and edema in his extremeties. Lab results indicated elevated ALT and AST in the blood. Which of the following statements can most accurately be made based on this information? A. Patient has alcoholism B. Patient has excessive ammonia in their blood C. Patient has excessive bilirubin glucuronidation D. Patient is not producing enough albumin E. Patient is not producing enough clotting factors

D. Patient is not producing enough albumin.

Which epigenomic regulatory genes mutated in 20% of acute myeloid leukemia?

DNMT3A which functions as a DNA methylation

Hartnup disease

Defect in transport of neural amino acids, malabsorption of amino acids. High levels of some amino acids in urine (may be only symptom) Some may eventually develop pellagra-like symptoms (pellagra is dermatitis, diarrhea, and dementia) (deficiency in Trp, a precursor for NAD+ and NADP+) -Triggered by illness, stress, poor diet. -Dermatitis, cerebellar ataxia, and depression or psychosis possible.

Hereditary Fructose Intolerance (HFI)

Deficiency in aldolase B Fructose-1-P build up which inhibits breakdown of glycogen and gluconeogenesis Causes- hypoglycemia, high lactate, low ATP Can be fatal

ubiquitin-proteasome system

Degradation of Intracellular Proteins (lysosomes also do this via proteases). 19S regulatory particle (1 or 2 of these) bind with the protein targeted for destruction (via ubiquitin) and attaches to the 20s proteasome via ATP and creates an active proteasome complex (26S proteasome). Proteolysis then requires ATP.

Favorable reaction

Delta G<0, exothermic/exogonic- release energy.

Free energy change formula

Delta G= -RT ln(p)/(s) p = product s = substrate T = temperature (kelvin) R = Universal gas constant (for reaction at equilibrium)

Unfavorable reaction

Delta G>0, endothermic/endogonic- Energy must be put into system.

Receptor processes Receive stimuli -> cell body Greater diameter than axons Unmyelinated Contain organelles of cell body @ base. *Dendritic spines* - Projections from the dendrite - *Dendritic trees* -- Increase receptive SA (spine apparatus) -- Vary in shape

Dendrites

Desmin marker for

Desmin is a protein that is found in all types of muscle (i..e, skeletal, smooth, and cardiac muscle). Therefore, immunostaining with desmin would be positive for a sarcoma arising from muscle (i.e., rhabdomyosarcoma). As sarcomas mimic the cell of origin on histology, muscular sarcomas will show skeletal/smooth/cardiac muscle cells in various stages of differentiation.

A 26 year-old patient with sickle-cell anemia presents with pain in his extremities, low-grade fever, nausea, and jaundice. What liver process is being overwhelmed, as indicated by this patient's presentation?

Detoxification is impaired as indicated by his jaundice state. Liver not filtering bilirubin causes its accumulation and leads to jaundice.

What is input and output of protein in intestinal epithelial cell. Where does the product go afterwards?

Di- and tri- peptides turn into amino acids in intestinal epithelial cells and then go into the blood. Amino acids go into intestinal epithelial cells and then directly into blood.

Sources and fates of serum amino acids

Dietary proteins and endogenous proteins go to the blood. From the blood, amino acids can be used to: 1. Synthesis of new proteins 2. Purines, pyrimidines, heme, neurotransmitters, hormones, and other functional nitrogen products (with urinary metabolites as waste) 3. Produce urea (CO(NH2)2) and NH4+ (ammonium). 4. Used as carbon skeleton for glucose and lipid synthesis (CO2 waste product).

How is dietary fiber digested?

Digested by bacteria: - produce gas and short chain fatty acids - 10% of caloric intake

Digestion of starch and complex carbohydrates where?

Digestion begins in mouth with a-amylase in saliva: -endoglucosidase: cleaves a-1,4 glycosidic bonds No digestion in stomach, acid inhibits amylase. Digestion completed in small intestine: Pancreas secretes HCO3- (neutralize the acid) and a-amylase. (Mouth, small intestine)

Liver's role in ketone body formation

During fasting state: Liver cannot fully metabolize FA when fasting. - only liver produces ketone bodies. Liver cannot use ketone bodies Brain, skeletal muscle, and some other tissues can use ketone bodies.

What is the fate of protein during fasting state?

During fasting, amino acids released via proteolysis from muscles, alanine and glutamine (via TCA in skeletal muscle converting glutamate to glutamine) released- major skeletal muscle exports. Carbon skeleton used for fuel, nitrogen group is removed and excreted from the body as NH4+ or urea. Glutamine converts to alanine. Alanine is the major gluconeogenic amino acid, converted to either glucose or ketone bodies in the liver. Glutamine converts to alanine and directly into NH4+ (via glutaminase) in the kidneys. NH4+ excreted in urine, alanine transported to liver. Liver makes urea with one N group coming from amino acids and the other N group coming from Aspartate (aspartic acid) and combining it with bicarbarbonate (HCO3-, made from CO2 and H20).

Livers role in synthesis, export of cholesterol and triglycerides.

During fed state: Hepatocytes responsible for most of body's cholesterol production. Cholesterol exported in lipoprotein particles (VLDL) Acetyl-CoA is precursor for FA, cholesterol synthesis.

Dinitrophenol

ETC Uncoupler Facilitates proton transfer across the inner mitochondrial membrane.

Rotenone and Amytal (interfere oxidative phosphorylation)

ETC inhibitors Inhibits transfer of electrons from complex I to coenzyme Q

Carbon monoxide (CO) and Cyanide (CN)(interfere oxidative phosphorylation)

ETC inhibitors Inhibits transfer of electrons from complex IV to oxygen.

How does the TCA cycle relate to glycolysis, fatty acid oxidation, ketone body oxidation, and amino acid oxidation?

Each of these metabolic pathways produces acetyl-coA.

*Elastic fibers* in the matrix (in addition to matrix material of hyaline cartilage) Dense network of branching fibers Surrounded by perichondrium Stains with resorcin-fuchsin or *orcein* Found in ear, Eustachian tube, epiglottis Does not calcify with aging (unlike hyaline cartilage).

Elastic cartilage

*Gap junctions* - Transmits ions from one cell to another.

Electrical Synapse

How is metabolism of amino acids affected in liver disease

Elevated amino acid levels in blood: - Especially elevation of Tyr, Phe, Met yet lower levels of BCAAs in cirrhotic patients (Because BCAAs typically oxidized by other tissues). - Increased rate of protein turnover. (replacement/renewal of protein) - Impaired amino acid uptake by diseased liver. Decreased urea production - More likely to develop hyperammonemia.

Mesenchyme: - Undifferentiated connective tissue - Very cellular, with sparse collagen and reticular fibers. - Viscous ground substance

Embryonic Connective Tissue: Mesenchyme

- Found in umbilical cord - Gelatin-like ECM (Wharton's jelly)

Embryonic Connective Tissue: Mucous CT

Begins later in gestation Mesenchymal cells aggregate and form chondroblasts which secrete cartilage matrix *Hyaline cartilage model* is formed Cartilage model grows by interstitial and appositional growth Perichondrium gives rise to a *bony collar* near the diaphyseal region (periosteum). Chondrocytes in mid-region become hypertrophic and begin to calcify the surrounding matrix. A large cavity is produced because of cell death Blood vessels grow into the cavity carrying mesenchymal stem cells that differentiate into osteoprogenitor cells -> osteoblasts Osteoblasts lay down bone matrix on calcified cartilage forming the *primary ossification center* Blood vessels invade the proximal epiphyseal cartilage bringing osteoprogenitor cells in to form the *secondary ossification center* *Epiphyseal growth plate* is responsible for maintaining growth. When the growth is complete forms an *epiphyseal line*

Endochondral ossification

What kind of antigens recognized by T cytotoxic cells

Endogenous antigens. They recognize and kill target cells (virus infected, cancer, or intracellular bacteria).

Other cell types in liver aside from hepatocytes (4)

Endothelial cells (no tight junctions, fenestrated) Kupffer cells (tissue macrophages Hepatic stellate cells (lipid-filled cells, control turnover of connective tissue, ECM) Pit cells (liver-specific NK cells)

Phagocytic killing mechanisms

Engulfment - Bug attaches to phagocyte and gets "swallowed" Oxygen Dependent killing (most important) Oxygen Independent killing (not as effective at eliminating pathogen)

What is allelic exclusion?

Ensures antigenic specificity. Allelic exclusion shuts off rearrangement of the other alleles so we keep that 1 cell specificity.

Von Gierkes disease

Enzyme affected: Glucose 6-phosphatase (glucose 6-phosphate to glucose). Primary organ involved: Liver Causes: Enlarged liver and kidney, growth failure, severe fasting hypoglycemia, acidosis, lipemia, thrombocyte dysfunction

McArdles disease

Enzyme affected: Muscle glycogen phosphorylase (breaks down glycogen) Primary organ involved: Skeletal muscle Causes: Excercise induced muscular pain, cramps, and progressive weakness, sometimes myoglobinuria (rhabdomylosis)

Hers disease

Enzyme: Liver glycogen phosphorylase. Primary organ involved: liver Causes: Hepatomegaly, mild hypoglycemia. Good prognosis.

1. Bilobed nucleus, eosinophilic granules 2. Granules: - Azurophilic (primary)- lysosomes; myeloperoxidase, acid hydrolases, etc. - Specific (secondary)- crystalloid body; MBP, ECP, EPO, EDN; also contain histaminase, arylsulfatase, collagenase, and cathepsins. 3. Migrate into CT; associated with allergic reactions, parasitic infections and chronic inflammation. 4. CBC (allergies, parasitic infection) = eosinophilia.

Eosinophil key points

Single layer Cuboidal-to-columnar Epithelium-like cells (no basal lamina) Apical - Cilia & Microvilli - Produce & absorb *CSF* Lines fluid-filled cavities of CNS - Central canal of spinal cord - Ventricles of brain

Ependymal cells

What is muscle glycogenolysis stimulated by?

Epinephrine (primarily)

Surface epithelia and epithelia of many simple glands belong to category of *continuously renewing cell populations*. Rate of cell turnover is characteristic of specific epithelium. For example, cells lining small intestine renewed every 4 to 6 days. Replacement cells produced by mitotic activity of self-maintaining adult stem cells which are located in sites called niches at lower portion of the intestinal glands. These stem cells differentiate into enterocytes (columnar) goblet cells (mucus-secreting), enteroendocrine cells (hormone-secreting), and Paneth cells cells. The enterocytes, goblet, and enteroendocrine cells continue to differentiate and mature while they migrate up along the villi to the surface of the intestinal lumen. Migration of these new cells continues until they reach the tips of the villi, where they undergo apoptosis and slough off into the lumen. Paneth cells migrate downward and reside at the bottom of the crypt. *Transcription factor Math1* expressed in intestinal epithelium determines the fate of the cells. Cells committed to secretory lineage (ie differentiate into goblet, enteroendocrine, and paneth cells) have increased expression of Math1. Inhibition of Math1 expression characterizes the defailt developmental pathway into absorptive intestinal cells (enterocytes). Epithelial cells belong to the category of continuously renewing cell populations. The replacement cells are produced by mitotic division of adult stem cells residing in different sites (niches) in various epithelia.

Epithelial cell renewal

Proerythroblast -> basophilic erythroblast -> polychromatophilic erythroblast -> orthochromatophilic erythroblast (normoblast) -> polychromatophilic erythrocyte (reticulocyte) -> erythrocyte.

Erythrocyte development

1. Made in bone marrow. 2. Anucleate, few organelles 3. Oxygen and carbon dioxide transport: hemoglobin 4. Biconcave disc, 7.8 micrometers in diameter, flexible - Shape is maintained by cytoskeleton 5. Mean corpuscular volume is 80-99 fL 6. Live ~120 days, 90% phagocytosed in spleen > bone marrow > liver.

Erythrocytes key points

What can excess glucose cause and what marker would test for prolonged glucose in blood

Excess glucose can cause non-enzymatic glycosylation of proteins. Hemoglobin A1C- measure of prolonged glucose in blood

Exocrine glands may be: 1. Unicellular (i.e. goblet cells (mucous secreting)) 2. Multicellular - Duct (simple, compound) - Secretory portion (tubular, acinar/alveolar, tubuloacinar) Merocrine secretion: This secretory product is delivered in membrane-bounded vesicles to the apical surface of the cell. Here vesicles fuse with the plasma membrane and extrude their contents by exocytosis. This is the most common mechanism of secretion and is found, for example, in *pancreatic acinar cells*. Holocrine secretion: The secretory product accumulates within the maturing cell, which simultaneously undergoes destruction orchestrated by programmed cell death pathways. Both secretory products and cell debris are discharged into the lumen of the gland. This mechanism is found in *sebaceous glands of skin* and the tarsal (Meibomian) glands of the eyelid. Apocrine secretion: Th e secretory product is released in the apical portion of the cell, surrounded by a thin layer of cytoplasm within an envelope of plasma membrane. Th is mechanism of secretion is found in the *lactating mammary gland*, where it is responsible for releasing large lipid droplets into the milk.

Exocrine glands characteristics

Exocrine: Secrete products onto surface directly or through epithelial ducts or tubes that are connected to a surface. Endocrine: Secrete products into the connective tissue, from which they enter the bloodstreatm to reach their target cells. Hormones.

Exocrine vs endocrine glands

Class II HLA characteristics?

Expressed on antigen presenting cells (APCs) including macrophages, B cells, and dendritic cells. Present exogenous antigens (extracellular bacteria) to T helper cells. Highly polymorphic Composed of an alpha and beta chain that come together to form a cleft that binds peptides of 12-15 aa in length. A1 and B1 combine to form the peptide binding cleft Hydrophobic transmembrane region (APCs express both class I and class II HLA (MHC)) Class II MHC can accomidate for larger peptides because the antigen can sometime hang over the sides of it. Class II MHC is more sturdy than Class I MHC.

IgD

Expressed on mature B cells, can be used to tell apart an immature B cell (only IgM) and a mature B cell (IgM and IgD). Not really secreted so very low levels in the plasma Antigen receptor on B cells Unsure of its main function besides as part of the B cell receptor.

Phagocytosis

Extension of pseudopodia Formation of phagosome Fusion with lysosome to form phagolysosome Digestion Exocytosis

Liver fuels and metabolism - lipids

FA (major fuel during overnight fast and starvation) - Uses energy from FA oxidation to supply glucose to the body - Primarily long chain FA during fasting (from adipose) - Also medium chain FA oxidation (absorbed and released directly to portal circulation). Peroxisomal oxidation of very long chain FA (too long for mitochondria) - PPARs induce peroxisome proliferation - Nuclear receptors that bind a number of hypolipidemic agents, toxins, and NSAIDs - Regulate genes involved in FA uptake, oxidation - PPARa knock out mice - Normal phenotype on regular diet. - Fatty livers when fasted or high-fat diet; hypoglycemia and hypoketosis. Unable to increase rate of fatty acid oxidation.

Adipose tissue characteristics

Fat stored as triglycerides: - Fatty acid uptake from blood (LPL (lipoprotein lipase)) -Uses glucose to make glycerol - Most synthesized triglycerides are made in liver and transported in VLDL. Releases fatty acids when hormone-sensitive lipase (HSL) stimulated. - stimulated by glucagon, epinephrine, cortisol, growth hormone. - fatty acids carried by albumin in blood, used as fuel. Can make /very small quantities/ of FA and TG from carbohydrates.

Favism

Fava bean (falafel) has divicine which causes hemolytic anemia in those with deficiency in glucose-6-Phosphate dehydrogenase. Hemolytic anemia can also be caused by certain malaria drugs like primaquine

What is CD16 also known as

Fc receptor

Features of CT: 1. Cells -erythrocytes -leukocytes - Granulocytes - Agranulocytes - Thrombocytes 2. Extra cellular matrix Functions: 1. Delivery of nutrients/removal of wastes 2. Gas transport 3. Transport of hormones and other regulatory substances 4. Buffer 5. Coagulation 6. Thermoregulation 7. Immune

Features and functions of blood (specialized CT) connective tissue.

Muscle fuel use and energy states

Fed state: - Glucose and FA. - Regulates by monitoring cytoplasmic citrate. Brief fast: - Fatty acids (preferred) - Ketone bodies - Glucose - Muscle glycogen- minor Prolonged fasting: - FA (preferred) - Ketone bodies - minor Excercise/increased demand: - Glucose - FA (preferred) - Muscle glycogen - Ketone bodies In addition to fiber type-related preference, resting muscle can also use BCAAs for up to 20% of ATP needs. Cytoplasmic citrate (energy sufficient state) activates Acetyl CoA carboxylase 2 which makes malonyl-CoA which inhibits CPTI

TG storage and release from adipose tissue summary

Fed state: - Insulin promotes storage of TG (and inhibits lipolysis) - Lipoprotein lipase (LPL) active in adipose and muscle tissues Fasting state: - Low insulin: glucagon promotes lipolysis - Lipolysis promoted by HSL activation (Glucagon, epinephrine, cortisol, and growth hormone).

Regulation of purine synthesis?

Feedback inhibition, particularly of PRPP synthetase. *PRPP synthetase* (converts ribose 5-phophate to PRPP) inhibited by GMP, GDP, GTP, AMP, ADP, ATP. *Glutamine phosphoribosyl amidotransferase* (converts PRPP to 5-phosphoribosyl 1-amine) Inhibited by GMP, GDP, GTP, AMP, ADP, ATP. *IMP dehydrogenase* (converts IMP to XMP) Inhibited by GMP. *Adenylosuccinate synthetase* (converts IMP to adenylosuccinate) inhibited by AMP

Combination of dense regular connective tissue and hyaline cartilage Large amount of type I collagen fibers Chondrocytes are sitting in rows or isogenous groups Fibroblasts present No perichondrium Resistant to compression- serves as a shock absorber Found in Intervertebral discs, the pubic symphysis, articular discs, and menisci

Fibrocartilage

Found in *White matter* Fewer process, relatively straight

Fibrous Astrocytes

What are the products of non-oxidative pentose phosphate pathway? What is the most clinically important enzyme in this pathway.

Final net result of nonoxidative PPP from 3 mol of ribulose 5-P (from 3 glucose-6-phosphates): 2 mol fructose 6-P and 1 mol of glyceraldehyde 3-P (2 NADPH produced in oxidative phase of PPP) Transketolase is clinically important- transketolase requires thiamine. If patient's transketolase activity increases when thiamine is added to the sample, then the patient is thiamine deficient. Chronic thiamin deficiency is the cause of beriberi. Common in alcoholics.

What is the location of the urea cycle reactions

First 2 reactions are in the mitochondria. Next reactions are in the cytosol. All occur mostly in the liver (gut has some activity)

Innate immunity characteristics

First line of defense against pathogens. - *Are present intrinsically*- you're born with it and it never changes. - *Limited specificity*- does not differentiate between different bacteria just knows its a bacteria and attacks. - *Limited diversity*- not a bunch of different cell types - *No memory*

What are the main oxygen dependent killing mechanisms

First line: NADPH oxidase. Turns O2 into superoxide radicals then to hydrogen peroxide, hydroxyl radicals, peroxide radicals. Second: Myeloperoxidase. Turns hydrogen peroxide into hypochloride which is kind of like bleach. Myeloperoxidase isn't really needed unless plan A doesn't work (NADPH oxidase).

Which APCs don't express Class II MHC?

Follicular dendritic cells (other dendritic cells do). Don't function as APC for Th cell activation. Main role in formation of memory B cells.

What do CDK4; D cyclins main functions

Form a complex that phosphorylates RB, allowing the cell to progress through G1 restriction point

Hematopoiesis characteristics

Formation and development of red and white blood cells from stem cells. Begins in the yolk sac then migrates to the fetal liver and spleen As gestation continues, the bone marrow becomes the major site of hematopoiesis. Remains there during the lifetime of that individual. Hematopoiesis initiates in the bone marrow from pluripotent hematopoietic stem cells (PHSC) - Self renewing - Capable of developing into all cells of the blood lineage. Relatively rare population of cells representing only 1-2% of total bone marrow.

Hematopoiesis

Formation and development of red and white blood cells from stem cells. Begins in the yolk sac then migrates to the fetal liver and spleen. As gestation continues, the bone marrow becomes the major site of hematopoiesis and remains there during lifetime of individual.

Oligosaccharides

Found attached to glycoproteins, lipoproteins, proteoglycans (from bacteria), glycosaminoglycans (found in extracellular connective tissue and joints).

CD59

Found in blood cells, endothelial cells, and epithelial cells. Blocks C9 binding and prevents formation of the MAC. Inhibits the MAC attack.

Adipose tissue functions

Fuel storage (85% of body's stores) - Many kg of fat can be stored. - More energy-dense than glycogen. - Water not needed to store fat (as with glycogen) - Insulin-stimulated fuel storage. Heat insulation - Brown adipose tissue in infants actually generates some heat via thermogenesis.

Cytotoxic t cells ammunition

Function of cytotoxic T cells requires IL-2 from an activated Th1 cell. Same ammo as NK cells. Perforin: - Membrane punching, pore forming molecule. Granzymes: - Enzymes that damage target cell Cytokines - IFN-y and TNF-B are secreted by cytotoxic T cells. - Induce metabolic changes in target cells that lead to apoptosis Fas and FasL - Cytotoxic T cells express FasL and target cells express Fas - Interaction between Fas and FasL causes apoptosis.

Which transporter does fructose use? What can it cause in the eye?

GLUT 5 transporter Can cause cataract formation in the eye.

Nonclassical galactosemia caused by defect in what enzyme?

Galactokinase Accumulation of galactose Causes cataracts

Classical galactosemia caused by defect in what enzyme?

Galactose 1-phosphate uridylyltransferase Accumulation of galactose 1-phosphate Causes cataracts

What is the associated neoplasm and etiologic agent in chronic cholecystitis

Gallbladder cancer Bile acids, bacteria, gallbladder stones

What is the associated neoplasm and etiologic agent in gastritis/ulcers

Gastric adenocarcinoma, MALT lymphoma H. pylori

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome acanthosis nigricans

Gastric carcinoma, lung carcinoma, uterine carcinoma. Immunologic; secretion of epidermal growth factor.

Avascular connective tissue Typically found in areas of support (weight-bearing) and movement. *Chondrocytes*- large rounded cells with light cytoplasm and small nucleus- produce matrix. *Matrix*- composed of type II collagen, glycosaminoglycas (GAGs) and multiadhesive glycoproteins.

General appearance of cartilage

*Extracellular Matrix*: - Hydroxyapatite crystals - Type I collagen - Ground substance: noncollagenous matrix proteins. Cells: - Osteoprogenitor cells - Osteoblasts - Osteocytes - Bone lining cells - Osteoclasts

General features of bone

Hyperammonemia symptoms

General: growth retardation, hypothermia. Combativeness, lethargy, coma. Papilledema (eyes) Shortness of breath Enlarged liver Poor coordination, dysdiadochokinesia, hypotonia or hypertonia, ataxia, tremor, seizures, decorticate or decerebrate posturing.

Urogenital system including gonads, ducts, and accessory glands

Germ layer derivatives: What comes from Intermediate mesoderm?

Epithelial lining of: - Respiratory tract (trachea, bronchi, lungs) - GI tract (pharynx, esophagus, stomach, small and large intestines) - Urinary bladder and urachus Epithelial parts of: - Thyroid gland - Tympanic cavity - Auditory tube - Tonsils - Parathyroid glands - Liver - Pancreas

Germ layer derivatives: What comes from ectoderm?

Cranium (skull) Connective tissue of head Dentin

Germ layer derivatives: What comes from head mesoderm?

Connective tissue and muscle of viscera Serous membranes of pleura, pericardium, and peritoneum. Blood and lymph cells Cardiovascular and lymphatic systems. Spleen Adrenal cortex

Germ layer derivatives: What comes from lateral mesoderm?

Cranial and sensory ganglia and nerves Adrenal medulla Melanocytes Pharyngeal arch cartilages Head mesenchyme and connective tissue Schwann cells Odontoblasts

Germ layer derivatives: What comes from neuroectoderm (neural crest) ?

Central nervous system Retine Pineal body Posterior pituitary gland

Germ layer derivatives: What comes from neuroectoderm (neural tube)?

Skeletal muscle of trunk and limbs except cranium Muscle of head Dermis of skin Connective tissue

Germ layer derivatives: What comes from paraxial mesoderm?

Epidermis, hair, nails, cutaneous, and mammary glands. Anterior pituitary gland Enamel of teeth Internal ear Corneal epithelium and lens of eye.

Germ layer derivatives: What comes from surface ectoderm?

What are the germinal centers?

Germinal centers are found in secondary lymphoid tissues (lymph nodes, spleen) and it is where B cells develop and start to proliferate under T cell dependent b cell response, germinal centers only form under T cell dependent response. Goes from primary follicle to secondary follicle and then finish in the germinal centers. Germinal centers have proliferating B cells and some T cells. The B cells then travel down to the medullary area (where plasma cells found) after the germinal centers and then out to the lymphatice -> blood. 3 things happen in germinal centers. 1. Affinity maturation 2. Class switching 3. Plasma cells or B cell differentiation.

Which hormone stimulates hunger?

Ghrelin

Leptin vs. Ghrelin

Ghrelin: Appetite stimulator. Released from stomach and when elevated sends signal to brain letting you know you're hungry. Age, gender, blood glucose, and leptin levels can all affect ghrelin levels. Leptin: Appetite suppressor. Leptin, which is stored and secreted by fat cells, is considered to be the master regulator of hunger. When you eat a meal, leptin is released from fat cells and sends a signal to your brain to let you know you're full and to stop eating.

Glial fibrillary acidic protein (GFAP) marker for

Glial fibrillary acid protein (GFAP) is a cytoskeletal protein found exclusively in some cells of the CNS (i.e., astrocytes, Schwann cells, and oligodendrocytes), so immunostaining with GFAP would be positive in certain CNS tumors (e.g., astrocytoma, glioblastoma). As this patient has a tumor of neuroendocrine origin, cells from this mass would not stain with GFAP.

Glycogenolysis stimulated by what in the liver?

Glucagon and/or epinephrine

Glucokinase vs hexokinase

Glucokinase = In Liver Hexokinase = Non-liver cells Glucokinase not subject to regulation, has higher km.

How much ATP does gluconeogenesis consume?

Gluconeogenesis costs 6 ATP

The polyol pathway steps

Glucose + aldose reducase -> sorbitol (polyol) + sorbitol dehydrogenase -> fructose 1. Aldose reducase 2. Sorbitol dehydrogenase Important in semen since sperm use fructose Can also be used with galactose with galactitol as intermediate and fructose the product.

Which substrate in the liver can be used in glycolysis, pentose phosphate pathway, glycogen synthase, TG synthesis, TCA cycle, or just released in blood glucose

Glucose 6- phosphate

Lactose intolerance is the inability to convert lactose into?

Glucose and galactose

What is activated during brief fast.

Glucose via glycogenolysis. Substrates for gluconeogenesis (Alanine, Lactate, Glycerol) FA oxidation provides energy

Which cycle is alanine (one of the major muscle exports along with glutamine) used for?

Glucose-alanine cycle (moving carbons and nitrogen between muscle and liver)

Facilitated glucose transporters (2)

Glut 4- insulin sensitive transporter found in adipose, skeletal, and heart muscle. Glut 5- Fructose transporter.

What combines to form N-Acetyl- glutamate?

Glutamate + Acetyl CoA

How is alpha ketoglutarate formed?

Glutamate + PLP in transamination reaction -> alpha ketoglutarate. (NH3+ group removed from glutamate to make alpha ketoglutarate) and vice versa. Alpha ketoglutarate + PLP in transamination reaction -> glutamate. (NH3+ group added to alpha ketoglutarate to make glutamate). Alpha ketoglutarate is part of TCA cycle.

What are the major amino acids involved in urea cycle

Glutamate and aspartate. Each contributes N atom for incorporation into urea.

Sources of NH4+ for urea cycle

Glutamate can collect N from other amino acids via transamination reactions, then release N via *glutamate dehydrogenase (GDH)* as NH4+. Gut releases urea as NH4+ source (bacteria produced) Glutamine -> glutamate reaction releases NH4+. Asparagine -> aspartate reaction releases NH4+. Any transamination reactions with PLP release NH4+, all of these reactions require NH4+ group to be given to a-ketoglutarate to make glutamate which then releases the NH4+ via glutamate dehydrogenase (like glutamate -> a-ketoglutarate, serine-> pyruvate, threonine -> a-ketobutyrate) Aspartate to fumarate via purine nucleotide cycle in brain and muscles.

Which enzyme provides sources of NH4+ for urea cycle from glutamate

Glutamate dehydrogenase (uses NAD+ or NADP+ as cofactor) to turn Glutamate to alpha-ketogluterate and release NH3+ in the process. Is reversible (uses NADH and NADPH in that case)

What enzyme converts glutamine to glutamate

Glutaminase

_______ in kidney releases NH4+ from glutamine for direct excretion in urine.

Glutaminase.

glutamine vs glutamate

Glutamine has NH2 instead of OH on the carboxylic carbon like in glutamate. *Glutamine* can be converted to alanine. Glutaminase (produces glutamate from glutamine) in kidneys allow NH4+ to be released from glutamine directly. *Glutamate* can be made from a-ketoglutarate + NH3 + PLP. Glutamate dehydrogenase acts on glutamate to release NH4+

What enzyme converts glutamate to glutamine?

Glutamine synthetase by adding NH3 to glutamate to form glutamine. *Uses ATP*

How are glycogen synthase and glycogen phosphorylase activated/inactivated

Glycogen phosphorylase (glycogen break down)- activated by phosphorylation. Glycogen synthase (building glycogen) - inactivated by phosphorylation.

Which enzyme adds glucose to the growing chain in glycogen synthesis? What other enzyme used during this process

Glycogen synthase = adds to the growing chain. Branching enzyme cleaves growing chain after 11 residues were added, cleaves off about 6-8 residues and attaches them to primer chain.

Sensory innervation Encapsulated receptor for muscle load - Force of contraction Located at junction between muscle and tendon.

Golgi Tendon Organ

Neutrophils

Granulated cytoplasm that stains with acid and basic dyes Multi-lobed nucleus Formed in bone marrow, released into blood, migrate 7-10 hours then home to the tissue where they have a 3 day lifespan In response to infection, bone marrow releases more neutrophils leukocytosis 1st at the site of inflammation (first ones to arrive) When neutrophils die they become pus

Basophils

Granulated cytoplasm that stains with basic dye (methylene blue) Lobed nucleus Non-phagocytic Release of pharmacologically active substances contained within granules Allergies and help eliminate parasites. Found in blood and then differentiate to Mast cells in the tissues.

What does IL-3 do?

Growth factor for WBC's

Demyelination disease of PNS - Axon exposure = ↓ transmission of impulses - Most common life-threatening disease of PNS Symptoms: - Paralysis - Loss of muscle coordination 0 Loss of cutaneous sensation

Guillain Barre Syndrome

How are proteins digested in the stomach? (2) What due protein turn into in stomach?

HCL and pepsin. Pepsinogen secreted and turns into pepsin as the pH drops due to HCL secretion. Protein -> peptides and then go into small intestine.

What does pancreas release to digest protein? (4) What is input and exit of the protein in small intestine?

HCO3- (raises pH so that the zymogens can become active) Pancreas releases exocrine pancreas enzymes 1. Trypsinogen 2. Chymotrypsinogen 3. Proelastase 4. Procarboxypeptidases A and B (close to C-terminus) These enzymes turn peptides into smaller peptides by cleaving at the amide bond between the amine and the carboxylic acid

Class switching on B cells

Hallmark of humoral immunity Requires T cell help (CD40-CD40L) and cytokines dependent. In this case, after communication with the T helper cell, the B cell rearranges only the constant region. One way event Does not effect variable region (still has the same specificity) Occurs after a B cell has come in contact with antigen. Loops the DNA we don't want and that gets cut out and we join the variable region with this new constant region. Picture is an example of IgG.

What are 2 diseases caused by impaired amino acid transport?

Hartnup and cystinuria

2 conditions caused by defect in transport of amino acids?

Hartnup disease and Cystinuria. Both characterized by high levels of amino acids in urine.

4-month-old female, uncomplicated birth Normal at birth, but last few weeks less attentive to surroundings Delayed psychomotor maturation, tremor in extremities now noted Urine has musty odor Whats the diagnosis?

Heel prick blood sample reveals excessive Phe in blood.

Is the erythrocyte (RBC) component of blood. Typically 39-50% in males and 35-45% in females of whole blood.

Hematocrit

What anchores cells to the underlying connective tissue at the basal domain?

Hemidesmosomes: Anchors intermediate filaments to the extracellular matrix. (Link protein = integrins) and Focal adhesions: Anchors the actin cytoskeleton to the extracellular matrix, detects and transduces signals from outside the cell. (Link protein = integrins)

Involved the development of RBC, WBC, and platelets. 1. Organs involved: Bone marrow and some lymphatic tissues after birth. Yolk-sac, liver, spleen, and bone marrow before birth. 2. Monophhyletic theory of hemopoiesis is the theory that all blood cells arise from a common stem cell.

Hemopoiesis key points

Hemopoiesis

Hemopoiesis pathway

What are the linked human cancers to this product and where is this product found? Vinyl chloride

Hepatic angiosarcoma Refrigerant; monomer for vinyl polymers; adhesive for plastics; formerly inert aerosol propellant in pressurized containers.

What removes phosphates from phosphorylase kinase, glycogen phosphorylase, and glycogen synthase.

Hepatic protein-phosphatase-1 (PP1) Activated by insulin inactivated during fasting

What is the associated neoplasm and etiologic agent in hepatitis

Hepatocellular carcinoma Hep B and/or C virus

Which enzymes consume ATP during glycolysis?

Hexokinase and Phosphofructokinase

Which enzymes serve as controlling steps in glycolysis since their delta G is so large that it is physiologically irreversible.

Hexokinase, phosphofructokinase, and pyruvate kinase.

Glucokinase 3 characteristics

High Km for glucose (low affinity) Only found in liver Induced by insulin

What would cause ATP synthase to run in reverse

High amount of ATP intracellularly and low proton levels in intermembrane

Urea cycle during fasting

High early on in fasting but decreases as the days/weeks progress due to less proteolysis of muscle.

Warburg effect

High rate of glucose uptake and glycolysis in cancer despite presence of functioning mitochondria and O2.

Left is cross section of skeletal muscle. Right is longitudinal section of skeletal muscle. Cross section: Shows polygonal to cylindrical shape organized by CT. Longitudinal section: Shows striations. Parallel organization. 1 cell = length of muscle. *Multinucleated syncytium*- Peripheral nuclei.

Histological characteristics of skeletal muscle

2 problems that stem from cysteine

Homocystinuria and cystinuria.

Problems with amino acid metabolism: cysteine

Homocystinuria: -Methionine (M) and Homocysteine (Hcy) are high, cysteine is low. -Possible causes: defective cystathionine B-synthase (uses PLP as cofactor, inhibited by cysteine) or deficient cystathionase (uses PLP as cofactor) (measure serum cystathionine to distinguish). Could also be inadequate intake of dietary folate or B12 (cobalamine). Methionine -> Homocysteine + Serine + PLP + *cystathionine B-synthase* -> cystathionine +PLP + *cystathionase* -> cysteine

Digestion of TG and how they cross intestinal epithelium

Hormone cholecystokinine (CCK) stimulates gallbladder, pancreas secretions (bile salts, lipase, colipase, HCO3-) when triglycerides in small intestine. Bile salts (synthesized by liver, stored in gallbladder and secreted to small intestine when lipids present). Bile salts emulsify the triglycerides to break up into smaller droplets, this allows more efficient access by enzyme lipase which works together with colipase (both lipase/colipase from pancreas). Digestion produces 2-Monoacylglycerol and FA which crosses into epithelial cells and turn back into triglycerides once inside via chylomicrons (FA + 2-MG + chylomicrons), chylomicrons then transport the triglyceride to the blood.

3 fiber types mixed in one muscle - Differ in diameter, color, and functional characteristics. - *Proportion of each type varies according to functional role of the muscle*

How do the 3 muscle types differ in one muscle

tissue sections are 2-dimensional slices of 3-dimensional structures. Different sections show differences in appearance. The size and internal structural appearance are reflected in the plane of section.

How do tissue slices appear?

Humoral immunity vs cell mediated immunity

Humoral immunity is immune response to things that are extracellular like bacteria. Uses antigens produced by plasma cells (B cells) to take care of them. Cell mediated immunity is immune response to things that are more intracellular like viruses, pathogens, and some bacteria. Uses T cells to take care of them. This is not always the case with viruses though because when they are leaving cells to infect over cells they can trigger the humoral immunity. Humoral immunity = B cells Cell mediated immunity = T cells

Appears glassy Chondrocytes located within lacunae - Produce and maintain matrix Provides low friction surface, lubricates synovial joints, and distributes forces Calcifies with aging

Hyaline Cartilage

*Perichondrium*: Composed of dense connective tissue, serves as a source of new cartilage cells. - Not present in articular cartilage *Chondrocytes*: Inactive cells- light cytoplasm (lipid and glycogen storage). - *Isogenous groups*: recently divided chondrocytes are sitting in clusters in the lacunae. *Pericellular matrix*- immediately around chondrocyte. *Territorial matrix*: basophilic "capsule" around the isogenous groups - high concentration of GAGs. *Interterritorial matrix*: lighter matrix surrounds territorial matrix- low concentration of GAGs.

Hyaline Cartilage Features

Endochondral ossification Epiphyseal growth plate Most cartilage replaced by bone Hyaline cartilage remains on articular surfaces.

Hyaline cartilage provides a model for the developing fetus

Diabetes mellitus symptoms (6)

Hyperglycemia - high blood glucose -Can cause hyper-osmotic coma by pulling water out of cells (particularly brain cells) Polyuria - urge to urinate frequently Polydipsia - increased thirst Weight loss - despite good appetite Increased reliance on lipid metabolism Non-enzymatic glycosylation of proteins -easily detected on hemoglobin (HbA1c) -retinopathy, nephropathy, neuropathy, vascular

Symptoms of pyruvate dehydrogenase complex deficiency

Hypotonia, lethargy, neurological defects (brain structure abnormalities), and lactic acidosis.

What are the essential amino acids?

I keep twerking while real mets fans lose via homerun Arginine which is only essential during growth. Isoleucine (I) Tryptophan (W) Arginine (R) Leucine (L) Threonine (T) Lysine (K) Valine (V) Histidine (H) Phenylalanine (F) Methionine (M) and Arginine (only essential during growth, humans are able to synthesize later in life but most used in urea cycle). These are all needed from dietary sources

Clinical uses for IFN

IFN-a - HBV (hepatitis B) HCV (hepatitis C) - HTLV-1 (human T cell leukemia virus) - HHV-8 (human herpes virus 8) IFN-B - Multiple sclerosis IFN-y - Chronic granulomatous disease - Pro-inflammatory cytokine, monoclonal antibodies against IFN-y may be used to treat certain autoimmune diseases to reduce inflammation.

Which cytokines increase the expression of HLA? Which viruses decrease the expression of HLA?

IFN-y and TNF can increase the expression of class II MHC by inducing the formation of specific transcription factors that bind to promotors of MHC genes MHC expression is also increased, but more commonly decreased, by a certain # of viruses (CMV, HBV, and Adenovirus) CMV (cytomegalovirus) proteins can bind to B2 microglobulin preventing the proper assembly of class I MHC molecules

What is IL-1, what cells secrete it, what is the target cell, and what does it do?

IL-1 is a pro-inflammatory cytokine. It is secreted by macrophages. It targets the hypothalamus, endothelial cells, and the liver. Hypothalamus: fever Endothelial cells: Increase expression of ICAMs (intercellular adhesion molecules) Liver: Stimulates production of acute phase proteins

What are the 3 main proinflammatory cytokines?

IL-1, IL-6, and TNF-a.

TH1 vs TH2 vs TH17

IL-12 or IL-1: Converts Th0 to Th1. IL-2: essential for activating cytotoxic T cells. Also releases IFN-y. IL-4: Activates Th2. IL-4 and IL-13 causes class switching to IgE. TGF-B: Class switching to IgA. IL-10 (and IL-4): Turns off Th1. Th1: Cell mediated immunity (intracellular infections) turned on by IL-12 or IL-1. Then turns on IL-2 which turns on cytotoxic T. IL-2 also stimulate production of IFN-y. IFN-y stimulates macrophages more and causes class switching to IgG which allows opsonization. IFN-y also amplifies Th1 response and inhibits Th2 response. Th1 is turned off by IL-10 (released by regulatory T cell) and IL-4 (which stimulates TH2 pathway). Th2: Parasites. Pathway turned on by IL-4. IL-4 amplifies Th2 response and along with IL-10 inhibits Th1 response. IL-4 and IL-13 cause isotype switching to IgE. TGF-B causes isotype switching to IgA. IL-5 drives eosinophil maturation. Mast cells, B cells, and eosinophils activated (mostly B cells). Th17: Responsible for aiding inflammatory response. Pathway turned on by IL-23. Main role is chemotaxis and mainting barrier function of particular tissue so that pathogens don't get out.

What cytokines do T helper cells make to help B cells make antibodies?

IL-4, IL-13, and TGF-B

What is IL-6, what cells secrete it, what is the target cell, and what does it do?

IL-6 is a pro-inflammatory cytokine. Secreted by macrophages Targets the liver. Liver: synthesis of acute phase proteins.

What is IL-8, what cells secrete it, what is the target cell, and what does it do?

IL-8 is a chemokine. Secreted by macrophages. Targets leukocytes. Induces adherence of leukocytes to endothelium, chemotaxis, extravasation

What is the most important chemokine (cytokine)

IL-8 which causes CD18 to bind more tightly.

Which cytokine is a major contributor of chemotaxis?

IL-8. Major cytokine involved in recruiting WBC from blood into tissue.

(Stained with Mallory-Azan, section through the epiglottis) Red line: epithelium Yellow line: Loose connective tissue Green line: Dense connective tissue. Loose connective tissue typically contains many cells of several types. Their nuclei vary in size and shape The elongated nuclei most likely belong to fibroblasts. Dense connective tissue contains thick collagen bundles, stains more intensely with the blue dye. Has fewer nuclei. ============================== (Mallory-stained specimen of dense connective tissue) Numerous, densely packed collagen fibers. Few nuclei are present and belong to fibroblasts. Relatively few small blood vessels. Red arrow: Nuclei Black arrow: blood vessels

Identify

1. Articular cartilage 2. Bone 3. Epiphyseal plate 4. Marrow 5. Bone

Identify

1. Articular cartilage 2. Bone 3. Superficial zone 4. Intermediate zone 5. Deep zone 6. Calcified zone

Identify

1. Bone 2. Perimysium 3. Blood vessel 4. Muscle fiber 5. Tendon 6. Epimysium 7. Endomysium 8. Fascicle

Identify

1. Bone marrow 2. Bone 3. Chondrosarcoma Photomicrograph of a chondrosarcoma (grade 1) from the epiphysis of the long bone, stained with H&E. This photomicrograph shows a tissue mass of chondrosarcoma infiltrating intertrabecular spaces of the bone marrow. Note the presence of malignant chondrocytes in various stages of maturity. Small area of active bone marrow is visible in the upper left corner of the image

Identify

1. Cartilage 2. Bone

Identify

1. Cartilage 2. Bone-lining cells (periosteal cells) 3. Osteocytes 4. Osteoblasts 5. Osteoprogenitor cells 6. Mesenchymal stem cells 7. Bone lining cells (endosteal cells) 8. Active osteoclasts 9. Inactive osteoclasts 10. Granulocyte/monocyte progenitor (GMP, CFU-GM)

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1. Cartilage 2. Endochondral bone 3. Diaphyseal bone 4. Bone marrow cavity 5. Diaphyseal bone 6. Bone marrow cells 7. Endochondral bone 8. Cartilage 9. Joint cavity --------------------------- The bone shown in this micrograph represents a later stage of development. Most of the diaphysis of the bone contains bone marrow cavity (Cav) filled with marrow, part of which is highly cellular and represents accumulations of hemopoietic bone marrow cells (BMC). The nonstaining areas consist of adipose tissue, which occupies much of the remainder of the bone marrow cavity. Th e thin bony collar seen earlier has now developed into a relatively thicker mass of diaphyseal bone (DB). The part of the bone in which bone tissue is being deposited by endochondral bone (EB) formation is seen at both ends of the bone marrow cavity. Note that its eosinophilic character is similar to the diaphyseal bone. As these processes continue in the shaft of the bone, cartilage (C) on both proximal and distal epiphyses are invaded by blood vessels and connective tissue from the periosteum (periosteal bud), and it undergoes the same changes that occurred earlier in the shaft (except that no periosteal bony collar is formed). (Developing bone, fetal finger, human)

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1. Cartillage 2. Endochondral bone 3. Cartillage 4. Secondary ossification center 5. Epiphyseal growth plate 6. Joint cavity 7. Calcified cartilage 8. Endochondal bone 9. Endochondral bone 10. Dashed line = Epiphyseal center of ossification. --------------------------- Th is micrograph shows considerable developmental advancement beyond that of the bone in the above micrograph. A secondary ossification center (SOC) has been established in the proximal epiphysis of this long bone. At a slightly later time, a similar epiphyseal ossification center will form at the distal end of the bone. The process of endochondral bone formation occurs the same way as in the diaphysis. With time, these epiphyseal centers of ossifi cation will increase in size to form much larger cavities (dashed line). Th e consequence of this activity is that an epiphyseal growth plate (EGP) is formed. included in the plane of section, appear as small, condensed basophilic bodies. Note how the cartilage matrix in this region is calcified and has been compressed into narrow linear bands of tissue surrounding the chondrocytes. The calcified cartilage matrix (CCM) stains more intensely with hematoxylin in routine H&E preparation and appears darker. At this stage of development, bone tissue has been produced to form the early periosteal bony collar (BC) around the cartilage model. Th is bone tissue is produced by appositional growth from bone-forming cells that were derived from the mesenchyme in the tissue surrounding the cartilage. Th is process represents intramembranous bone formation, which will be described later. Th is plate, consisting of cartilage, separates the secondary ossification centers at the proximal end of the bone from the primary ossification center formed in the shaft of the bone. Th is cartilaginous plate is essential for the longitudinal growth of the bone and will persist until bone growth ceases. The inset shows the secondary ossification center at higher magnifi cation. Within this area, new endochondral bone (EB) is already being produced. The new bone appears eosinophilic in contrast to the more basophilic appearance of the surrounding cartilage (C). Note that its staining pattern of endochondral bone in the secondary ossification center is identical to the more abundant endochondral bone (EB) that replaces calcified cartilage (CC) at the upper end of the diaphysis (Developing bone, proximal epiphysis of long bone)

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1. Chondrocytes with visible nuclei. 2. Interterritorial matrix 3. Growing cartilage 4. Dense connective tissue 5. Perichondrium 6. Interterritorial matrix 7. Territorial matrix 8. Chondrocytes with visible nuclei 9. Interterritorial matrix ---------------------------- Photomicrograph of a typical hyaline cartilage specimen stained with H&E. The upper portion of the micrograph shows the dense connective tissue (DCT ) overlying the perichondrium (P), from which new cartilage cells are derived. A slightly basophilic layer of growing cartilage (GC ) underlying the perichondrium contains chondroblasts and immature chondrocytes that display little more than the nucleus residing in an empty-appearing lacuna. This layer represents deposition of new cartilage (appositional growth) on the surface of the existing hyaline cartilage. Mature chondrocytes with clearly visible nuclei (N) reside in the lacunae and are well preserved in this specimen. They produce the cartilage matrix that shows the dark-staining capsule or territorial matrix (TM) immediately surrounding the lacunae. The interterritorial matrix (IM) is more removed from the immediate vicinity of the chondrocytes and is less intensely stained. Growth from within the cartilage (interstitial growth) is reflected by the chondrocyte pairs and clusters that are responsible for the formation of isogenous groups

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1. Choroid plexus 2. Pia 3. Ependymal cells 4. Brain tissue 5. Ventricle (CSF)

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1. Dense connective tissue 2. Myotendinous junction 3. Muscle

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1. Developing teeth 2. Blood vessels 3. Bone spicules 4. Connective tissue 5. Connective tissue ---------------------- This higher magnification view of the boxed area in the upper micrograph shows the interconnections of the bone spicules (BS) of the developing mandible. Within and around the spaces enclosed by the developing spicules ismesenchymal tissue. These mesenchymal cells contain stem cells that will form the vascular components of the bone as well as the osteoprogenitor cells that will give rise to new osteoblasts. The denser connective tissue (CT) will differentiate into the periosteum on one side of the developing mandible. Other structures shown in the field include numerous blood vessels (BV) and the enamel organ of a developing tooth (DT). (Intramembranous bone formation, fetal head, human)

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1. Dura matter 2. Subarachnoid space 3. Pia matter 4. Arachnoid matter Blood vessels found in the middle in the subarachnoid space.

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1. Endoneurium 2. Perineurium 3. Epineurium

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1. Epimysium 2. Fascicle 3. Fascicle 4. Nerve 5. Fiber 6. Fiber

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1. Epiphysis 2. Metaphysis 3. Diaphysis 4. Metaphysis 5. Epiphysis 6. Articular cartilage on articular surface 7. Epiphyseal line 8. Spongy bone 9. Marrow cavity 10. Periosteum 11. Compact bone 12. Spongy bone 13. Epiphyseal line 14. Articular cartilage on articular surface.

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1. Haversian canal 2. Osteocyte 3. Compact bone 4. Osteoclast 5. Periosteum -------------------------- Bone from the diaphysis within the bottom right box on the orientation micrograph is shown here at higher magnification. The outer surface of the bone is covered by dense connective tissue known as periosteum (P). Th e remaining tissue in the micrograph is compact bone (CB). Haversian canals (HC) are surrounded by the osteocytes (Oc) and are recognized by their nuclei within the bone matrix. Another feature worth noting in this growing bone is the presence of bone-resorbing cells known as osteoclasts (Ocl). They are large multinucleated cells found at sites in bone where remodeling is taking place (see Plate 14). (Compact bone, long bone)

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1. Intercalated discs Asterisks: Perinuclear cytoplasmic areas

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1. Joint cavity 2. Epiphysis 3. Bony collar 4. Hypertrophic chondrocytes 5. Bony collar 6. Calcified cartilage matrix 7. Epiphysis 8. Joint cavity --------------------- An early stage in the process of endochondral bone formation in the fetal digit is shown in this micrograph. Proximal and distal epiphyses (E) of this developing bone are made of cartilage. Th is bone of the fetal digit is connected by joints with other bones; note joint cavities (JC) on both edges of this micrograph. The midregion of this long bone reveals chondrocytes that have undergone marked hypertrophy (HCh). The cytoplasm of these chondrocytes appears very clear or washed out. Their nuclei, when included in the plane of section, appear as small, condensed basophilic bodies. Note how the cartilage matrix in this region is calcified and has been compressed into narrow linear bands of tissue surrounding the chondrocytes. The calcified cartilage matrix (CCM) stains more intensely with hematoxylin in routine H&E preparation and appears darker. At this stage of development, bone tissue has been produced to form the early periosteal bony collar (BC) around the cartilage model. This bone tissue is produced by appositional growth from bone-forming cells that were derived from the mesenchyme in the tissue surrounding the cartilage. Th is process represents intramembranous bone formation, which will be described later. (Developing bone, fetal finger, monkey)

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1. Lacuna 2. Haversian canal 3. Lacuna 4. Interstitial lamellae (In ground bone, long bone) ------------------------- This figure shows a higher magnification micrograph of the labeled osteon from the upper figure. It includes some of the interstitial lamellae (IL) that are now seen at the bottom of the micrograph (the micrograph has been reoriented). Note the lacunae (L) and the fine thread-like profiles emanating from the lacunae. These thread-like profiles represent the canaliculi, spaces within the bone matrix that contain cytoplasmic processes of the osteocyte. The canaliculi of each lacuna communicate with canaliculi of neighboring lacunae to form a three-dimensional channel system throughout the bone.

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1. Oral cavity 2. Developing teeth 3. Epidermis 4. Meckel's cartillage 5. Developing teeth 6. Bone spicules 7. Tongue 8. Bone spicules 9. Oral cavity 10. Developing teeth 11. Epidermis ---------------------------- A cross-section of the developing mandible, as seen at this relatively early stage of development, consists of bone spicules (BS) of various sizes and shapes. The bone spicules interconnect and, in three dimensions, have the general shape of the mandible. Other structures present that will assist in orientation include developing teeth (DT), Meckel's cartilage (MC), seen on the left side, and the oral cavity (OC). The bottom surface of the specimen shows the epidermis (Ep) of the submandibular region of the neck. A large portion of the developing tongue is seen in the upper half of the figure. The tongue consists largely of developing striated visceral muscle fibers arranged in a three-dimensional orthogonal array that is characteristic of this organ. (Intramembranous bone formation, fetal head, human)

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1. Osteoblast 2. Calcified cartilage 3. Endochondral bone 4. Osteoclast 5. Osteocyte 6. Epiphyseal growth plate 7. Calcified cartilage 8. Endochondral bone 9. Bone marrow 10. Zone of reserve cartilage 11. Zone of proliferation 12. Zonge of hypertrophy 13. Zone of calcified cartilage 14. Zone of resorption 15. Calcified cartilage 16. Endochondral bone 17. Matrix? ------------------------------ is is a photomicrograph of an epiphysis at higher magnification than that seen in Plate 13. Different zones of the cartilage of the epiphyseal plate reflect the progressive changes that occur in active growth of endochondral bone. These zones are not sharply delineated, and the boundaries between them are somewhat arbitrary. They lead toward the bone marrow (BM) cavity, so that the first zone is furthest from the cavity. Th ere are five zones: • Zone of reserve cartilage (ZRC). The cartilage cells of this zone have not yet begun to participate in the growth of the bone; thus, they are reserve cells. These cells are small, usually only one to a lacuna, and not grouped. At some point, some of these cells will proliferate and undergo the changes outlined for the next zone. • Zone of proliferation (ZP). The cells of this zone undergo divisions and are increasing in number; they are slightly larger than the chondrocytes in the zone of reserve cartilage and are close to their neighbors; they begin to form rows. • Zone of hypertrophy (ZH). The cells of this zone are aligned in rows and are significantly larger than the cells in the preceding zone. • Zone of calcified cartilage (ZCC). In this zone, the cartilage matrix is impregnated with calcium salts. The calcified cartilage will serve as an initial scaffold for the deposition of the new bone. Chondrocytes positioned in the more proximal part of this zone undergo apoptosis.• Zone of resorption (ZR). This zone is represented by eroded cartilage that is in direct contact with the connective tissue of the marrow cavity. Small blood vessels and accompanying osteoprogenitor cells invade the region previously occupied by the dying chondrocytes. They form a series of spearheads, leaving on both sides the calcified cartilage (CC) as longitudinal spicules. Osteoprogenitor cells give rise to osteoblasts that begin lining the surfaces of exposed spicules. Endochondral bone (EB) is then deposited on the surfaces of these calcified cartilage spicules by osteoblasts, thus forming mixed spicules as seen in the inset. Note the osteoblasts (Ob), some of which are just beginning to produce bone in apposition to the calcified cartilage (CC). Th e lower right of the inset shows endochondral bone (EB) with an osteocyte (Oc) already embedded in the bone matrix. (Endochondral bone formation, epiphysis of long bone)

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1. Osteoblast 2. Osteocyte

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1. Osteoclast 2. Ruffled border of osteoclast 3. Osteoclast 4. Osteoblast 5. Osteocyte 6. Trabeculae 7. Osteoblast 8. Osteoclast 9. Zone of hypertrophy 10. Trabeculae ---------------------------- This is a higher magnifi cation of the lower area from the above figure. It shows calcified cartilage spicules on which bone has been deposited. In the lower portion of the figure, the spicules have already grown to create anastomosing bone trabeculae (T). These initial trabeculae still contain remnants of calcified cartilage, as shown by the bluish color of the cartilage matrix (compared with the red staining of the bone). Osteoblasts (Ob) are aligned on the surface of the spicules, where bone formation is active. Th e inset reveals several osteoclasts (Ocl) in higher magnification. They are in apposition to the spicules, which are mostly made of calcifi ed cartilage. A small amount of bone is evident, based on the red-stained material. The light area (arrow) represents the ruffled border of the osteoclast. (Endochondral bone formation, epiphysis of long bone)

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1. Osteocyte 2. Mesenchymal cells 3. Active osteoblast 4. Inactive osteoblast 5. Connective tissue 6. Inactive osteoblast ------------------------------ This higher magnification micrograph of a portion of the field in the lower left micrograph shows the distinction between newly deposited osteoid, which stains blue, and mineralized bone, which stains red. Osteoblasts are seen in two different levels of activity. Osteoblasts that are relatively inactive (IOb) and are in apposition to well-formed osteoid exhibit elongate nuclear profiles and appear to be flattened on the surface of the osteoid. Those osteoblasts that are actively secreting new osteoid (AOb) appear as tall, columnar-like cells adjacent to the osteoid. One of the spicules shows a cell completely surrounded by bone matrix; this is an osteoblast that has become trapped in its own secretions and is now an osteocyte (Oc). At this magnification, the embryonic tissue characteristics of the mesenchyme and the sparseness of the mesenchymal cells (MeC) are well demonstrated. Th e highly cellular connective tissue (CT) on the right margin of the micrograph is the developing perichondrium. Some of its cells have osteoprogenitor cell characteristics and will develop into osteoblasts to allow growth of the bone at its surface. (intramembranous bone formation, fetal head, human).

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1. Osteocyte lacunae 2. Canaliculi 3. Haversian canals

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1. Osteocytes 2. Resorption canal 3. Compact bone 4. Articular cartillage 5. Haversian canal 6. Chondrocytes 7. Osteocytes 8. Chondrocytes 9. Resorption canal --------------- The articular surface of the epiphysis within the top right box on the orientation micrograph containing articular cartilage and the underlying bone tissue is shown here at higher magnification. The lighter staining area is the articular cartilage (AC) of the glenohumeral (shoulder) joint. Note the presence of isogenous groups of chondrocytes (Ch), a characteristic feature of growing cartilage. Belowthe cartilage is a darker staining area of compact bone (CB). It can be distinguished from the cartilage by the presence of Haversian canals (HC) and arrangement of the osteocytes (Oc). The osteocytes lie within the bone matrix but are typically recognized only by their nuclei. Because bone matrix is laid down in layers (lamellae), bone characteristically shows linear or circular patterns surrounding Haversian canals. The irregular spaces seen within the bone tissue are resorption canals (RC) that contain, in addition to blood vessels, the osteoclasts and osteoblasts. Presence of resorption canals indicates an active process of bone remodeling. (Articular surface, long bone)

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1. Osteon 2. Haversian canal 3. Haversian canal 4. Circumferential lamellae 5. Interstitial lamellae 6. Volkmann's canal (In ground bone, long done) --------------------------------- Th is figure reveals a cross-sectioned area of a long bone at low magnification and includes the outer or peripheral aspect of the bone, identified by the presence of circumferential lamellae (CL). (Th e exterior or periosteal surface of the bone is not included in the micrograph.) To their right are the osteons (O) or Haversian systems that appear as circular profiles. Between the osteons are interstitial lamellae (IL), the remnants of previously existing osteons. Osteons are essentially cylindrical structures. In the shaft of a long bone, the long axes of the osteons are oriented parallel to the long axis of the bone. Thus, a cross-section through the shaft of a long bone would reveal the osteons in cross-section, as in this figure. At the center of each osteon is an osteonal (Haversian) canal (HC) that contains blood vessels, connective tissue, and cells lining the surface of the bone material. Because the organic material is not retained in ground sections, the Haversian canals and other spaces will appear black, as they do here, if filled with India ink or air. Concentric layers of mineralized substance, the concentric lamellae, surround the Haversian canal and appear much the same as growth rings of a tree. The canal is also surrounded by concentric arrangements of lacunae. These appear as the small, dark, elongate structures. During the period of bone growth and during adult life, there is constant internal remodeling of bone. This involves the destruction of osteons and formation of new ones. The breakdown of an osteon is usually not complete; however, part of the osteon may remain intact. Moreover, portions of adjacent osteons may also be partially destroyed. Th e space created by the breakdown process is reoccupied by a new osteon. The remnants of the previously existing osteons become the interstitial lamellae. Blood vessels reach the Haversian canals from the marrow through other tunnels called perforating (Volkmann's) canals (VC). In some instances, as here, Volkmann's canals travel from one Haversian canal to another. Volkmann's canals can be distinguished from Haversian canals in that they pass through lamellae, whereas Haversian canals are surrounded by concentric rings of lamellae.

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1. Perimysium 2. Nerve 3. Internal capsule 4. Nerve fibers 5. Spindle cells 6. Blood vessels 7. External capsule This is all inside a muscle spindle

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1. Periosteum 2. Osteoid 3. Osteoblasts 4. Osteocytes

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1. Resorption bay 2. Osteoclast 3. Bone

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1. Resorption canal 2. Resorption canal 3. Osteons 4. Haversian canal 5. Osteocytes ------------------------ The area in the top left box in the orientation micrograph containing spongy bone in the epiphysis is shown here at higher magnification. Although the bone tissue at this site forms a three-dimensional structure consisting of branching trabeculae, its structural organization and components are the same as that seen in compact bone. Note the nuclei of osteocytes (Oc). As bone matures, the bone tissue becomes reorganized and forms osteons (O), which consist of Haversian canals (HC) and surrounding layers (lamellae) of bone matrix. The two circular spaces are the resorption canals (RC), in which bone tissue has been removed and will be replaced by new tissue in the form of osteons. The spaces surrounding the spongy bone contain bone marrow consisting mainly of adipocytes. Other cells that have the capacity to form bone or hemopoietic tissue are also present. (Spongy bone, long bone)

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1. Zone of reserved cartillage 2. Zone of proliferatin 3. Zone of hypertrophy 4. Zone of calcified cartilage 5. Zone of resorption 6. Osteoclasts 7. Osteoblasts 8. Bone 9. Calcified cartilage 10. osteocytes 11. Osteoid

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A is lacunae. B is chondrocytes nuclei. Cartilage is hyaline cartilage.

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A. Lymphocyte B. Monocyte C. Eosinophil D. Basophil E. Neutrophil F. Normal erythrocyte G. Sickle Cell erythrocyte

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A.) I band B.) A band C.) H band D.) M line E.) Z line F.) Sarcoplasmic reticulum

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Arrow pointing to the nodes of ranvier in the peripheral nerve, schwann cells there.

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Asterisk: Central canal of spinal cord. Arrow: pointing to ependymal cells

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Autonomic ganglion

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Axon

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Axon hillock

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Basophil

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Black arrow: neutrophils Red arrow: macrophages

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Blood

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Blue: Axon hillock Red: Axon Between the arrows is the initial segment of the axon where initiation of impulse occurs.

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Blue: Nerve cell processes Orange: Dense connective tissue Green: Adipose

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Blue: Nucleolus Red: Cell body (nucleus)

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Bone

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Bone Marrow with active hemopoiesis. a. Schematic drawing of bone marrow shows several features: erythroblastic islets engaged in the formation of erythrocytes, megakaryocytes discharging platelets into the sinusoids, endothelial cells (pink) resting on a basal lamina (dark red) that is absent where blood cells are entering the sinusoids, adventitial or reticular cells (blue) extending from the basal lamina into the hemopoietic compartment, and dispersed adipose cells. b. Photomicrograph of bone marrow section stained with H&E shows active hemopoietic centers in a close proximity to bone marrow sinusoids

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Both are Elastic fibers (Reticular is branched, Elastic fibers aren't really)

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Cardiac Muscle Longitudinal 1. Connective Tissue 2. Intercalated Discs Arrows: Sites where fibers branch

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Cardiac Muscle both pictures 1. Connective Tissue 2. Nuclei of cardiac muscle cell 3. Nuclei of cardiac muscle cell 4. Capillaries 5. Venule 6. Nuclei of cardiac muscle cell 7. Connective tissue 8. Arteriole 9. Nuclei of cardiac muscle cell 10. Venule

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Cardiac muscle

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Cardiac muscle with scar tissue

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Cartilage connective tissue

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Central nervous tissue

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Collagen and elastic fibers

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Connective tissue with RBC and WBC

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Dendrite

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Dendrites

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Dense irregular connective tissue (collagen fibers)

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Dense regular connective tissue (tendon)

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Elastic cartilage

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Elastic fibers

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Elastic fibers (cartilage)

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Elastic fibers (wall of artery)

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Embryonic connective tissue

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Endochondral ossification

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Eosinophil

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Ependymal cells

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Epithelium

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Erythrocytes

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Fibroblasts in connective tissue.

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Fibrocartilage

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Fibrocartilage Arrows pointing to small number of fibroblasts with elongated nuclei. More numerous chondrocytes with dark round nuclei seen. The chondrocytes exhibit close spatial groupings and are arranged either in rows among the collagen fibers or in isogenous groups

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Fibrocartilage in the pubic synthesis

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Fibrocartilage with chondrocytes (arrow) collagen is type I.

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Golgi Tendon Organ

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Green arrow: Neuron Red arrow: Supporting cells (neuroglia) Black arrow: Extracellular matrix

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Ground bone, long bone L stands for lacuna Arrows are pointing to lamellar boundary (lamellae of the bone) In a still higher magnification, the circumferential lamellae are found around the shaft of the long bone at the outer as well as the inner surface of the bone. The osteoblasts that contribute to the formation of circumferential lamellae at these sites come from the periosteum and endosteum, respectively,whereas the osteons are constructed from osteoblasts in the canal of the developing Haversian system. This figure reveals not only the canaliculi but also the lamellae of the bone. The latter are just barely defined by the faint lines (arrows) that extend across the micrograph. Collagenous fibers in neighboring lamellae are oriented in different directions. This change in orientation accounts for the faint line or interface between adjacent lamellae.

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Hyaline cartilage

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ICS: Inner collar of Schwann cell cytoplasm OCS: Outer collar of Schwann cell cytoplasm C: Collagen fibrils constitute the fibrillar component of the endoneurium. BL: Basal (external) lamina. Arrow in bottom right signifies the intercellular space between axon and schwann cell. Mt: Microtubules Mit: Mitochondria

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Immature bone

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Immature bone, osteocytes inside. Osteoblasts on the outside.

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Immature bone. Osteoblasts at the outside. Osteocytes on the inside.

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Keratinized stratified squamous epithelium

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Lateral folds: A. Zonula Occludens/Tight junctions (ZO) B. Zonula adherens (ZA) C. Macula Adherens/Desmosomes (MA)

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Left picture: Blue: Nerve fibers in longitudinal sectioning Yellow: Cell bodies Orange: Blood vessels. Right picture: Purple: Nucleolus Red: Nucleus Black: don't worry about Green: Dendrites Orange: Blood vessels

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Left picture: Cross section of smooth muscle Right picture: Longitudinal section of smooth muscle.

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Left picture: Mallory-stained section of a peripheral nerve. *Brown* arrow is axons, the space between the axons (white) previously contained myelin that was dissolved and lost during preparation. The *red* arrow is connective tissue. Right picture: An Azan-stained nerve ganglion. *Red* arrow is the large, spherical nerve cell bodies. *Brown* arrow is nuclei of the small satellite cells that surround the nerve cell bodies. *Black lines* are nerve fiber bundles between clusters of the cell bodies.

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Left: ATPase stain Blue = type I Purple = type IIa green = type IIb Right: NADH-TR Stain (stains mitochondria) Pink = type IIa Yellow = type I Orange = type IIb

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Left: Immature bones Right: Mature bone Photomicrographs of decalcifi ed immature and mature bone. a. Decalcified immature bone, stained with H&E, showing the relationship of cells to the extracellular matrix. The immature bone has more cells, and the matrix is not layered in osteonal arrays. b. This cross-section of decalcifi ed mature compact bone stained with H&E shows several osteons (O) with concentric lamellae. The Haversian canals contain blood vessels, nerve, and connective tissue. Osteocytes undergo considerable shrinkage during routine slide preparation, revealing empty lacunae with a small nucleus attached to their walls. Mature bone has fewer osteocytes per unit area than immature bone. Note the presence of interstitial lamellae between neighboring osteons

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Left: Myelinated Peripheral nerve cross section. Axons = A Dark ring surrounding the axons is the myelin. The asterisk shows myelin cut at Schmidt-Lanterman cleft Epi stands for epineurium. Right: Myelinated peripheral nerve longitudinal section. NR stands for nodes of Ranvier SL stands for Schmidt-Lanterman cleft (the number of Schmidt-Lanterman clefts correlates with the diameter of the axon.)

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Left: Smooth muscle Middle: Peripheral Nerve Tissue (yellow arrow pointing to Nodes of Ranvier) Right: Dense connective tissue

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Longitudinal view of skeletal muscle

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Loose connective tissue

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Loose connective tissue in the center (collagen fibers with many cells). Dense irregular connective tissue in the upper left and lower right (abundant collagen of thick fibers with few nuclei).

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Lymphocyte

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Mast cell

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Mature bone with osteon, haversan canal, and osteocytes at the outside.

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Megakaryocyte

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Microglia

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Monocyte

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Muscle spindle

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Muscle tendon junction via Van Gieson stain. 1. Collagen fibers 2. Fibrocyte nuclei 3. Skeletal muscle fibers

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Myotendinous Junction 1. Terminating Muscle Fibers 2. Terminating Muscle Fibers 3. Terminating Muscle Fibers 4. Tendon 5. Muscle Fibers 6. Nuclei

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Nerve Tissue A. Neuron/cell body/soma B. Neuroglia C. Extracellular matrix

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Nerve tissue Blue: Epineurium Red: Perineurium Green: Endoneurium

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Neuron

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Neuron Black arrow: Nucleolus Green arrow: Axon hillock Yellow arrow: Dendrites with Nissl bodies Blue arrow: Axon

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Neuronal cell bodes (3 big ones) Neuropil Found in the gray matter (spinal cord)

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Neutrophil

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Nodes of Ranvier

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Normal immunostain for dystrophin

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Osteoclast

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Osteocytes

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Peripheral nerve tissue. Dorsal root ganglion, dots are satellite cells. CT: Connective tissue CB: Cell bodies NF: Nerve fibers

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Peripheral nerve with arrow pointing to a dark axon in myelin sheath. Looks like spokes of wheel

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Photomicrograph of a mixed bone spicule formed during endochondral bone formation. In this Mallory-Azan-stained section, bone has been deposited on calcified cartilage spicules. In the center of the photomicrograph, the spicules have already grown to create an anastomosing trabecula. The initial trabecula still contains remnants of calcified cartilage, as shown by the light-blue staining of the calcified matrix compared with the dark-blue staining of the bone. In the upper part of the spicule, note a lone osteoclast (arrow) aligned near the surface of the spicule, where remodeling is about to be initiated

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Photomicrograph of a tracheal ring from an elderly individual, stained with H&E. The darker, somewhat basophilic areas on the left side of the micrograph represent normal cartilage matrix (C). The lighter and more eosinophilic areas represent bone tissue (B) that has replaced the original cartilage matrix. A large marrow cavity has formed within the cartilage structure and is visible in the center of the micrograph.

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Photomicrograph of an osteoclast on a bone spicule. This Mallory-stained specimen shows a spicule made of calcified cartilage (stained light blue) and a covering of bone tissue (stained dark blue). An osteoclast (huge cell thing) on the left side of the spicule has resorbed bone tissue and lies in a depression (Howship's lacuna) in the spicule. The light band between the osteoclast and the bone spicule corresponds to the ruffled border of the osteoclast. The *arrows* on the nongrowing surface indicate cytoplasm of inactive bone-lining cells (osteoprogenitor cells). In contrast, bone is being deposited on the opposite side of the spicule, as evidenced by the presence of osteoblasts on this surface and newly formed osteocytes just below the surface of the spicule.

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Photomicrograph of young, growing cartilage. This specimen was preserved in glutaraldehyde, embedded in plastic, and stained with H&E. The chondrocytes, especially those in the upper part of the photomicrograph, are well preserved. The cytoplasm is deeply stained, exhibiting a distinct and relatively homogeneous basophilia. The clear areas (arrows) represent sites of the Golgi apparatus.

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Protoplasmic astrocytes

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Psuedostratified cillated epithelium of the trachea. Basement membrane (part of connective tissue and composed of densely packed collagen fibrils) is right underneath the pseudostratified epithelium.

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Purkinje fibers

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Red arrow: Epimysium Green arrow: Perimysium Black arrow: Endomysium

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Red arrows: Neuroglia Blue arrow: Extracellular matrix

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Red cell is RBC found in lung capillaries

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Reticular fibers (Silver stained)

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Reticular fibers in the lymph node.

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Section of mandible developing by the process of intramembranous ossification. This photomicrograph shows a section from a developing mandible stained with H&E. In this relatively early stage of development, the mandible consists of bone spicules of various sizes and shapes. The bone spicules interconnect with each other and form trabeculae, providing the general shape of the developing bone (no cartilage model is present). The numerous osteoblasts responsible for this growing region of spicules are seen at the surface of the newly deposited bone. The older, calcified portion of spicules contains osteocytes surrounded by bone matrix. In the right portion of the figure, adjacent to the bone spicules, the connective tissue is very cellular and is developing into the early periosteum.

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Sensory ganglion

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Simple columnar

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Simple cuboidal

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Skeletal Muscle Cross Section 1. Connective tissue 2. Muscle fibers

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Skeletal Muscle Cross Section 1. Fascicle 2. Perimysium 3. Muscle Fibers 4. Fascicle 5. Epimysium

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Skeletal Muscle Electron Micrograph, longitudinal section 1. Myofibril 2. Myofibril 3. Myofibril 4. Muscle Fiber 5. Nucleus 6. Endomysium 7. Muscle Fiber 8. Endomysium 9. Nucleus 10. Myofibril 11. Muscle Fiber

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Skeletal Muscle Longitudinal Section 1. Capillary 2. Blood vessel 3.. Nuclei 4. Fascicle 5. Nuclei 6. Fascicle

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Skeletal Muscle Longitudinal Section 1. Muscle Fiber Nuclei 2. Muscle Fiber Nuclei 3. Muscle Fiber Nuclei 4. Capillaries 5. Nucleus 6. Muscle Fiber 7. Muscle Fiber 8. Muscle Fiber 9. Muscle Fiber

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Skeletal Muscle Longitudinal Section 1. Perimysium 2. Fascicle 3. Perimysium 4. Fascicle 5. Fascicle 6. Fascicle 7. Nerve

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Skeletal muscle Yellow: Epimysium Red: Perimysium Blue: Endomysium

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Skeletal muscle - muscle spindle

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Skeletal muscle cross section 1. Fibroblast Nuclei 2. Muscle Fiber Nuclei 3. Muscle Fiber 4. Capillaries 5. Muscle Fiber Nuclei 6. Muscle Fiber 7. Muscle Fiber Nuclei 8. Muscle Fiber 9. Capillaries 10. Endothelial Cell Nuclei 11. Muscle Fiber Nuclei 12. Capillaries 13. Fibroblast Nuclei

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Skeletal muscle on right side. Epimysium (connective tissue) on the left side.

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Skeletal muscle: Left arrow = hypertrophy Middle arrow = atrophy Right arrow = scar tissue

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Skeletal muscle: 1. Perimysium 2. Endomysium 3. Epimysium 4. Muscle fiber 5. Myofibril 6. Muscle fascicle

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Smooth muscle

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Smooth muscle cross section

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Smooth muscle external lamina via PAS stain with hematoxylin counterstain.

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Smooth muscle, small intestine 1. Longitudinal sectioned bundles 2. Longitudinal sectioned bundles 3. Dense Irregular Connective Tissue 4. Cross-sectioned bundles 5. Dense irregular connective tissue 6. Cross-section bundles 7. Smooth muscle bundle 8. Dense irregular connective tissue

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Squamous metaplasia of the uterine cervix. Cervical canal lined by simple columnar epithelium. Center of image is occupied by an island containing squamous stratified epithelium. This metaplastic epithelium is surrounded on both sides by simple columnar epithelium.

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Stratified cuboidal

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Stratified squamous (not keratinized)

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Tendon

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Top: Dense regular connective tissue (tendon) Bottom left: Dense regular connective tissue (tendon) Bottom right: Dense regular connective tissue (tendon) BV, blood vessel Ent, endotendineum Ept, epitendineum TC, tendinocyte nuclei TF, tendon fascicle dashed line, arbitrary cross-sectional cut of tendon

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Top: Loose and dense irregular connective tissue (mammary gland) Left bottom: Loose connective tissue (colon) Right bottom: Loose connective tissue (colon) CF, collagen fibers DICT, dense irregular connective tissue Ep, epithelial cells GE, glandular epithelium L, lymphocyte LCT, loose connective tissue M, macrophage MM, muscularis mucosa P, plasma cells

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Top: Lymphocytes. Arrows pointing to platelets Middle: Monocytes. Arrows pointing to platelets. Bottom: Bone marrow smear. A, adipocytes BN, band neutrophil E, eosinophils Ey, erythrocytes M, megakaryocyte arrows, platelets

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Top: Neutrophil Middle: Eosinophil Bottom: Basophil

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Top: Skeletal muscle Middle: Cardiac muscle Bottom: Smooth muscle

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Top: White adipose tissue Bottom: Brown adipose tissue

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Unmyelinated Peripheral nerve P: perineurium Arrowheads: Extensions of perineurium BV: Blood vessel - Blood-nerve barrier MF: myelinated nerve

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Unmyelinated nerve fibers. The individual fibers or axons (A) are engulfed by the cytoplasm of a Schwann cell. The arrows indicate the site of mesaxons. In effect, each axon is enclosed by the Schwann cell cytoplasm, except for the intercellular space of the mesaxon. Other features evident in the Schwann cell are its nucleus (N), the Golgi apparatus (G), and the surrounding basal (external) lamina (BL). In the upper part of the micrograph, myelin (M) of two myelinated nerves is also evident.

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Upper: Elastic fibers Lower left: Elastic fibers Lower right: Elastic lamellae BV, blood vessel C, collagen fi bers D, duct of sweat gland E, elastic fi bers

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White matter (myelinated axons)

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Zones on it's size. Left most is zone of reserve cartilage etc,.

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osteocytes, osteoblasts, and osteoclasts are the multinucleated big cells.

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peripheral Nervous Tissue - cell showing axon and many nuclei

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A. Skeletal muscle fibers (H&E stain) B. Cardiac muscle fiber (Mallory-stained) C. Smooth muscle of intestine (H&E stain)

Identify A, B, C

A. Junctional complex B. Apical domain C. Lateral domain D. Intercellular space E. Basal domain F. Basement membrane

Identify A-F of this epithelial tissue

Arrow is pointing to osteocyte. Photomicrograph of a growing bone spicule stained with Mallory-Azan. Osteocytes are embedded within the bone matrix of the spicule, which is stained dark blue. These cells are metabolically active, laying down the unmineralized bone matrix (osteoid). A number of osteoblasts are aligned on the right side of the spicule. Between these cells and the calcified bone spicule is a thin, light-blue-stained layer of osteoid. This is the uncalcified matrix material produced by the osteoblasts. One of the cells (arrow) has virtually surrounded itself by its osteoid product; thus it can now be called an osteocyte. On the left side of the spicule, the nongrowing part, are inactive osteoblasts. The cells exhibit flattened nuclei and attenuated cytoplasm

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Osteoprogenitor cells

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Bone lining cells (periosteal and endosteal cells)

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Fibroblasts

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Fusiform appearance of fibroblasts (usually not seen)

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Pseudostratified epithelium with cilia- goblet cell.

Identify cells

A = band cell (didn't learn) B = monocyte C = lymphocyte D = eosinophil E = neutrophil F = basophil G = erythrocyte (The tiny purple dot next to A is thrombocytes (platelet).

Identify each letter

A. Simple columnar epithelium lining a cavity of a small cyst. B. Dense regular connective tissue forming a tendon-like structure C. Area showing hyaline cartilage (C) and developing bone spicules (B). D. Brain tissue with glial cells E. Cardiac muscle fibers F. Skeletal muscle fibers cut in cross-section.

Identify each tissue (A-F) in this ovarian teratoma.

1. Simple epithelium (exocrine pancreas): Circle shows acinus with simple columnar cells. Arrows show ducts with simple squamous. Asterisk shows duct with simple cuboidal epithelium. 2. Simple cuboidal epithelium (kidney) 3. Simple columnar epithelium (colon) 4. Pseudostratified epithelium (trachea) 5. Pseudostratified epithelium (epididymis) 6. Stratified squamous epithelium (vagina) BC, basal cell C, cilia CC, columnar cell CT, connective tissue GL, intestinal gland arrows, upper left, duct composed of simple squamous epithelium; upper right, lateral boundaries of cuboidal tubule cells; middle left, mucus cups of goblet cells asterisk, duct or tubule of simple cuboidal epithelium

Identify epithelium

1. Stratified epithelia (esophagus, monkey) 2. Stratified epithelia (skin) 3. Epithelial transition (anorectal junction) 4. Transitional epithelium (urinary bladder, monkey) 5. Epithelioid tissues (testis, monkey) 6. Epithelioid tissues (endocrine pancreas) C, capillary CT, connective tissue En, endocrine cells Ex, exocrine cells IC, interstitial (Leydig) cells SCol, simple columnar epithelium SS, stratified squamous epithelium StCu, stratified cuboidal epithelium arrowhead, transition site of simple stratified epithelium to stratified cuboidal arrows, surface cuboidal cells asterisks, dome-shaped cells

Identify epithelium

1. Simple squamous epithelium. (mesovarium) 2. Simple squamous epithelium (mesentary, rat) 3. Simple squamous epithelium (kidney) 4. Simple cuboidal epithelium (pancreas) 5. Simple cuboidal epithelium (lung) 6. Simple cuboidal epithelium (liver) A, adipose tissue AW, airway C, canaliculus CC, cuboidal cells CT, connective tissue H, hepatocytes MC, mesothelial cells N, nucleus PCT, proximal convoluted tubule PD, pancreatic duct S, sinusoid SSE, simple squamous epithelium TB, terminal bar US, urinary space

Identify epithelium left to right

Compound (branched) tubular. (duodenum)

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Compound acinar (pancreas) - serous secretions.

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Compound tubuloacinar (parotid)- serous secretions

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Mucus-secreting compound gland. Compound acinar gland.

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Mucus-secreting surface cells of stomach. Cells lining gastric pits. Simple tubular glands. (might be simple branched tubular?)

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Serous-secreting compound gland. Pancreatic acinar. Compound acinar gland.

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Simple branched tubular.(stomach)

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Simple coiled tubular- (skin, stratified squamous epithelium- eccrine sweat gland)

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Sebaceous Gland- holocrine secretion.

Identify gland secretion

Green are ducts Yellow is mucous secreting

Identify green and yellow arrows

A. Zonula occludens B. Zonula adherens C. Gap junctions D. Focal adhesions E. Hemidesmosomes F. Maculae adherentes (desmosomes) G. Basal lamina

Identify labels

Left: White adipose tissue Right: Brown adipose tissue

Identify left and right tissues

A. Keratinized, stratified squamous epithelium of the skin. B. Loose connective tissue C. Dense irregular connective tissue

Identify letters A-C

Epimysium which has dense connective tissue

Identify outside part

Left is normal. Right picture shows demyelination on myelin stain (white is unmyelinated) characteristic in multiple sclerosis in CNS.

Identify pathology

Musclar dystrophy, abnormal dystrophin via immunostain

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Unmyelinated peripheral axon. Schwann cells still envelope the axon. If it was properly myelinated it would surround each axon individually.

Identify pathology

Osteoblasts

Identify pink area

Osteoclasts

Identify pink region

Plasma cells

Identify the cell

Bone marrow smear with megakaryocytes

Identify this smear

Connective tissue

Identify this tissue

Transitional epithelium (stratified)

Identify this tissue type

Dense regular connective tissue

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Pseudostratified ciliated simple columnar epithelial tissue

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So this is in intramembranous ossification Top line: Mesenchyme Middle line: Trabecula (bone spicule) Bottom line: blood vessel

Identify top, middle, and bottom line

Reticular fibers (in the lymph node)

Identify what arrows are pointing to

Arrows are pointing to the basement membrane of goblet cells which is seen as a thin pink/magenta layer. This was stained with PAS which colors polysaccharides as a pink/magenta color. The mucin within these goblet cells also shows up as pink/magenta.

Identify what the arrow is pointing to and stain used

Arrows pointing to satellite cells surrounding the cell bodies in a ganglion.

Identify what the arrows are pointing to

Hyaline cartilage B. Territorial matrix A. Dense connective tissue, fibroblasts found here.

Identify what type of cartilage, ID B, and what cells types are found within A?

Endomysium which has delicate connective tissue

Identify white part

Perimysium which has thick connective tissue

Identify white part

Arginine supplementation can help disorders of the urea cycle under what condition?

If the block is after argininosuccinate. (argininosuccinate turns to arginine)

Which membrane receptors allow for opsonization

IgG or C3b (only complement protein that does opsonization). Both can bind to the pathogen and bring it to a phagocyte. IgG binds to the Fc receptor (CD16). Enhances phagocytosis up to 4,000 fold.

B cell selection

Immature B cell in bone marrow (IgM only), if it doesn't bind self within the bone marrow it gets to go to the periphery. If it binds self it gets deleted (clonal deletion). If we are not sure if it binds to self, we let it go into the periphery but if it binds to self in the periphery it becomes anergic- shut down/can't function.

Nonlamellar - Woven bone Cells randomly arranged Matrix is less mineralized, more ground substance. - Intense basophilic staining Found in fetal bones, adult alveolar sockets, and tendon attachments

Immature bone is less organized than mature bone

Clearance of immune complexes

Immune complexes (antigen and antibody complex) need to be cleared after the pathogen is eliminated or else the complexes can become trapped in certain organs and unleash inflammation, etc. like in lupus. To clear these immune complexes, C3b on the immune complexes binds to the C1 receptor on RBC's and get a ride to the liver and spleen where they can be removed by professional phagocytes (macrophages).

Variable vs constant region of antibody

Immunoglobulin (antibody) has 2 chains, heavy chain and light chain. The heavy chain has a variable and constant region and the light chain has a variable and constant region. The constant region is responsible for the different isotypes/classes like IgM, IgD, IgG, IgA, and IgE, determines the biological function of the antibody. The variable region is responsible for binding to the antigen, antigen binds in between the variable heavy and variable light chain. The light chain genes found on different chromosomes kappa and lambda. The constant region of kappa chains are essentially identical whereas the constant regions of the lambda chain are expressed in 4 different forms called subtypes. The heavy chain genes found on the same chromosome. IgG and IgA can further divide into subclasses, IgG with gamma 1, gamma 2, gamma 3, and gamma 4. IgA with a1 and a2. 1 antibody can bind 2 antigens.

Antibody dependent cellular cytotoxicity (ADCC) vs opsonization

In ADCC you have a viral infected cell and use antibodies (IgG) to recognize them and bring them to cells with CD16 (NK cells, neutrophils, macrophages) most often NK cells which then kill the whole cell. In opsonization, you have either an antibody (IgG) or complement (C3b) bind to a bacteria and bring it to a phagocyte (macrophages, neutrophils, or dendritic cells) and then that bacteria can be engulfed by the phagocyte.

alpha-ketoglutarate in muscle pathway to liver.

In muscle: Alpha-ketoglutarate + NH4+ +NADPH (or NADH) via glutamate dehydrogenase -> glutamate. Glutamate + NH4+ + ATP via glutamine synthetase -> glutamine. Glutamine then travels from muscle to liver via blood. In liver: Glutamine via glutaminase removes NH4+ -> glutamate. Glutamate + NADP+ (or NAD+) via glutamate dehydrogenase removes NH4+ -> alpha-ketogluterate. The NH4+ then combine to form urea and are excreted in urine.

Where is lipoprotein lipase (LPL) found?

In the capillaries of muscle and adipose tissue. LPL releases fatty acids from lipoprotein lipase in the muscle and adipose tissue for tissue uptake.

Where does aerobic metabolism take place?

In the mitochondria- TCA cycle in mitochondrial matrix and electron transport chain in the inner mitochondrial membrane.

Where does the naive resting B cell turn to activated B cell?

In the periphery (lymph nodes, spleen). Once it binds to antigen it becomes an activated B cell and either turns into a plasma cell or a memory B cell. If the memory B cell gets hit again with the same antigen, it turns into a plasma cell.

Where are triglycerides resynthesized?

In the smooth endoplasmic reticulum of intestinal epithelial cells. (smooth ER makes lipid component of chylomicrons) (rough ER makes ApoB-48)

Glucose 6-phosphatase induced by?

Increase in gene transcription during fasting

Which molecules stimulate glycolysis?

Increases in: - AMP -Fructose-2,6-bisP -Fructose-1,6-bisP

Which molecules inhibit glycolysis?

Increases in: -ATP -Citrate -Glucose-6-P -NADH -acetyl-CoA -alanine (basically anything downstream of glycolysis)

Dietary carbohydrates

Indigestible Fiber - (Cellulose) Complex Carbohydrates: Starch and amylopectin Glycogen Disaccharides Lactose Sucrose Maltose Monosaccharides Fructose (some fruit, "soda pop") Ribose (from DNA & RNA) Glycerol (from triglycerides) Oligosaccharides Found attached to glycoproteins, lipoproteins, proteoglycans (from bacteria), glycosaminoglycans (found in extracellular connective tissue and joints).

Cellulose

Indigestible fiber

Phosphoenolpyruvate carboxykinase regulated by?

Induced (increase in gene transcription) by glucagon, epinephrine, glucocorticoids (cortisol) Repressed by insulin

Oxygen Independent Killing

Inducible nitric oxide synthetase (iNOS) generates nitric oxide (NO) in both phagocytic cells and non-phagocytic cells. Cathepsin G, a neutral protease Lactoferrin Lysozyme Defensins

What does Th17 cause

Inflammation, extracellular bacterial and fungal infections.

Fructose 1,6-bisphosphatase controlled by?

Inhibited by F 2,6 BP AMP Induced (increase in gene transcription) during fasting

Regulation of Citrate synthase

Inhibited by citrate

Hexokinase allosteric regulators

Inhibited by- Glucose-6-P

Regulation of B-oxidation

Inhibited by: ATP, NADH, FADH2, Malonyl CoA (made in liver, insulin stimulated, AMPK inhibited). Stimulated by: Increase in energy demand, (AMPK, ADP)-> HSL releasing more fatty acid in blood -> increase in b-oxidation, glucagon

Regulation of malate dehydrogenase

Inhibited by: NADH

What does a C1 inhibitor (C1 INH) do?

Inhibits C1r and C1s serine protease activity which essentially inhibits the classical pathway of complement system. Is a plasma protein

Glucose-6-P regulation of glycolysis and TCA (1)

Inhibits Hexokinase

Acetyl-CoA regulation of glycolysis and TCA

Inhibits Pyruvate dehydrogenase

Citrate regulation of glycolysis and TCA (2)

Inhibits: 1. Phosphofructokinase 2. Citrate synthase

NADH regulation of glycolysis and TCA (4)

Inhibits: 1. Pyruvate dehydrogenase. 2. Isocitrate dehydrogenase 3. a-ketoglutarate dehydrogenase 4. Malate dehydrogenase

ATP regulation of glycolysis and TCA (2)

Inhibits: 1.Phosphofructokinase 2. Pyruvate kinase

Inflammation

Initial response to infection (innate) Recruitment of WBC's Rolling adhesion - Selectins -- Vascular endothelium: P-selectin, E-selectin -- Neutrophil:sialyl lewis carbohydrates on WBC. Tight binding - Integrin -- Vascular endothelium: ICAM-1 -- Neutrophils: CD18 Diapedesis (the passage of blood cells through the intact walls of the capillaries, typically accompanying inflammation.) Migration (Swelling comes from increased vascular permeability).

Fuels used during exercise chart vs hours exercising

Initially- Muscle glycogen main fuel source but rapidly decreases after peaking ~ 20 minutes in and then plateauing 1 hour in at the bottom until completely exhausted after > 4 hours of exercise. Blood-born fatty acids become dominant energy source about ~40 minutes in and continue past the point of muscle glycogen exhaustion. Blood-borne glucose use increases similar (slightly lower utilization) to blood-borne fatty acids but then starts dropping off somewhat after ~1h 30m while blood-borne fatty acid use continues going up slightly more.

Innate vs Acquired immune system

Innate - Physical barriers (skin, etc.) - Physiologic barriers - Cellular response - Inflammation Acquired - B and T cells - Memory response

Heart beats spontaneously in rhythm - Initiated & coordinated by cardiac conducting cells - Organized into nodes = *Purkinje fibers* Similar system of contraction to skeletal muscle - Different initiation & regulation

Innervation of cardiac muscle

Innervation similar to skeletal muscle Initiation of contraction: - *Mechanical impulse*: -- Passive stretch - *Electrical depolarization* -- Neurotransmitters & Ca2+ channels - *Chemical stimuli* -- Hormones & receptors -- Second-messenger pathways Slow cross-bridge cycle - *Peristaltic movement* - Able to remain in "latch state"

Innervation of smooth muscle

Isoluble vs soluble fiber examples (3 each)

Insoluble: -cellulose -hemicellulose -lignins Soluble: -pectins -mucilages -gums

Increase in albumin synthesis in liver stimulated by what?

Insulin

What stimulates Glycogen synthesis?

Insulin

What stimulates the liver to synthesize VLDL

Insulin

Insulin vs glucagon secondary messengers

Insulin: Tyrosine Kinase -> PIP3 -> PKB Glucagon: G-protein -> cAMP -> PKA

Intercalated discs are junction between cardiac muscle cells. Green: *Fascia Adherens* - Anchor thin filaments - Transverse component Yellow: *Maculae Adherens* (Desmosomes) - Hold cells together during repetitive contractions - Transverse & lateral component Blue: *Gap Junctions* - Allows cells to communicate - Lateral component

Intercalated Discs Identify

What is interferon-y, who is it secreted by, and what does it do?

Interferon-y is a cytokine. Made by T helper cells. Directs macrophages to kill intracellular bacteria. Promotes class switching to IgG

Which adipokine is proinflammatory

Interleukin-6

Where are chylomicrons found

Intestinal epithelial cell, lymph, and blood

Begins during gestation Mesenchymal cells aggregate and differentiate into osteoblasts Mesenchymal cells -> osteoprogenitor cells -> osteoblasts Osteoblasts secrete osteoid -> osteocytes Osteoid mineralizes Bone undergoes appositional growth (enlarging existing bone) and forms woven bone.

Intramembranous ossification

Problems with amino acid metabolism: branched chain amino acids

Involves valine, isoeucine, and leucine. Maple syrup disease: A branched-chain a-keto acid dehydrogenase is defective; the amino acid and its a-keto acid accumulate and appear in urine. Leads to neurologic complications.

Which 2 metals are important in electron transport chain complexes.

Iron and copper. Iron allows the complexes (I, III, and IV) to accept electrons better. Cytochrome C binds to Cu on the IV complex

What does C5a do?

Is a complement protein that is chemotactic, allowing and recruiting cells from the blood into the tissues. Also anaphylatoxins- causes degranulation of mast cells and basophils without IgE.

What does a Decay accelerating factor (DAF) do?

Is a membrane protein found in the blood cells, endothelial cells, and epithelial cells. Blocks formation of C3 convertase in the alternative pathway. Inhibits the alternative pathway in the complement system.

What property of skeletal muscle makes it dedicated to glycolytic pathway for energy production?

It doesn't have glucose-6 phosphatase. (found in liver)

What is the hinge region of antibodies?

Its a region between Ch1 and Ch2 that is rich in prolines (prevent formation of globular structure) and cysteines (S-S bonds) that permits flexibility of the 2 arms of the antibody and allows them to move a bit in order to pick up 2 antigens.

Microtubule disease causing abnormal cilia. Causes: sinusitis, situs inversus, sterility, and bronchiectasis.

Kartagener's syndrome?

Alternative ketone body metabolism

Ketone bodies can also be made from amino acids. Carbon skeleton from amino acid can be converted to ketone body (acetoacetyl CoA) or ketone body precursors (Acetyl CoA). Acetoacetyl-CoA can be used to synthesize cholesterol.

Receptors of Innate Immunity

Know TLR4 and NLRP-3. Recognize patterns like how the early ones recognize lipopeptides, peptidoglycan by TLR-2 which almost all bacteria have. The later TLR recognize viral components such as DS RNA, we don't make DS RNA so it signals to cell that something isn't right. Good trigger for interferons.

LPL vs HSL in adipose tissue

LPL in capillaries of muscle, adipose tissues -Allows FA uptake into these tissues HSL (hormone sensitive lipase) in adipose tissue -Allows FA release from adipose tissue

Where do the 3 carbon skeleton come from in gluconeogenesis?

Lactate (RBCs), glycerol (fat), and alanine/AA (protein)

Tissue dendritic cells

Langerhans cells - epidermis and mucous membranes Interstitial dendritic cells - most organs Interdigitating- T cell zones of secondary lymph tissue and thymic medulla Circulating dendritic cells- blood *Follicular Dendritic Cells* - exclusively located in follicles of lymph node (B cell rich) - Don't express Class II MHC - Don't function as APC for TH cell activation - Have many receptors for Ab/C' and bind circulating antigen-antibody complexes - Antigen-antibody complexes can be retained on follicular dendritic cell membranes for weeks to years - *Role in formation of memory B cells* (WIll not test on all the different names- only follicular dendritic cells which have a special role of maintaining a pool of memory cells.)

Hypoglycemia can lead to?

Leads to depletion of ATP: brain- dizziness, drowsiness, coma blood- hemolysis due to loss of integrity of membranes.

Hyperglycemia can lead to?

Leads to osmotic dehydration of tissues and can lead to hyperosmolar coma from brain dehydration

Oxidation vs reduction in relation to electrons

Leo the lion says GER: Lose Electrons Oxidation, Gain Electrons Reduction.

Which adipokine suppresses appetite

Leptin

Leptin

Leptin regulates appetite and energy expenditure. Leptin supresses hunger and increases energy expenditure. Weight loss causes decreased leptin levels and in turn hunger and decreased energy expenditure. Weight gain causes increased leptin levels and in turn fullness and increased energy expenditure. Some individuals are leptin resistant.

CD antigens

Lineage Maturation Activation Common CD markers - CD4 (TH) - CD8 (TC) - CD3 (all T cells) - CD14 (macrophages) - CD16, CD56 (NK cells) - CD19, CD20, CD21 (all B cells) - CD34 (stem cells) - CD40 APC's (antigen presenting cells) (dendritic cells, B cells, and macrophages) - CD40L activated TH cells KNOW THIS

What can an antibody (b cells) do?

Links the innate to the acquired immune system Activate complement (IgG and IgM) Opsonization (IgG or C3b) Antibody dependent cellular cytotoxicity (ADCC)- NK cells are part of the innate system and non specifically kill virus and cancer cells. When antibodies are unleashed, NK cells have a receptor for them (CD16) and binds them creating a more specific response. Antibodies are secreted only by plasma cells. (B cells) The function of an antibody is defined by its constant region (ex. IgG, IgM, etc.)

What allows TG storage and release? Excess fat is stored where?

Lipases allow TG storage and release Excess fat is stored in adipocytes (also known as lipocytes) which expand in size until the fat is used for fuel.

This tumor marker is found in what tumor types? a-fetoprotein

Liver cell cancer, nonseminomatous germ cell tumors of testis

Liver fuels and metabolism - carbohydrates

Liver consumed ~20% total O2 used by body. Uses glucose, fructose, galactose - Converts to glucose, glycolysis intermediates *Glucose is the major fuel after high-carbohydrate meal* - Liver GLUT2, glucokinase have high Km.

Liver's role in amino acid metabolism? (3)

Liver contains all enzymes necessary for amino acid synthesis and degradation. Fed state: carbons converted to glucose (glycogen) and TGs Fasting state: carbons used to make glucose, KBs as fuels.

What primarily produces complement proteins?

Liver, spleen, and macrophages.

Liver, adipose, and skeletal muscle in fed/fasting states.

Liver- Fed state: Glycolysis, Glycogen synthesis, Triglyceride synthesis. Fasting states: Glycogenolysis, gluconeogenesis. Adipose- Fed state: Store FA as triglycerides (from chylomicrons and VLDL), glucose disposal via GLUT4 activity. Fasting state: Release FA into blood via HSL activity. Skeletal muscle- Fed state: Glucose disposal via GLUT4 activity. Fasting state: May contribute amino acids for gluconeogenesis.

Adiponectin functions in liver, muscle, and heart. What does it protect against?

Liver: Decrease glucose output Decrease fat accumulation Decrease inflammation Muscle: Increase glucose uptake Decrease fat accumulation Increase energy expenditure Heart: Decrease inflammation Decrease endothelial adhesion Decrease foam cell formation Protects against: Insulin-resistance Type 2 diabetes Coronary artery disease

In starvation, what is the major source of fuel for the Liver, Muscle, RBC, and brain?

Liver: fatty acids Muscle: Fatty acids Brain: Ketone bodies (glucose) RBC: glucose

Adiponectin and obesity

Lower adiponectin reported in individuals with obesity and those in type 2 diabetes. Adiponectin lowers inflammation and is anti-metabolic, anti-cancer. Low adiponectin can lead to cancer, obesity, cardiovascular disease, diabetes, and inflammation

What are the linked human cancers to this product and where is this product found? Nickel compounds

Lung and oropharyngeal carcinoma Nickel plating; component of ferrous alloys, ceramics, and batteries; by-product of stainless-steel arc welding.

This tumor marker is found in what tumor types? TP53, RAS mutants in sputum and serum

Lung cancer

What are the linked human cancers to this product and where is this product found? Berylium and berylium compounds

Lung carcinoma Missile fuel and space vehicles; hardener for lightweight metal alloys, particularly in aerospace applications and nuclear reactors.

What are the linked human cancers to this product and where is this product found? Chromium compounds

Lung carcinoma Component of metal alloys, paints, pigments, and perservatives.

What are the linked human cancers to this product and where is this product found? Radon and its decay products

Lung carcinoma From decay of minerals containing uranium; potentially serous hazard in quarries and underground mines

What are the linked human cancers to this product and where is this product found? Arsenic and arsenic compounds

Lung carcinoma, skin carcinoma By-products of metal smelting; component of alloys, electrical and semiconductor devices, medications and herbicides, fungicides, and animal dips.

What are the linked human cancers to this product and where is this product found? Asbestos

Lung, esophageal, gastric, and colon carcinoma; mesothelioma. Formerly used for many applications because of fire, heat and friction resistance; still found in existing construction as well as fire-resistant textiles, friction materials (i.e brake linings), underlayment and roofing papers, and floor tiles

1. Most common agranulocyte, ~30% of all WBC. 2. Most circulating lymphocytes are 6-15 micrometers in diameter; scant cytoplasm, dark staining, round nucleus (small lympocytes). 3. Large lymphocytes- in blood, not completely differentiated: a. Activated - T cells (thymus): cell mediate immunity; 60-80% - B cells (bursa of Fabricius): make circulating antibodies; 20-30%. b. Natural killer lymphocytes: kill virus-infected cells and some tumor cells; secrete interferon y (gamma). 4. Can return to circulation.

Lymphocyte key points

Comparison of Innate and Adaptive immunity

MALT = mucosa-associated lymphoid tissue

What is the associated neoplasm and etiologic agent in sjogren syndrome, hashimoto thyroiditis

MALT lymphoma

Which epigenomic regulatory gene mutation found in 90% of infants with acute leukemia?

MLL1: histone methylation

Which epigenomic regulatory gene mutation found in 90% of follicular lymphoma?

MLL2: histone methylation

What are the mononuclear cells

Macrophages (monocytes in the blood, macrophage in tissues), granulocytes (neutrophils, eosinophils, basophils, and mast cells), and dendritic cells.

What does a mast cell do in an inflammatory response? What triggers it?

Macrophages can send complements to bind directly on Mast cells on C5a and degranulate them releasing histamines, prostaglandins, and leukotrienes which are all involved in inflammation.

Which cells are phagocytes?

Macrophages, neutrophils, and dendritic cells.

Macula adherens (desmosomes) Couples the intermediate filaments to the plasma membrane at regions of cell-cell adhesion. Major link protein: Cadherins Cytoskeleton components: Intermediate filaments

Macula adherens/desmosomes (Anchoring junction)

What does the MAC attack protect against?

Mainly Neisseria infection. MAC can't lyse gram positive bacteria because of their thick wall, can't lyse gram negative bacteria because of their LPS. But Neisseria has lipooligopolysaccharide which it can lyse.

What are some of the major and minor regulators stimulating/inhibiting release of glucagon.

Major regulators- Glucose- inhibits Insulin- inhibits Amino Acids- stimulates Minor regulators Cortisol- Stimulates Neural (stress)- Stimulates Epinephrine- Stimulates

Insulin action (major targets, stimulates, inhibits)

Major targets include skeletal muscle, liver, and adipose tissue Stimulates: - glucose uptake - Fat synthesis and storage - Protein synthesis - Glycogen formation Inhibits: - Glycogenolysis - Gluconeogenesis - Lipolysis

Two fates of alanine in the liver during fasting?

Makes glucose or ketone bodies

Starch is digested in the mouth by amylase to what product?

Maltose and limit dextrins

Abnormal expression of *fibrillin-1 gene* (Elastic fibers disorder) Mutation in fibrillin results in abnormal formation of elastic tissue. Decreased tissue elasticity Presentation: - Tall with thin, long limbs - Sternal abnormalities - Scoliosis - Vision defects Risk of aortic dilatation or dissection

Marfan syndrome

Mast cells

Mast cells precursors are formed in the bone marrow during hematopoiesis and released into the blood. They do not differentiate until they leave the blood and enter the tissue - Allergies and parasites (Basophils in blood convert to mast cells in the tissue)

Lamellar bone *Osteon* (Haversian systems) -Concentric lamellae of bone surrounding a central canal (Haversian canal) - *Haversian canals* contain vessels and nerves - *Volkmann's canal* connects Haversian canals *Interstitial lamellae* - Between the osteons *Outer circumferential lamellae* - Lining the outer surface of the bone under the periosteum *Inner circumferential lamellae* - Lining the inner surface of the bone under the endosteum

Mature bone is composed of osteons

This tumor marker is found in what tumor types? calcitonin

Medullary carcinoma of thyroid

1. Found in bone marrow 2. Give rise to thrombocytes (platelets) 3. Platelet demarcation channels

Megakaryocyte key points

What is the receptor on B lymphocytes?

Membrane bound Ig (like IgA, IgG, etc.)

Connective tissue coverings of the CNS: A. *Dura mater* - Thick, outermost dense CT - Meningeal & periosteal layers split to enclose *venous sinuses* B. *Arachnoid mater* - Delicate sheen of CT - *Subarachnoid space* -- CSF & cerebral arteries -- *Arachnoid trabeculae*: strands of loose CT C. *Pia mater* - Delicate, innermost CT - Intimately attached to surface of brain & spinal cord

Meninges

What is the associated neoplasm and etiologic agent in asbestosis, silicosis

Mesothelioma, lung carcinoma asbestos fibers, silica particles

Metabolic syndrome and criteria

Metabolic syndrome: group of risk factors that raises risk for CVD and other diseases (e.g. diabetes, stroke, some cancers) Criteria are ≥ 3 of the following: - Abdominal obesity - TG > 150 mg/dL - HDL < 40 mg/dL (<50 for females) - BP ≥130/85 - Fasting blood glucose ≥ 100 mg/dL

Certain basic dyes react with tissue components that shift their normal color from blue to red or purple; this absorbance change is called metachromasia. The underlying mechanism for metachromasia is the presence of polyanions within the tissue. When these tissues stained with concentrated basic dye solution (such as toluidine blue) the dye molecules are close enough to form dimeric and polymeric aggregates. Cells and tissue structures with high sulfate and phosphate groups such as: ground substance of cartiage, heparin-containing granules of mast cells, and rough endoplasmic reticulum of plasma cells- exhibit metachromasia. Toluidine blue will appear purple to red when it stains these components.

Metachromasia

What does NLRP-3 target?

Microbial products and molecules from damaged or dying cells (ATP, uric acid crystals, reactive oxygen species). Downstream effects: Inflammasome. NLRP-3 (sensor) + adaptor protein links procaspase 1 and activates it to caspase that cleaves the pro-IL-1b to generate IL-1b.

Smallest neuroglial cells (~5% of glial cells in adult CNS) Small, dark, elongated nuclei Short, twisted processes (+ spikes) *Phagocytotic* - Proliferate & activate in regions of injury & disease - Mediate neuroimmune reaction Originate from *granulocyte/ monocyte progenitor cells*

Microglia

Where's the location of TCA enzymes?

Mitochondrial matrix

1. Mononuclear phagocytic system: travel from blood into CT. 2. Largest WBC, C-shaped nucleus. 3. Transform into macrophages and functions as an antigen presenting cell.

Monocyte key points

Monocyte/Macrophages

Monocytes found in the blood Macrophages found in the tissue Develop in the bone marrow and enter the blood where they further differentiate into mature monocytes. Monocytes circulate in blood for ~8 hours then migrate into tissues and differentiate into specific tissue macrophages

Phenylketonuria symptoms

Most sever = classic PKU: - Appear normal until ~few months old. - Musty or mouse-like odor to urine (from excess Phe) - Tend to have lighter skin and hair than unaffected family members. -Likely to have skin disorder (e.g. eczema) - Seizures, delayed development, behavioral problems, and psychiatric disorders common in untreated children. - Permanent intellectual disability w/o treatment. Have to consume phenyl-free foods.

*Motor neurons* innervate skeletal muscle - Innervate multiple muscle fibers at a time *Motor unit* - Motor neuron + muscle fibers it innervates Smaller motor unit - ↑ coordination *Efferent* *SNS* *Neuromuscular junction* (motor end plate) - Axonal contact with a muscle fiber Impulse = release of *Acetylcholine (ACh) -> depolarization* of sarcolemma.

Motor innervation of skeletal muscle: Motor unit and neuromuscular junction *Efferent*

Compound multicellular glands: - Duct system with multiple branches; one duct per secretory unit. ------------------------------ Compound tubular: - Found in duodenum: submucosal glands of Brunner. (Compound tubular glands with coiled secretory portions are located deep in the submucosa of the duodenum) Compound acinar: - Found in pancreas: exocrine portion. (Compound acinar glands with alveolarshaped secretory units are formed by pyramid-shaped serous secreting cells) Compound tubuloacinar: - Found in submandibular and parotid salivary gland. (Compound tubuloacinar glands can have both mucous branched tubular and serous branched acinar secretory units; they have serous end-caps (demilunes))

Multicellular Gland Classification- Compound

Simple multicellular glands: - No duct, or single unbranched duct, leads to epithelial surface. -------------------------------- Simple tubular: - Found in large intestine- intestinal glands of the colon. (Secretory portion of the gland is a straight tube formed by the secretory cells (goblet cells)) Simple coiled tubular: - Found in skin- eccrine (merocrine) and apocrine sweat gland. (Coiled tubular structure is composed of the secretory portion located deep in the dermis) Simple Branched tubular: - Found in stomach - mucus-secreting glands of the pylorus. - Found in uterus - endometrial glands. (Branched tubular glands with wide secretory portion are formed by the secretory cells and produce a viscous mucous secretion) Simple acinar: - Found in urethra- paraurethral and periurethral glands. (Simple acinar glands develop as an outpouching of the transitional epithelium and are formed by a single layer of secretory cells) Simple branched acinar: - Found in stomach- mucus secreting glands of cardia. - Found in skin- sebaceous glands. (Branched acinar glands with secretory portions are formed by mucus-secreting cells; the short, single-duct portion opens directly into the lumen)

Multicellular gland classification - simple (Duct is the yellowish, secretory portion is purple) (Unicellular gland = the mucus secreting goblet cell)

Demyelination disease of CNS - Axon exposure = ↓ transmission of impulses - Destruction of oligodendroglia - Autoimmune disease Symptoms: - Neurologic deficits -- Unilateral vision impairment -- Loss of cutaneous sensation -- Lack of muscle coordination & movement -- Incontinence

Multiple Sclerosis (MS)

Homocystinuria symptoms

Multiple forms of homocystinuria, differ by signs, symptoms, and genetic cause. Most common form: -Myopia (nearsightedness) and dislocation of lens - increased risk of abnormal blood clotting -Brittle bones or other skeletal abnormalities. - May have developmental delay and learning problems. Less common forms: - intellectual disability - Problems with movement - Failure to thrive - Seizures - Megaloblastic anemia

This tumor marker is found in what tumor types? immunoglobulins

Multiple myeloma and other gammopathies

Acetaminophen detoxification in the liver

Multiple pathways (can get glucuronylated or sulfonated, etc.) with multiple enzymes that are not specific, one example: Actaminophen is detoxified by CYP2E1 (also detoxifies EtOH) and forms a toxic intermediate benzoquinoneimine in the process. In large amounts ( especially when combining alcohol with acetaminophen) the intermediate can become toxic.

Oxidation of FA by: muscle, liver, brain, rbc

Muscle and kidneys: Completely oxidize FA. Liver: oxidizes to acetyl-coA but then converts to ketone bodies (insufficient oxaloacetate in TCA cycle). Brain- very limited use of FA RBC- Cant oxidize FA.

Glucagon release does not alter muscle metabolism because of which of the following?

Muscle cells lack the glucagon receptor (mainly controlled by epinephrine)

Aggregates of specialized elongated cells. - Primary role of contraction Shortening of muscle cells (fibers) produces movement. - Accomplished by contractile proteins in the *sarcoplasm* (cytoplasm) ---*Thin filaments* (6-8 nm) -----*Actin* ---*Thick filaments* (~15 nm) -----*Myosin* Typically eosinophilic in H&E stains - Most often with basophilic nuclei.

Muscle characteristics

Composed of contractile cells Produces movement Three subclassifications: Skeletal, cardiac, and smooth

Muscle characteristics

1. *Striated Muscle* - Striations ("striped appearance") --- Myofilaments organized in sarcomeres. 2. *Smooth muscle* - No striations --- Highly labile (easily altered) Both skeletal and cardiac muscle is striated. Smooth muscle is not.

Muscle classification

Sensory innervation Stretch receptor Info on muscle length and stretch velocity.

Muscle spindle

X-linked recessive genetic disorder Variable expression of dystrophin - No link sarcomere & extracellular matrix - Hypertrophy Diagnosed young Signs/symptoms: - Frequent falls - Abnormal gait - Fatigue

Muscular Dystrophy

Autoimmune disease Weak muscle response to stimulus Treatment: - Acetylcholinesterase inhibitor -- Enzyme breaks down ACh -- Extend ACh life in synaptic cleft

Myasthenia Gravis

Picture on right is just zoomed in version of the left picture Shows the different appearance of myelinated vs unmyelinated axons.

Myelinated vs unmyelinated axons

What does glutamate dehydrogenase use as cofactor

NAD+ (or NADP+). Glutamate + NAD+ via glutamate dehydrogenase -> a-ketoglutarate.

How many ATP made from NADH? FADH2?

NADH: 10 H+ pumped out for every NADH and 4 H+ needed to synthesis 1 ATP so NADH makes 2.5 ATP. FADH2: 6 H+ pumped out for every FADH2 (6/4=1.5). FADH2 makes 1.5 ATP.

Which enzymes in TCA produce NADH? Which produce FADH2?

NADH: Isocitrate dehydrogenase, a-ketoglutarate dehydrogenase, and Malate dehydrogenase. FADH2: Succinate dehydrogenase

Oxygen dependent killing

NADPH oxidase - Generates toxic oxygen radicals - Deficiencies result in chronic granulomatous disease (increased body sensitivity to infections by bacteria/fungi) and can be severe. Myeloperoxidase - Generates hypochlorite (bleach) - Deficiencies are usually mild to asymptomatic (because plan A is NADPH oxidase).

Intracellular killing mechanisms

NADPH oxidase is a big one- key component to a lot of things and a disease we talk about immunodeficiency. Takes molecular oxygen and converts it to superoxide radicals- hydroxide, hydrogen peroxide, etc. These molecules are unstable. When you have these molecules they will degrade and kill pathogen. Another enzyme called myeloperoxidase- back up plan. Takes hydrogen peroxide and converts it to hypochlorite which is kind of like bleach. Plan A= NADPH oxidase. Plan B = Myeloperoxidase. Anything that is taken up by this phagocyte will die unless it escapes. This back up plan isn't needed unless plan A isn't working.

Formula for urea?

NH2-CO-NH2

How is urea made?

NH4+ and amino (NH2) group from Aspartate (aspartic acid (negative charged)) Takes the NH2 from aspartate (via purine nucleotide cycle) and combines it with NH4+ (from other amino acids) and HCO3- (bicarbonate) to create urea (NH2(CO)NH2) in the liver via *urea cycle*. (urea also made in gut by bacteria)

Allergy or parasitic infection (Eosinophil)

Name a condition in which these cells will be elevated

Bacterial infection (neutrophil)

Name a condition in which these cells will be elevated?

Monocyte

Name the cell type

Platelet- blood clotting.

Name the cell type and its primary function

Specialized connective tissues include bone, cartilage, and blood. These connective tissues are characterized by the special nature of their extracellular matrix. Bone: matrix that is mineralized by calcium and phosphate molecules that are associated with collagen fibers. Cartilage: posseses a matrix that contains a large amount of water bound to hyaluronan aggregates. Blood: consists of cells and an extracellular matrix in the form of a protein-rich fluid called plasma that circulates throughout the body. In all of these tissues, it is the extracellular material that characterizes the tissue, not the cells.

Name three specialized connective tissues and why they are special

Dendritic cells

Named because of long processes resembling dendrites of nerve cells Constituitively express high levels of class II MHC and B7, thus better APC's (antigen presenting cells) than Macrophages and B cells. After capturing antigen in the tissues, migrate into blood or lymph and circulate to various lymphoid organs where they present antigen to T cells.

Very high rate of galactose metabolism in who?

Neonates

Composed of neurons and support cells Receives, transmits, and integrates information Central vs. Peripheral nervous system.

Nervous tissue characteristics

Neural (bb barrier) vs non-neural and glucose

Neural: 1. tight junctions between endothelial cells. 2. Narrow intercellular space 3. lack pinocytosis 4. Continuous basement membrane 5. Glucose transporters in both membranes. Non-neural: 1. No tight junctions 2. Sometimes wide intercellular gaps. 3. Pinocytosis 4. Discontinuous basement membrane 5. Glucose can diffuse between cells and into interstitial fluid.

Functional unit of the nervous system A. Types of neurons i. Motor (efferent) ii. Sensory (afferent) iii. Interneurons B. Anatomy of a neuron i. Cell body ii. Dendrites iii. Axons C. Arrangements of neurons i. Uni/Pseudounipolar ii. Bipolar iii. Multipolar

Neurons

*Excitatory synapse* - *acetylcholine, glutamine, serotonin* - Prompts influx of *Na+* -> depolarization -- Initiates action potential & generates nerve impulse *Inhibitory synapse* - *GABA, glycine* - Prompts influx of *Cl-* -> hyperpolarization -- Making it more difficult to generate an action potential.

Neurotransmitters

1. Most numerous of WBC's 2. Nucleus is characteristically multilobed: polymorphonuclear neutrophil 3. In females, the Barr body may be observed. 4. Granules: - Azurophilic (primary)- lysosomes; myeloperoxidase, acid hydrolases, etc. - Specific (secondary)- enzymes, compliment activators - Tertiary- phosphatases, metalloproteinases 5. Motile- first wave to arrive with tissue damage 6. Express surface receptors to bind bacteria, etc.

Neutrophil key points

a. A neutrophil traveling in the blood vessel expresses a high number of cell-to-cell recognition molecules, such as Sialyl Lewisx (s-Lex) carbohydrates, integrin, and interleukin receptors. b. Circulating neutrophils are slowed down by the interaction of their surface s-Lex molecules with E- and P-selectins expressed on the endothelium of the postcapillary venule. c. As a result of this interaction, the cell rolls on the surface of the endothelium. The neutrophil then adheres to the endothelium and responds to chemokines (e.g., interleukin-8) secreted by the endothelial cells. d. Their secretion induces the expression of other adhesion molecules on the surface of the neutrophil, such as integrins (e.g., VLA-5), which provide tight bonds with the immunoglobulin superfamily of adhesion molecules (e.g., intercellular adhesion molecule-1 [ICAM-1]) expressed on the surface of the endothelium. These interactions provide firm adhesion of the neutrophil to the endothelial surface. e. The neutrophil then extends a pseudopod to an intercellular junction previously opened by histamine and heparin released from the mast cells in the connective tissue, allowing the neutrophil to migrate through the vessel wall. f. Once the neutrophil leaves the circulation and enters the connective tissue, its further migration is directed by chemoattractant molecules that interact with specific receptors on its surface.

Neutrophil migration

Which cells are the first ones to arrive at site of inflammation?

Neutrophils

Chart of differentiation of pluripotent stem cell

Neutrophils are the most predominant WBC. Various growth factors determine what the cell differentiates into.

Opsonization and complement

Neutrophils can't phagocytose encapsulated bacteria so an antibody binds to the encapsulated bacteria and activates complement and binding of C3b to the bacteria. Now the neutrophil can engulf the bacteria thanks to the binding of Fc receptors (CD16) to IgG and complement receptors to C3b.

What are the vitamin derivatives of NADH and FADH2

Niacin (nicotinic acid): NADH Riboflavin: FADH2

Precursor for NAD+ and FAD synthesis

Niacin is precursor for NAD, Riboflavin precursor for FAD.

Positive vs negative nitrogen balance.

Nitrogen balance is when N ingested = N excreted Positive balance = more N is ingested than excreted (e.g., growth) Negative balance = more N is excreted than ingested (e.g., Kwashiorkor)

Is glucose inhibitory in muscle glycogenolysis?

No

Which cells are lacking in Chediak-Higashi?

No NK cells, increased incidence in lymphomas.

What happens in lactose intolerance? Whats the treatment?

No lactase to break down lactose so bacteria ferment lactose to lactic acid, methane and hydrogen which causes: -bloating flatulence, diarrhea -diagnosed by hydrogen breath test Treatment: -decrease milk products consumption - substitute acidophilus (contains lactase) treated milk for whole milk - take lactase pills

Specificity of digestive proteases characteristics (3)

No single protease can completely digest proteins Stored as inactive zymogens until release signaled Digestion occurs in lumen of intestine.

Junction between Schwann cells (*Internodal segment*) - Exposed axon between each myelin sheath. Impulse regenerates - Aids high-speed propagation - ↑ density of Na+ channels Schwann cells function in *Salutatory conduction* - Propagation of AP across segment

Nodes of Ranvier

*Nonfatal myocardial infarction*: - Localized injury to the cardiac muscle often due to lack of oxygen or blood supply - Cardiac function lost at site. The second row in picture shows hypertrophy The 3rd row in picture shows fibrous connective tissue replacing dead cells.

Nonfatal myocardial infarction

Fuel use in cardiac muscle normal tissue vs ischemic tissue

Normal tissue: - Mostly oxidative generation of ATP (98%) - *Fatty acids* are preferred (60-80%). Lactate and glucose also used (20-40%). Most glucose uptake by GLUT4 (induced by insulin, ischemia.) Ischemic tissue: - Increased rate of glycolysis (anaerobic), stimulates GLUT4 for glucose uptake. *Lactate forms* and H+ accumulates (damaging). - Reperfusion with O2 can cause damage: -Rapid FA oxidation -> NADH accumulation -> lactate accumulation -> *pH drops* -> difficult to maintain ion gradients. -Increased superoxide production (reactive oxygen species, ROS) which damages membranes and proteins.

Tryptophan metabolism and disorder

Note that tryptophan can be a precursor for synthesis of NAD(P)+. Higher levels of Tryptophan, less dependence on niacin to prevent pellagra symptoms. - 4 D's of pellagra: Dermatitis, diarrhea, dementia, death. Hartnup: deficiency in transporting tryptophan causing pellegra like symptoms. Tryptophan (produces formate) -> kynurenine (a-keto acid) + PLP + Kynurenine hydroxylase -> alanine, acetyl CoA

A 55 year-old male presents to the emergency department with crushing chest pain, shortness of breath, and fatigue. An abnormal EKG and elevated cardiac enzymes confirm the suspected diagnosis. Inside this patient's cardiomyocytes, what would you predict to find in terms of: O2 level, ATP, H+, and Na+?

O2 level: down due to ischemia [ATP]: down, can't make ATP by oxidative phosphorylation. [H+]: Up, due to the lactic acid build up [Na+]: Up, Na-K pump not working

What is the last electron acceptor

O2 to make h2o

Orotic acid (orotate) in the urine found in which 2 disorders?

OTC enzyme deficiency (urea cycle disorder) and hereditary orotic aciduria. OTC enzyme deficiency: - Ornithine transcarbamoylase deficiency (most common urea cycle defect, 2nd step found in mitochondria). - Carbamoyl phosphate (CP) is the substrate for OTC, accumulates. - CP from urea cycle accumulates, ends up in cytosol. - CP now used in pyrimidine synthesis pathway, converted to orotate. -/Orotate excreted in urine/. - *Pyrimidines can still be made* - *NH4+ accumulates, toxic to CNS* - *Treat urea cycle defect with N-removing compounds, low-protein diet.* Hereditary orotic aciduria: - Orotate phosphoribosyltransferase and orotidine 5'-phosphate decarboxylase (both enzymes in pyrimidine synthesis) are defective (very rare disease) - Orotate is the substrate (UMP is product), orotate accumulates. - /Orotate excreted in urine/ - *Pyrimidines cannot be made* - *Normal growth does not occur* - *Treat pyrimidine synthesis defect with oral administration of uridine*

Adipose dysfunction in obesity: altered adipokine expression and secretion

Obesity causes: Decrease Adiponectin Increase MCP-1 Increase IL-6 Increase TNFa Increase Leptin which leads to inflammation, insulin resistance, and atherosclerosis.

Zonula Occludens (ZO)/Tight junctions -Act as selectively permeable diffusion barrier Seals adjacent cells together, controls passage of molecules between them (permeability), defines apical domain of plasma membrane, involved in cell signaling. Major Link Proteins: occludins, claudins, JAMs Cytoskeleton components: Actin filaments

Occluding junctions

Where does the last step of gluconeogenesis occur and why

Occurs in the endoplasmic reticulum because glucose 6-phosphatase is located in the ER membrane.

Purine degradation

Occurs mainly in the liver Very little energy captured this way, makes more sense to salvage Uric acid can be excreted - Excess uric acid in blood, tissues can ppt. - Excess may be from overproduction or decreased excretion. - Precipitate causes gout (uric acid crystals deposit in joints); treat w/allopurinol. (pyrimidine degradation doesn't cause any problems in humans)

*Myelinates* axons of the CNS Small, few processes - Align in rows between axons 1 cell myelinates 1+ axons nearby - *Internodal segment*- process wrap. - *Nodes of Ranvier* larger -- *Saltatory conduction* ↑ efficient Unmyelinated axons are bare.

Oligodendrocytes

Cori cycle

Only in the liver. Lactate from RBCs and skeletal muscle transferred to liver where they undergo gluconeogenesis and turn to glucose which is then returned to the RBC or skeletal muscle.

What is the main job of C3b

Opsonization and removing immune complexes (antigen/antibody) by binding to them and then binding to red blood cells via CR1 receptor and then taken to the spleen and liver where the immune complexes are removed by phagocytic cells.

Olestra and orlistat

Orlestra: modified artificial fat that is resistant to pancreatic lipase, inhibits ~30% dietary fat absorption. Orlistat- pill that inhibits pancreatic lipase (alli)

What is ornithine

Ornithine is an amino acid but there is no codon for this amino acids and therefore it is not found in proteins.

What is the most common defect in disorders of the urea cycle?

Ornithine transcarbamylase deficiency (step 2).

Derived from osteoprogenitor cells Capable of dividing Secretes osteoid- type I collagen and ground substance Become osteocytes Cuboidal in shape and form a single layer on the surface of growing bone Initiate calcification process

Osteoblasts

Large multi-nucleated cells found at site of bone resorption Derived from ganulocyte/macrophage progenitor cells (RANK/RANKL) Rest in *resorption bay* (howship's lacuna) Surface in contact with resorbing bone forms membrane infoldings (*ruffled border*) Osteoclasts decalcify bone (carbonic acid) and then resorb bone by releasing hydrolytic enzymes.

Osteoclasts

Completely surrounded by osteoid or mineralized bone (lacunae) Maintains bone matrix Elongated cells with numerous processes Processes communicated with the neighboring cells through gap junctions and occupy canaliculi Death of osteocytes result in bone resorption

Osteocytes

Derived from mesenchymal stem cells Flattened cells resemble fibroblasts with ovoid nuclei. Locations: - Inner layer of periosteum - Endosteum - Line Haversian and Volkmann's canals Differentiate into osteoblasts Also able to form chondroblasts, adipocytes, and fibroblasts.

Osteoprogenitor cells

This tumor marker is found in what tumor types? CA-125

Ovarian cancer

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome hypoglycemia?

Ovarian carcinoma, fibrosarcoma, other mesenchymal sarcomas. Insulin or insulin-like substance

leptin and obesity

Overnutrition/specific nutrients (fatty acids, sugars, a.a) increases fat stores which increases leptin and pro-inflammatory cytokines which leads to hyperleptinemia and inflammation. This can then lead to central and peripheral leptin resistance which causes *impaired glucose and lipid metabolism, increase in food intake, and impaired nutrient absorption.*

Catabolism

Oxidative, exergonic pathways that release free energy and reducing power that are captured in the form of ATP and NADPH, respectively. (releases energy)

P-glycoprotein marker for

P-glycoprotein (Pgp) is a transporter protein found in most cells of the body and functions to remove certain metabolites, toxins, and drugs from within the cell (i.e., it is an efflux transporter). Pgp is overexpressed by several tumors (e.g., HCC, colonic cancer, adrenocortical tumor), but not carcinoid tumor, which this patient presents with.

What is the CIP/KIP family and their main functions?

P21, P27 (CDKN1A-D) Block the cell cycle by binding to cyclin-CDK complexes P21 is induced by tumor suppressor p53 P27 responds to growth suppressors such as TGF-B

Which epigenomic regulatory gene mutation found in 30% of renal carcinoma

PBRM1: nucleosome positioning/chromatin remodeling.

Inhibition of glycogen synthesis.

PKA phosphorylates glycogen synthase on multiple serine residues Glycogen synthesis is inhibited.

What is PPARa necessary for?

PPARa is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissues.

Overview of purine synthesis

PRPP (5- Phosphoribosyl 1-pyrophosphate) is activated ribose. IMP (inosine monophosphate) is branch point GTP is required to make AMP (adenosine monophosphate) ATP is required to make GMP (guanosine monophosphate)

This tumor marker is found in what tumor types? TP53, RAS mutants in stool and serum

Pancreatic cancer

What is the associated neoplasm and etiologic agent in pancreatitis

Pancreatic carcinoma Alcoholism, germiline mutations (e.g., in the trypsinogen gene).

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome venous thrombosis (trousseau phenomenon)

Pancreatic carcinoma, bronchogenic carcinoma, other cancers. Tumor products (mucins that activate clotting).

Which vitamin is the precursor to coenzyme A (aka CoA aka CoA-SH)?

Pantothenic acid

*Dopamine* - Neurotransmitter responsible for synaptic transmission - Coordinates smooth & focused movement. Neurologic disorder - Loss of dopamine secreting cells in brain Resting Tremor & Festinating Gait

Parkinson's disease

Delayed growth, listless, irritable, tires easily. Foul-smelling, glistening, bulky stools. Low levels of serum albumin and pre-albumin. What does this patient have? What would doctor prescribe?

Patient has cystic fibrosis. Doctor prescribes pancreatic enzymes.

Which pathway serves as the only source of NADPH for RBCs?

Pentose Phosphate Pathway

The ability of bleached basic fuchsin (Schiff reagent) to react with aldehyde groups results in a distinctive *red/magenta color* and is the basis of the periodic acid-Schiff and Feulgen reactions. Stains carbohydrates and carbohydrate-rich macromolecules. Used to demonstrate *glycogen in cells, mucus in various cells and tissues, the basement membrane that underlies epithelia (based on content of proteoglycans), and reticular fibers in connective tissue*. Schiff reagent is also used in *Feulgen stain* which relies on a mild hydrochloric acid hydrolysis to stain *DNA* (not RNA) a *magenta* color (pinkish) and the reaction of the Schiff reagent with DNA is stoichiometric, meaning product of this reaction is measurable and proportional to the amount of DNA. PAS reaction based on the following facts: - Hexose rings of carbohydrates contain adjacent carbons, each of which bears a hydroxyl (-OH) group. - Hexosamines of glycosaminoglycans contain adjacent carbons, one of which bears an -OH group, whereas the other bears amino group (NH2). - *Periodic acid cleaves bond between these adjacent carbon atoms and forms aldehyde groups.* - *Aldehyde groups react with Schiff reagent to give a distinctive magenta color.*

Periodic acid-Schiff (PAS)

*Sensory ganglion* - Dorsal Root Ganglion (afferent) - NO synapses *Autonomic Ganglion* - Visceral Motor (efferent) - Synaptic station Look at satellite cell arrangement to differentiate.

Peripheral Ganglia

Surrounded by connective tissue *Endoneurium* - Loose CT - Surrounds axon *Perineurium* - Specialized CT - Surrounds nerve fascicle - Squamous cells - Create blood-nerve barrier *Epineurium* - Dense irregular CT - Surrounds peripheral nerve - Binds fascicles

Peripheral Nerves

Composed of: I: *Nerves (& nerve endings)* - Collection of different axons from multiple neurons. II: *Ganglia* - Collection of nerve cell bodies outside CNS. Types: - Sensory - Autonomic

Peripheral Nervous System

It is possible to regrow peripheral nerves b. When the fiber is injured, the neuronal nucleus moves to the cell periphery, and the number of Nissl bodies is greatly reduced. The nerve fiber distal to the injury degenerates along with its myelin sheath. Schwann cells dedifferentiate and proliferate; myelin debris is phagocytosed by macrophages. c. Proliferated Schwann cells form cellular cords of Bunger that are penetrated by the growing axonal sprout. The axon grows at a rate of 0.5 to 3 mm/day. Note that the muscle fibers show a pronounced atrophy. d. If growing axonal sprout reaches the muscle fiber, the regeneration is successful and new neuromuscular junctions are being developed; thus, the function of skeletal muscle is restored ??? is atrophied muscle

Peripheral nerve injury

Phagocytes

Phagocytes - *Neutrophils* -- Circulating, short lived, rapid response but not prolonged defense - *Monocytes/Macrophages* -- Monocytes circulate, become macrophages in the tissue -- Prolonged defense -- 2 major functions: --- M1 classical macrophages induced by innate immunity play a role in inflammation --- M2 alternative macrophages induced by IL-4 and IL-13 and play a role in tissue repair and control of inflammation - *Dendritic cells* -- Found in all tissues, antigen processing and presentation -- 2 major functions: --- Initiate inflammatory response --- Initiate adaptive immune response (acute inflammation from neutrophils, chronic inflammation from macrophages)

Phagocyte receptors

Phagocytic cells have many receptors for antigen Referred to as either Patter Recognition Receptors (PRR) which recognize Pathogen Associated Molecular Patterns (PAMPS) or Damage Associated Molecular Patterns (DAMPs) - Toll receptors -- CD14, TLR-4 (LPS receptor) - NOD receptor - RIG receptors - CR3, CR4 complement receptors

Macrophage function

Phagocytosis Macrophage activity can be enhanced by TH cytokines Activated macrophages more efficient at eliminating pathogens than resting macrophages Activated macrophages have: - Increased phagocytic activity - Increased ability to activate TH cells - Higher levels of Class II MHC on the cell surface.

Mandated newborn screening in Pennsylvania (9)

Phenylketonuria (PKU) Maple Syrup Urine Disease Classical glactosemia Pompe disease (glycogen storage disorder) Sickle cell disease Congenital adrenal hyperplasia Congential hypothyroidism Mucopolysaccharidosis type I X-linked adrenoleukodystrophy

What enzyme is reversible and convert Glucose-6-phosphate to Glucose-1-phosphate both ways

Phosphoglucomutase

Enzymes which generate ATP in glycolysis

Phosphoglycerokinase and pyruvate kinase

Plasma makes up 55% of whole blood. Buffy coat: leukocytes and platelets = <1% of whole blood

Plasma and buffy coat

Found in loose connective tissue of GI and respiratory tracts, salivary glands, lymph nodes, etc. (wandering) Derived from *B lymphocytes* Abundant cytoplasm, basophilic (rER), pale area (Golgi) Eccentric and heterochromatic nucleus Produce antibodies

Plasma cells

Thrombocytes (platelets) are derived from megakaryocytes. Zones: 1. Peripheral zone: cell membrane, glycocalyx. 2. Structural zone: cytoskeleton 3. Organelle zone: organelles, granules a. α - fibrinogen, coagulation factors, plasminogen, etc b. δ - ADP, ATP, serotonin, histamine c. γ - lysosomes 4. Membrane zone: a. Open canalicular system - remnants of platelet channels b. Dense tubalar system: Ca++ storage.

Platelets and their zones

What transfers IgA across and into the mucosa? What protects IgA in the mucosa?

Poly Ig receptor transports IgA into the mucosa. The secretory component is responsible for protecting IgA in the mucosa.

Which pathway synthesizes fructose from glucose in the body?

Polyol pathway

No/little Ach attachment No signal received Weak response to stimulus can be caused by example: *Myasthenia gravis*

Postsynaptic blockade

What are xenobiotics?

Potentially toxic waste metabolite with no nutritional value.

Whats the precursor for bile salts? Where is bile made? What's the rate limiting step? Where is it stored? What are 2 bile salts names?

Precursor: cholesterol Made in the liver Rate limiting step is = 7 alpha hydroxylase Stored in gallbladder 2 bile salts: chenodeoxycholic acid and cholic acid. Bile salts are amphipathic - thats why they can emulsify fats and form micelles.

IgM

Predominant antibody made during the primary immune response First antibody made in neonates Can activate the classical complement pathway Pentameric in serum High avidity (most binding sites), low affinity Monomeric IgM, part of the BCR (b cell receptor). Only one when on the surface of the B cell but when it is secreted from plasma cells it is 5. First antibody made in any infection, soaks up antigens.

No/little release of Ach No depolarization/impulse Decreased response to stimulus can be caused by example: *botulism toxin* botox.

Presynaptic blockade

What are the primary lymphoid tissues? Secondary lymphoid tissues?

Primary lymphoid tissue = bone marrow and thymus. Where B and T cells are made. Secondary lymphoid tissues = spleen, lymph nodes, and tertiary lymphoid tissues. This is where these cells usually see an antigen for the first time.

Liver fuels and metabolism - amino acids

Primary site of amino acid metabolism: - Can use aspartate, glutamate, glutamine as fuel. - Can metabolize all amino acids. - Typically does not oxidize branched chain amino acids (BCAAs; other tissues do), but will use for synthesis as needed. - Maintains N balance. - Urea cycle- most tissues transfer amino acids N to liver for disposal. Converts toxic ammonium into nontoxic urea. Synthesis of proteins: including albumin, clotting factors.

Glucagon (primary target, stimulates, inhibits)

Primary target: Liver Stimulates: Glycogenolysis Gluconeogenesis (HSL in adipose tissue) Inhibits: Glycogen formation Fatty acid synthesis

Two products of pentose phosphate pathway. What is the substrate for this pathway?

Produces 2 NADPH (oxidative phase) and 1 ribulose-5-phosphate per glucose (nonoxidative) Substrate is glucose-6-phosphate

Thermogenesis definition

Production of heat

T cell development

Progenitor T cells are released from the bone marrow and migrate to the thymus where they develop and mature (only cells that complete maturation in the thymus). Undergo positive and negative selection. Positive selection: Can the T cell recognize MHC. Problem here means immunodificiency disease Negative selection: Does the T cell react to self. Problem here means autoimmune disease. Thymus is divided into 2 lobules Cortex: - Immature lymphocytes - Where selection takes place - Nurse cells (specialized epithelial cells). Medulla - Cells that survive selection - More mature thymocytes We have progenitor T cell (pro T), pre T, and mature T cells. Pro T cells: No markers, can't identify them. Once made in the bone marrow they head to the thymus. Once in the thymus they turn everything on (CD3+, CD4+, CD8+, and T cell receptor+) and become pre T cells. Pre T cells: Have everything turned on CD3+, CD4+, CD8+, and T cell receptor +. Selection happens in the cortex of the thymus. Pre T cells become either a T helper or T cytotoxic based on if it interacts with Class II MHC or class I MHC, respectively. CD4 stabilizes MHC II/TCR interaction CD8 stabilizes MHC I/ TCR interaction In pre-thymic cells only Tdt is turned on. In the thymus cortex, RAG expression is turned on, CD3 is turned on, TCR is turned on, CD4 and CD8 are both turned on but once a T cell completely maturity we only express one or the other.

Marasmus

Prolonged caloric deficiency Prolonged protein & energy malnutrition - diet is inadequate in caloric intake. Children have slowed growth, loss of muscle. Emaciated, appears as skin and bones. Loss of body fat and muscle wasting. BMI: 17-18.4 = Degree I of marasmus. BMI: 16-16.9 = Degree II of marasmus. BMI: <16 = Degree III of marasmus. (Patients with marasmus typically do not develop edema like with patients with kwashiorkor do).

Name 2 factors which promote lipolysis

Promoted by low insulin, low-carbohydrate diet.

This tumor marker is found in what tumor types? PSA and prostate-specific membrane antigen

Prostate cancer

What are the linked human cancers to this product and where is this product found? Cadmium and cadmium compounds

Prostate carcinoma Uses include yellow pigments and phosphors; found in solders; used in batteries and as alloy and in metal plating and coatings.

Kwashiorkor

Protein deficiency. Diet may be adequate in caloric intake but with a negative N balance, lack of essential amino acids. -Inability to synthesize necessary proteins. Edema: Hypoalbuminemia (serum protein), "potbelly" (huge belly because no albumin for transport which causes edema) Anemia May have areas of skin hyperpigmentation. May have fatty liver.

What are most dietary amino acids used for during fed state?

Protein synthesis. Excess converted to glucose and triglycerides for storage.

Cluster of differentiation antigens (CD markers)

Proteins present on the cell surface Most cell populations have unique CD markers (CD4, CD8), some CD markers are shared (CD3) Recognized by monoclonal antibodies

Nonreceptor tyrosine kinase Mode of activation in tumor, and associated human tumor?

Proto-oncogene ABL Translocation: Chronic myelogenous leukemia Point mutation: Acute lymphoblastic leukemia. (Proteins involved in signal transduction)

ALK Receptor Mode of activation in tumor, and associated human tumor?

Proto-oncogene ALK translocation or fusion gene formation: adenocarcinoma of lung, certain lymphomas Point mutation: Neuroblastoma. (Growth factor receptor)

RAS signal transduction Mode of activation in tumor, and associated human tumor?

Proto-oncogene BRAF: point mutation or translocation- melanomas, leukemias, colon carcinoma, others. (Proteins involved in signal transduction).

Cyclins Mode of activation in tumor, and associated human tumor?

Proto-oncogene CCND1 (cyclin D1) Translocation: Mantle cell lymphomas, multiple myeloma Amplification: Breast and esophageal cancers. (Cell cycle regulators)

Cyclin-dependent kinase Mode of activation in tumor, and associated human tumor?

Proto-oncogene CDK4: Amplification or point mutation. Glioblastoma, melanoma, sarcoma.

EGF-receptor family Mode of activation in tumor, and associated human tumor?

Proto-oncogene ERBB1 (EGFR): Mutation, adenocarcinoma of lung. ERBB2 (HER): Amplification, breast carcinoma (Growth factor receptors)

FMS Like tyrosine kinase 3 Mode of activation in tumor, and associated human tumor?

Proto-oncogene FLT3, Point mutation, Leukemia (Growth factor receptor)

HGF Mode of activation in tumor, and associated human tumor?

Proto-oncogene HGF, Overexpression, Hepatocellular carcinomas and thyroid cancer. (Growth factors)

Fibroblast growth factors Mode of activation in tumor, and associated human tumor?

Proto-oncogene HST1: overexpression, osteosarcoma FGF3: Amplification, stomach-bladder-breast cancer and melanoma. (growth factors)

JAK/STAT signal transduction Mode of activation in tumor, and associated human tumor?

Proto-oncogene JAK2: Translocation- Myeloproliferative disorders or Acute lymphoblastic leukemia (Proteins involved in signal transduction).

GTP-binding proteins Mode of activation in tumor, and associated human tumor? (5)

Proto-oncogene KRAS: Point mutation- colon, lung, and pacreatic tumors. HRAS: Point mutation- bladder and kidney tumors NRAS: Point mutation- Melanomas, hematologic malignancies. GNAQ: Point mutation- Uveal melanoma GNAS: Point mutation- pituitary adenoma, other endocrine tumors. (Proteins involved in signal transduction)

Transcriptional activators Mode of activation in tumor, and associated human tumor? (2)

Proto-oncogene MYC: Translocation- Burkitt lymphoma. NMYC: Amplification- Neuroblastoma (Nuclear regulatory proteins).

Notch signal transduction Mode of activation in tumor, and associated human tumor?

Proto-oncogene NOTCH1: Point mutation, translocation, or gene rearrangement. Leukemias, lymphomas, breast carcinoma. (Proteins involved in signal transduction).

PDGF receptor Mode of activation in tumor, and associated human tumor?

Proto-oncogene PDGFRB, overexpression or translocation, gliomas, leukemias. (Growth factor receptors)

Receptor for neutrophic factors Mode of activation in tumor, and associated human tumor?

Proto-oncogene RET, point mutation, MEN 2A, MEN 2B, and familial medullary thyroid carcinomas. (Growth factor receptors)

TGF-a Mode of activation in tumor, and associated human tumor?

Proto-oncogene TGFA, overexpression, astrocytomas (Growth factors)

Receptor for KIT ligand Mode of activation in tumor, and associated human tumor?

Proto-oncogene KIT, Point mutation, gastrointestinal stromal tumors, seminomas, and leukemias. (Growth factor receptor)

PDGF-b Mode of activation in tumor, and associated human tumor?

Proto-oncogene, PDGFB, overexpression, astrocytoma (growth factor)

Where are protons found that power ATP synthase

Protons found in intermembrane space. ATP synthase at the inner membrane.

Found in *gray matter* Numerous, short, branching processes - Extend to pia mater = *glia limitants*

Protoplasmic Astrocytes

Initiation of cardiac muscle contraction Exhibit spontaneous rhythmic contraction Organized into nodes in ventricles of heart Larger cells Lighter stain- Increase in glycogen Myofibrils @ periphery Lack T tubules

Purkinje Fibers

Carbamoyl phosphate serves as a substrate for what synthesis?

Pyrimidine synthesis.

Pyruvate dehydrogenase complex converts what (formula)

Pyruvate (3 carbon) + CoA-SH + NAD+ --> acetyl-CoA (2 carbon) + NADH + CO2 (expired)

Pyruvate to PEP in gluconeogenesis

Pyruvate + pyruvate carboxylase -> Oxaloacetate (can't leave mitochondria) Oxaloacetate converted to either aspartate or malate and then exits the mitochondria, converted back to Oxaloacetate, then converted to phosphoenolpyruvate (PEP) by phosphoenol-pyruvate carboxykinase (PEPCK) in the cytosol.

What does glycolysis produce for aerobic metabolism

Pyruvate and NADH

4 main enzymes of gluconeogenesis

Pyruvate carboxylase PEP carboxykinase Fructose 1,6 bisphosphatase Glucose 6-phosphatase

What is the enzymatic linker between glycolysis and the TCA cycle

Pyruvate dehydrogenase

Which 2 dehydrogenase enzymes stimulated by ADP

Pyruvate dehydrogenase and isocitrate dehydrogenase

What happens after glycolysis

Pyruvate shuttled into mitochondria via mitochondria pyruvate carrier.

Pyruvate dehydrogenase complex deficiency results in accumulation of?

Pyruvate, lactate, and alanine.

Tissues that may use anaerobic glycolysis

RBC (exclusively), WBC, kidney medulla, eye tissues, and skeletal muscle.

Normal adult blood counts RBC's, Platelets, Leukocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, and Basophils?

RBC's - 5 x 10^6 cells/mm^3 Platelets - 2.5 x 10^5 cells/mm^3 Leukocytes (all the below are termed leukocytes) - 7.3 x 10^3 Neutrophils - 50-70% Lymphocytes - 20-40% Monocytes - 1-6% Eosinophils - 1-3% Basophils - <1% ------------------------ Mononucleosis = increase in monocytes. Listeria monocytogenes = increase in monocytes. Increase in neutrophils = bacterial infection Increase in lymphocytes = viral infection Bordetella pertussis causes spike in lymphocytes not neutrophils because it inhibits early chemotaxis of neutrophils. Increase in basophils = worm, type 1 hypersensitivity (allergies).

RBC, Liver, Sketetal muscle and heart, and brain fuel usage in each state

RBC: glucose in all stages. Liver: glucose and some fatty acids in fed state. Fatty acids in overnight fast and starvation. Skeletal muscle and heart: Glucose and fatty acids in fed state. Fatty acids, ketone bodies in overnight fast. Fatty acids in starvation. Brain: Glucose in fed state. Glucose in overnight fast. Ketone bodies and glucose in starvation state.

Action of salivary and pancreatic amylases

Random cleavage until you reach limit dextrins (can't digest further with amylase). Limit dextrins: - 4 to 9 glucosyl units, a-1,6 branches. Starch is digested in the mouth by amylase to maltose (maltotriose) and limit dextrin.

Leukocyte adhesion deficiency

Rare autosomal recessive Absence of CD18 (common B2 chain of integrins) Leukocytes cannot migrate from blood into tissues, neutrophila (high number of neutrophils in blood (because they can't migrate out)) Omphalitis (umbilical cord stump swells, infection of umbilical stump) one of the early signs of leukocyte adhesion deficiency. Chronic recurrent bacterial infections No abscess or pus formation

Deficiencies in carnitine or acylcarnitines

Rare due to getting it from diet or synthesized. Synthesized in muscle->liver Most carnitine stored in skeletal muscle Soy-based formulas must be supplemented CPTII deficiency (CoA replaces carnitine in mitochondrial matrix) Causes: -Recurrent acute myoglobinuria episodes -Muscle pain and weakness Precipitated by prolonged fasting, exercise -Adolescents/adults Mild hypoglycemia, hypoketosis, Lipid deposits in muscles -Infants Severe hypoglycemia, hypoketosis, Hepatomegaly, Cardiomyopathy

Glycemic index

Rate of absorption. Low glycemic foods are digested more slowly resulting in fewer spikes in blood sugar- better for diabetics.

What is the rate limiting step of pentose phosphate pathway? What is it inhibited by?

Rate-limiting step is Glucose-6-P dehydrogenase Feedback inhibited by NADPH

What is the evidence for Mitchell hypothesis?

Reconstituted vesicles containing ATP synthase and bacteriorhodopsin used by Stoeckenius and Racker to confirm the Mitchell chemiosmotic hypothesis.

Metabolism of lipids in liver disease

Reduced levels of LCAT (made by liver) - LCAT esterifies cholesterol in the blood. - When reduced levels, more free cholesterol in blood. Reduced levels of LPL, HTGL (peripheral lipases) - Leads to elevated TG in blood Together, decrease in esterified cholesterol (increase in free cholesterol in blood) and increase in TG in blood = abnormal LDL composition. Also, altered HDL2:HDL3 ratio (effects unknown). May have impaired VLDL production with severe liver disease. Elevated NEFA (non-esterified fatty acids) levels - Likely due to reduced basal hepatic glucose output (leading to increased lipolysis)

Anabolism

Reductive, endergonic pathway consuming chemical energy in the form of ATP and using NADPH as source of high energy electrons for reductive purposes. (Consumes energy)

No T tubule system - *Caveolae* -- Cytoplasmic vesicles that deliver Ca2+ *Calmodulin-myosin light chain kinase system* -> activates myosin-actin interaction.

Regulation of Contraction in smooth muscle

Same regulation method as skeletal muscle - Controlling delivery & reuptake of Ca2. *But* in cardiac muscle: - Sarcoplasmic reticulum less organized. -- One T tubule per sarcomere -- *Terminal cisternae & T tubule = "Diad"* ---- *Located @ Z-line*.

Regulation of contraction in cardiac muscle

No sarcomeric arrangement *Dense bodies* - Anchor thin filaments (~ Z line) - In sarcoplasm near sarcolemma

Regulation of contraction in smooth muscle continued

Ca2+ is required for myosin-actin reaction. - Causes troponin to uncover myosin-binding site on actin 2 key structures in controlling delivery & reuptake of Ca2+: 1. *Sarcoplasmic reticulum* (modified smooth ER) - Network around myofibrils - Forms terminal cisternae (Ca2+ reservoirs) - Deposits: mitochondria and glycogen 2. *T-tubule system* - Invaginations of sarcolemma "Triad" @ A-I junction - 2 T-tubules per sarcomere

Regulation of cross-bridge cycle

What makes IL-10?

Regulatory T cells make IL-10 which shuts down the activation of Th1 cells. These are T cells that didn't make it past selection process and have one last chance to live by becoming regulatory T cells. Regulatory T cells require TGF-B for development. Deficiencies of regulatory T cells result in severe immune dysregulation and autoimmunity.

What is IL-10, what cells secrete it, what is the target cell, and what does it do?

Regulatory cytokine. Secreted by Macrophages and dendritic cells Targets macrophages and dendritic cells. Inhibition of IL-12 production, decreased expression of co-stimulatory molecules, decreased class II MHC expression.

What factors/cells responsible for insulin and glucagon release

Release of insulin from pancreas depends on blood glucose levels as sensed by b-cells in the islets of Langerhans Glucagon released by a-cells in response to reduction of glucose and/or rise in insulin in blood bathing a-cells

What does lipoprotein lipase do?

Releases fatty acids from lipoproteins (chylomicrons, etc.). Lipoprotein lipase use triglycerides as substraces and release fatty acids in the process.

Glutaminase function

Removes N from glutamine to form glutamate in the *liver, kidney, and intestine* -Kidney- NH4+ forms salts with metabolic acids in urine, excreted. -Intestine- Glutamine used as fuel. - Liver- NH4+ used for urea production.

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome polycythemia

Renal carcinoma, cerebellar hemangioma, hepatocellular carcinoma. Erythropoietin

Limited Possible if perichondrium present Blood vessels stimulate bone growth not cartilage repair When hyaline cartilage calcified it is replaced by bone.

Repair of Hyaline Cartilage

*Able to proliferate!* - Maintain or increase number of cells Respond to injury by mitosis - *Hyperplasia* - *Hypertrophy*

Repair of smooth muscle

What would a person with hx of renal colic and cystinuria require?

Requires higher fluid intake, medication to raise urine pH.

Large, round cells found in loose connective tissue. Thin rim of cytoplasm around a large lipid inclusion (unilocular) Nucleus flattened peripherally Primarily *adipocytes* surrounded by reticular fibers Specialized CT for energy homeostasis Adipocytes store energy in form of triglycerides Two types: white adipose and brown adipose.

Resident CT cells: Adipocytes

Fibroblasts: - Synthesize fibers and ground substance of CT - Fusiform cell with elongated nucleus ("pencil mark" in H&E) - *Myofibroblast*: - Characteristics of fibroblasts and smooth muscle cells - Role in wound healing

Resident CT cells: Fibroblasts

Derived from monocytes migrating from bloodstreatm (*Mononuclear phagocyte system* (MPS)) Mediate inflammatory response and phagocytose bacteria, cell debris, etc. - Antigen-presenting cell Difficult to identify without evidence of phagocytosis a. Kidney-shaped nucleus b. Abundant lysosomes c. Irregular plasma membrane Tissue-specific subtypes: - Kupffer cells, alveolar macrophages, langerhans cells, etc. -------------------------- Arrive on the scene ~24 hours after onset of immune response a. M1- chronic inflammation and tissue injury - Activated by IFN-y, TNF-a or LPS - Can form foreign body giant cells/Langhans giant cells (pathological) b. M2- resolution of inflammation and wound repair. - Activated by IL-4, 5, 10, or 13 - Involved in the pathogenesis of allergy and asthma.

Resident CT cells: Macrophages (M stands for macrophage in picture, N for neutrophile, BV for blood vessel)

Derived from hemopoietic stem cells in bone marrow - Related to basophil in blood Differentiate in connective tissue- numerous in skin and mucous membranes (*GI and respiratory tract*) Responsible for allergic reactions Activated by IgE antigen to release granules containing: - Histamine - Heparin - Serine proteases - ECF, NCF - Leukotrienes, TNF-a, *prostaglandin D2, interleukins*

Resident CT cells: Mast cells

What do you do if the fatty acid is odd chain number

Round down so 17 chain fatty acid would be 16. Then you would make 7 NADH, 7 FADH2, and 7 Acetyl Coa. Odd chain fatty acids produce propionyl CoA with the last 3 carbons. That's why you get 1 less acetyl coa with odd chains.

TCA cycle in gluconeogenesis

Runs in reverse, oxaloacetate converted to malate using NADH. Malate is precursor to gluconeogenesis.

Which epigenomic regulatory gene mutation found in 100% of malignant rhabdoid tumor?

SNF5: Nucleosome positioning/chromatin remodeling

Contractile unit (striations) - Shortens = contraction *Myofilaments* (contractile proteins) - *thin filaments* -- *Actin*, tropomyosin, troponin -- Held in place by *Z line* - *Thick filaments* -- *Myosin* -- Held in place by myomesium (*M line*) - Do not change size -> overlap *Dystrophin* protein - Connects cytoskeleton & extracellular matrix.

Sarcomere

Small cuboidal cells with small nuclei Insulation for neuronal cell bodies of *ganglia* - Controls microenvironment Functionally analogous to *Schwann cells* - Insulation (electrical & mechanical) Found in peripheral neuroglia around ganglia.

Satellite Cells (Sat C in picture)

Produce *myelin sheath* - A lipid-rich layer surrounding axons - Functions: -- Isolates axons -- Rapid conduction - *Myelination* -- Cytoplasm pushed out -- Exceptions Surround all PNS axons - Nurture - Clean up debris - Guide regrowth of axons Found in the peripheral neuroglia around axons.

Schwann Cells

What is IFN-a, what cells secrete it, what is the target cell, and what does it do?

Secreted by dendritic cells and macrophages. Targets all cells. Transient inhibition of protein synthesis, increased class I MHC expression and antigen presentation in all cells. Activates NK cells to kill virus-infected cells.

What is IFN-b, what cells secrete it, what is the target cell, and what does it do?

Secreted by fibroblasts. Targets all cells. Transient inhibition of protein synthesis, increased class I MHC expression and antigen presentation in all cells. Activates NK cells to kill virus-infected cells.

What is TGF-b, what cells secrete it, what is the target cell, and what does it do?

Secreted by macrophages, lymphocytes, etc. Anti-inflammatory Causes class switching to IgA.

*Muscle spindle* is *sensative to stretch*/rapidly stretching muscles and when stimulated travels down the *Ia fiber* afferent pathway to stimulate the *alpha motor fiber* in the brain (efferent) which causes contraction of stretching muscle (to prevent further stretching) and relaxation of the antagonist muscle (to allow more stretching) thus preventing injury. *Golgi tendon organ* is tension sensitive and travels down *Ib fibers* and via interneuron in the brain inhibits the *alpha motor fiber* causing relaxation of the muscle and prevents injury. *Gamma motor fiber* controls the muscle spindle from the brain, causes contraction of the muscle.

Sensory innervation

*Proprioception -> Proprioreceptors* - Sense degree of stretching & tension in muscle - Types: -- *Muscle Spindle* -- *Golgi Tendon Organ* *Extrafusal fibers* (muscle fibers) - Innervated by *alpha motor neurons* *Intrafusal fibers* (in muscle spindles) - Innervated by *gamma motor neurons* *Afferent*

Sensory innervation of skeletal muscle *Afferent*

What kind of protease are chymotrypsin, trypsin, and elastase?

Serine protease

What is the most important role of ETC

Set up an H+ gradient

What is an inflammasome?

Signalling system for detection of pathogens and stressors Involves the assembly of a sensor (NLRP-3) and adaptor and the inactive caspase into the inflammasome. The inflammasome activates the caspase which in turn results in the expression of IL-1. The inflammasome results in the production of both IL-1 and IL-18 which are potent inflammatory cytokines.

Glucose uptake in intestine

Since glucose is polar- does not readily cross membrane Facilitated diffusion (glucose transporters): -carry glucose down concentration gradient. Na+ dependent facilitated transport: - Cotransporter - Carry glucose against concentration gradient while Na+ moves down concentration gradient (maintained by Na+/K+ ATPase)

What two cells produce the most lactate?

Skeletal muscle cells and RBCs

Cells *DO NOT DIVIDE* Fibroblasts are the ones that divide and in connective tissue form scar tissue after muscle damage/tear. *Satellite cells* - Outside sarcolemma - Stem cells -> myogenic precursors - Limited regeneration (decreases with aging) - Not seen histologically *Innervation is necessary for muscle integrity* Causes a section of the skeletal muscle to atrophy near the scar tissue which causes the surrounding muscle to hypertrophy to compensate.

Skeletal muscle repair (Won't be responsible for differentiating the satellite cell from the muscle nucleus)

Skeletal vs smooth vs cardiac muscle characteristics

Skeletal: - Striated, multinucleated, long fibers - Attach to skeleton - Voluntary contraction -Different fiber types Smooth: - Not striated, mononucleated - Involuntary contraction Cardiac muscle - Striated, intercalated disks - Involuntary contraction

What are haptens

Small organic molecules that are antigenic not immunogenic, not immunogenic alone. Too small to elicit an immune response but when it binds to a carrier protein it will trigger an immune response. Immunization with hapten-carrier conjugates produces antibodies specific for hapten, carrier, and newly formed sites from conjugation. Multiple haptens hooked to a single carrier, the hapten becomes immunodominant. Many biologically important substances including drugs, peptide hormones, and steroid hormones can function as haptens.

This tumor marker is found in what tumor types? neuron-specific enolase

Small-cell cancer of lung, neuroblastoma

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome SIADH?

Small-cell carcinoma of lung, intracranial neoplasms Antidiuretic hormone or atrial natriuretic hormones

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome Cushing syndrome?

Small-cell carcinoma of lung, pancreatic carcinoma, and neural tumors. ACTH or ACTH-like substance

No striations -> more liable (easily altered) - No *Sarcomeric* arrangement Involuntary muscle -> *Autonomic* control Location: Organs, vessels, glands Arranged in bundles or sheets *Central nuclei* Cells communicate via *gap junctions* Possess myofilaments outside a sarcomere - *Dense bodies* anchor

Smooth muscle characteristics

Left longitudinal section: "Corkscrew" nuclei Fusiform & elongated cells (football-shape) Right cross section: Size variation Smaller Variable # of cells with visible nuclei due to cellular arrangement & plane of sectioning.

Smooth muscle characteristics continued

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome hypercalcemia?

Squamous cell carcinoma of lung, breast carcinoma, renal carcinoma, adult T-cell leukemia/lymphoma. Parathyroid hormone- related protein (PTHRP), TGF-a, TNF, IL-1

Complex carbs

Starch and amylopectin glycogen

Endogenous antigen processing and presentation

Start at the virus in cytoplasm. Making viral peptides within cell. That is way too big to fit into class I molecules. First step is the large viral protein targeted for distruction and enters the proteasome which is a molecular paper shredder. Takes these large proteins and spits them out in 8-10 amino acid pieces. Now it needs to get into the ER which is done by the TAP molecule. Once the peptide binds to the MHC I, the MHC I leaves the ER by budding (fusing to the golgi and gets some modification and then buds off) and goes to the cell surface. *Both TAP (transporter of antigen process) and B2 microglobulin needed for Class I MHC to work at all*

What is the rate limiting step in urea cycle?

Step 1: Carbamoyl phosphate synthetase I (CPSI).

First step: preserve structure. Use *Formalin*, a 37% aqueous solution of formaldehyde (reacts with amino groups of protein, proteins maintain ability to react with specific antibodies), at various dilutions and in combination with other chemicals and buffers, is the most commonly used fixative. 2nd step *Embedding and sectioning*: Preparation for embedding in paraffin to permit sectioning. Infiltration with an *embedding medium* that allows it to be thinly slices. The specimen is *washed* after fixation and *dehydrated* via alcohol in ascending concentration to remove water. In the next step, *clearing*, organic solvents such as xylol or toluol, which are miscible in both alcohol and *paraffin*, are used to remove alcohol before infiltration of specimen w/ melted paraffin. When melted paraffin is cool and hardened, it is trimmed into appropriately sized block. Block is mounted into a designed slicing machine- a microtome* - and cut with steel knife. The resulting sections are then mounted on glass slides using *mounting medium* (pinene or acrylic resins) as an adhesive. 3rd step *Staining*: Paraffin sections are colorless so need to color or stain the tissue sections paraffin is dissolved out, again with xylol or toluol, and slide rehydrated through series of descending alcohol concentration. Tissue is then stained with hematoxylin in water. Specimen is then dehydrated through series of alcohol solutions of ascending concentration (because *eosin* is more soluble in alcohol than water) and then counterstained with *eosin*. ------ After staining, specimen is then passed through xylol or toluol to a nonaqueous mounting medium and covered with a coverslip to obtain permanent preparation.

Steps of *Fixation*, *embedding and sectioning, and *staining*

IL-1 and IL-6 characteristics

Stimulate hematopoiesis (production of neutrophils) Induce the liver to make acute phase proteins (CRP)(C-reactive proteins can be a sign of inflammation) Both are major inflammatory cytokines. IL-1 is found in the inflammasome activated by NLRP-3 IL-6 drives antibody production by acting on plasma cells and can help with antibody switch to IgG

Pyruvate dehydrogenase allosteric regulators

Stimulate- ADP, pyruvate, Ca2+, CoASH, NAD+ Inhibit- Acetyl CoA, NADH

Regulation of ketone body synthesis (stimulate/inhibit)

Stimulate: Increased fatty acids in blood, CPTI, Acetyl CoA. Basically lipolysis (indirectly) Inhibit: Malonyl CoA, ATP. Basically inhibition of beta oxidation in liver.

Insulin stimulate/inhibit in relation to VLDL

Stimulate: synthesis of VLDL, glycogen synthesis, fatty acid synthesis, protein synthesis (Fed/surplus state). Inhibits: glycogen breakdown, fatty acid breakdown, gluconeogenesis.

Pyruvate carboxylase stimulated/inhibited by?

Stimulated by acetyl-CoA

Pyruvate dehydrogenase allosteric regulators

Stimulated by- ADP, Ca2+ Inhibited by- NADH, Acetyl CoA.

Phosphofructokinase-1 allosteric regulators

Stimulated by- AMP and F-2,6-bisP (produced by PFK2- stimulates PFK1 and inhibits gluconeogenesis) Inhibited by- ATP, citrate

Pyruvate kinase allosteric regulators

Stimulated by- F-1,6-bisP. Inhibited by- ATP

Phosphofructokinase-1 stimulated/inhibited by?

Stimulated by: F 2,6 BP AMP Inhibited by: ATP Citrate

Regulation of Isocitrate dehydrogenase

Stimulated by: ADP and CA2+. Inhibited by: NADH

Regulation of a-ketoglutarate dehydrogenase

Stimulated by: Ca2+ Inhibited by: NADH

Pyruvate kinase stimulated/inhibited by?

Stimulated: F 1,6 BP Inhibited: inhibited by ATP, alanine Inhibited by phosphorylation (glucagon and epinephrine lead to an increase in cAMP levels which activates protein kinase A)

Pyruvate regulation of glycolysis and TCA

Stimulates Pyruvate dehydrogenase

Role of AMPK in B-Oxidation

Stimulates b-oxidation. Phosphorylates acetyl CoA carboxylase which inactivates it and prevents the formation of Malonyl CoA (used in fatty acid synthesis for storage, inhibits CPTI) Facilitates GLUT4 recruitment (skeletal muscle)

AMP regulation of glycolysis and TCA (1)

Stimulates: 1. Phosphofructokinase

Fructose-2,6-bisP regulation of glycolysis and TCA (1)

Stimulates: 1. Phosphofructokinase.

ADP regulation of glycolysis and TCA (2)

Stimulates: 1. Pyruvate dehydrogenase 2. Isocitrate dehydrogenase

Fructose 1,6 bisphosphate regulation of glycolysis and TCA (1)

Stimulates: Pyruvate kinase

Where does protein digestion begin?

Stomach with pepsin (pepsinogen (zymogen-inactive precursor)) and HCL

Outer Surface: - *Periosteum* - dense fibrous connective tissue - outer fibrous layer - Inner cellular layer - Periosteal cells - *Sharpey's fibers* Inner surface - *Endosteum* - Endosteal cells - Bone marrow

Structure of bone

What is an adjuvant?

Substances that when mixed with an antigen can enhance immunogenicity. Often used to boost the immune response when Ag has low immunogenicity or when only small amounts of Ag are available. Sometimes used in vaccines. Your innate immune system can gobble up the vaccine so quickly that the adaptive immune system doesn't kick in. Therefore, we bind the antigen with an adjuvant to allow the adaptive immune system to respond.

Which drugs block K+ channels and therefore increase insulin secretion?

Sulfonylureas

A. *Peripheral Neuroglia* i. Schwann Cells ii. Satellite Cells B. *Central Neuroglia* i. Astrocytes ii. Oligodendrocytes iii. Microglia iv. Ependymal Cells

Supporting Cells (Neuroglia)

Specialized junction between neurons - Facilitates transmission of impulses Types: - *Axodendritic* (memory & learning) -- *Dendritic spines* - *Axosomatic* - *Axoaxonic* (+/- transmission) Classifications: I. *Electrical Synapse* II. *Chemical Synapse*

Synapse

Proinsulin synthesized as a what and why

Synthesized as preprohormone, the pre part tags to to the rough endoplasmic reticulum. It is then cleaved to proinsulin and makes its disulfide bridges. Afterwards transported to Golgi apparatus in microvesicles. Once Protease cleave off the C-peptide, the proinsulin turns to insulin.

What are the specific tyrosine kinase for T cell? B cell?

T cell = Zap- 70. B cell = Syk

T cell activation

T cell enter periphery in search of an antigen. 1. Bind to antigen. 2. Binding of co-stimulatory molecules 3. Cytokines released from the APC to the T cell. APCs are the only cells that can present antigens to T helper cells. Has to do with the co-stimulatory molecules present on APCs - APC's express a molecule called B7 that is only constitutively expressed on dendritic cells. - Dendritic cells (only cells that can activate naive T cells) - Macrophages can only activate naive T cells when activated by IFN-y - B cells can activate naive T cells after contact with antigen.

B cell activation

T cell independent antigens (anything except for proteins) - Stimulate B cells directly without T cell help, LPS is a good example, LPS binds to and cross links multiple B cell receptors and activate the B cell so it becomes a plasma cell and starts secreting IgM. - Weaker antibody responses - IgM predominates because there is no T cell help, no class switching to different antibody isotypes. - Higher avidity molecules (more binding sites) induce crosslinking of B cell receptors on B cell surface. - No germinal centers - No class switching - No memory response T cell dependent antigens (proteins) - Require T cell help - CD40 (found on APCs)/CD40L (found on T helper) interaction is essential for class switching (hyper IgM syndrome) - Hyper IgM syndrome is when you have a mutation in CD40L (ligand) and can't class switch, can only have IgM.

Which cell is only activated by APC's?

T helper cells. They are CD4+ and recognize antigen in association with class II MHC (exogenous antigen).

What is the receptor on T cells?

TCR (T-cell receptor) has to have an MHC when reacting with antigen. Class II MHC for T helper cells (exogenous) and class I MHC for T cytotoxic cells (endogenous) CD4 on T helper CD8 on T cytotoxic

What is TNF-a, what cells secrete it, what is the target cell, and what does it do?

TNF-a is a proinflammatory cytokine. Secreted by macrophages. Targets the hypothalamus, endothelial cells, liver, neutrophils, tumor cells, fat and muscle. Hypothalamus: Fever Endothelial cells: increases expression of ICAMs Liver: Stimulates production of acute phase proteins. Neutrophils: activation Tumor cells: apoptosis Fat, muscle: cachexia

What does TLR-4 target?

Targets LPS (lipopolysaccharide) Activation of transcription factors which results in the transcription of cytokines, adhesion molecules, and enzymes that are antimicrobial

What does free energy change depend on?

Temperature and concentration

A tumor composed of cells from more than one germ layer. These tumors can differentiate into virtually any tissue and often contain muscle, nerve, teeth, and hair.

Teratoma

Central Nervous System (CNS) - Brain - Spinal Cord Peripheral Nervous System (PNS) - Cranial, spinal, peripheral nerves -- Specialized nerve endings -*Ganglia* -- Collection of nerve cell bodies outside CNS Under PNS: Sensory (afferent) which synapses with Motor (efferent) Sensory (afferent) - Receive stimuli - Send to CNS Motor (efferent) - Initiate responses - Neural pathways -- *Reflex arcs* Motor is also separated by autonomic (ANS) *Involuntary* and Somatic (SNS) *Voluntary.* Autonomic (ANS) is further divided into Sympathetic *Fight or Flight* and Parasympathetic *Rest and Digest* which signal back and forth with the Enteric system.

The Nervous System

Where do aminopeptidases cleave

The amide bond (scissile bond- covalent peptide bond). Cleaves the bold part (same as exocrine pancreas enzymes). Between the carboxylic acid and the amine (close to N-terminus). Turns peptides to di and tri peptides on brush border. C-C*-*NH ......|| .....O

1. Zone of reserve cartilage 2. Zone of proliferation 3. Zone of hypertrophy 4. Zone of calcified cartilage 5. Zone of resorption

The distinct zones of epiphyseal cartilage (5)

X-linked SCID caused by?

The gamma chain of IL-2 is mutated. Cytokines can't function, the immune system can't function. Causes immunodeficiency.

What are hypervariable regions

The hypervariable regions are 3 distinct regions on the variable chain flanked by framework regions (FR). HVl and HVh constitute the antigen binding site (paratope, part that binds to the epitote) Thus: 2 IgG molecules with different antigen binding specificity will differ at these hypervariable regions.

What are the basic functions of the immune system and its 2 categories?

The immune system is designed to recognize and respond to non self antigens. Also eliminates cells that are diseased, damaged, distressed. Broken down into 2 arms: - Innate - Adaptive The innate immune system takes approximately 1-2 weeks to generate a response, we are born with innate immune system and it doesn't change throughout our lives. Is very limited in terms of specificity. Adaptive immune system is very specific.

What are epitopes

The immunologically active regions of an immunogen (antigen). T cell receptors and antibodies don't recognize an entire molecule but rather just its epitopes. B and T cells recognize different epitopes on the same antigenic molecule.

Pathologists may be asked to immediately evaluate tissue obtained during surgery, especially when instant pathologic diagnosis may determine how the surgery will process. This evaluation is called a *frozen section*. *Frozen section* is requested by a surgeon when no preoperative diagnosis was available or when unexpected intraoperative findings must be obtained. In addition, surgeon may want to know whether all of a pathologic mass within the healthy tissue limit has been removed and whether the margin of the surgical resection is free of diseased tissue. Also used during procedures such as endoscopy or thin-needle biopsy to confirm whether the obtained biopsy material will be usable in further pathologic examinations. --------------------------- Step 1: *Freezing the tissue sample*: Small tissue samples are frozen either by using compressed carbon dioxide or by immersion in a cold fluid (isopentane) at a temperature of -50°C. Freezing can be achieved in a special high-efficiency refrigerator. Freezing makes the tissue solid and allows sectioning with a microtome. Step 2: *Sectioning the frozen tissue*: Sectioning is usually performed inside a cryostat, a refrigerated compartment containing a microtome. Because the tissue is frozen solid, it can be cut into extremely thin (5 to 10 micrometers) sections. The sections are then mounted on glass slides. Step 3: *Staining the cut sections*: Staining is done to differentiate cell nuclei from the rest of the tissue. The most common stains used for frozen sections are H&E, methylene blue, and PAS stains. Entire process takes ~10 minutes.

The need for rapid histological examination of surgical biopsy specimens and the steps involved in obtaining microscope slides from such samples

Lymphoid cells

There are 10^10-10^12 lymphocytes in human body Continuously circulate in the blood and lymph Can't be differentiated based on morphology. Can't tell a T cell vs a B cell just by looking at it. B/T cells that have not yet come in contact with antigen are NAIVE, small (6μm) lymphocytes (resting cells in G0). They become activated once coming into contact with antigen and can then differentiate, etc. When contact Ag (antigen), progress from G0 - G1 then S, G2, M, enlarge to 15 μm and eventually differentiate into memory and effector cells.

How are inflammasomes made and what do they do

They are made when NLRP-3 binds with adaptor protein and inactive caspase-1 to form an NLRP-3 inflammasome. This inflammasome then activates Caspase-1 which cleaves/activates IL-1 and IL-18 from pro to active form. IL-1 and IL-18 are responsible for inflammation.

What do C3a and C5a do?

They cause degranulation of mast cells and basophils without IgE and play a major role in the inflammatory response causing increase in vascular permeability. C5a is a major chemotactic protein that recruits cells to come into an area of inflammation. They also stimulate phagocytosis.

Which cells do NK cells target?

They kill cells that have decreased MHC class I expression (virus infected or cancer cells). Have an inhibitory receptor and an activating receptor, inhibitory receptor trumps activating receptor. Inhibitory receptor recognizes class I MHC receptors on cells.

Delayed Type Hypersensitivity Reaction

This is the immune systems way to deal with facultative intracellular pathogens like listeria, mycobacterium, toxoplasma, and leishmania. The release of cytokines like IFN-y from Th1 cells activates macrophages. Activated macrophages release around them toxic stuff like ROS (h202, O2-), nitric oxide, and TNF-a to kill the surrounding cells. Very nonspecific way to kill these pathogens but with collateral damage.

Heavy chain/light chain rearrangement steps.

This rearrangement only happens in the variable regions of B cells and T cells. 1. Heavy chain rearrangement is always first. An enzyme called recombinase which is made by RAG I and RAG II (recombination activating gene) and only expressed by B and T cells comes in and splices the areas between the heavy chains D and J, then it takes a V segment and does the same thing. Recombinase grabs different segments every time. The constant region is not touched! Once a good heavy chain is made, the light chain starts rearranging. 2. Light chain rearrangement lacks D segments and it is going to be either kappa or lambda depending on which chromosome starts the rearrangement. Follows the same steps using recombinase as heavy chain, needs RAG I and RAG II. After a good light chain made it combines with the heavy chain. *Tdt (terminal deoxynucleotide transferase) inserts random nucleotides into this rearrangement before the recombinase sealed it up. Adds to the diversity.* Only heavy chains of B cells, light and heavy of T cells. T cell receptors do the same thing only the beta chains are the heavy chains. The alpha chains are the light chains. If there is no recombinase due to mutation of RAG I or RAG II then you can't have B or T cell receptors, get SCID (severe combined immunodeficiency).

1. Basement membrane 2. Cell polarity a. Free surface (apical) (except in epithelioid tissues) b. Lateral domain c. Basal domain 3. Closely apposed and adhered to each other.

Three main features of epithelial tissue?

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome red cell aplasia?

Thymic neoplasms Unknown

What is the main job of eosinophils

To eliminate parasites like worms. Can also cause allergies but basophils come before eosinophils in allergic response.

Why phosphorylate glucose?

To keep it in the cell and commit it to metabolism.

Where do nascent chylomicrons go?

To liver and blood stream

What is NADPH, made from pentose phosphate pathway, used for in RBCs? What arises from deficiency?

To make reduced glutathione (antioxidant). Deficiency in Glucose-6-Phosphate dehydrogenase leads to formation of heinz bodies and hemolysis.

What is the clinical significance of C-peptide?

To measure insulin release in blood. Represents how much insulin is made.

Why form lactate?

To regenerate NAD+ and keep glycolysis going.

What are the phagocyte receptors?

Toll receptors: CD14, TLR-4 (LPS receptor) NOD receptors RIG receptors CR3, CR4 complement receptors

What reactions remove N from amino acids?

Transamination reactions, occurs in almost all amino acids. Requires PLP (pyridoxal phosphate- from vitamin B6) as cofactor. These amino acids transfer their NH3+ group to a-ketoglutarate (which forms glutamate in the process) to form their corresponding a-keto acid (example aspartate -> oxaloacetate) Is a reversible reaction. Adds or removes NH3+.

Cystinuria

Transport of amino acids defect. Disorder caused by defective transport proteins; cysteine is not adequately resorbed from glomerular filtrate, insoluble cys form renal calculi (kidney stones). Limit protein intake (especially methionine) to treat

What are major components of chylomicrons?

Triglycerides (80-85%)

The primary type of lipids found in diet are?

Triglycerides.

Which enzyme in glycolysis produces NADH?

Triose phosphate dehydrogenase

Which enzyme creates 2 NADH in glycolysis

Triose phosphate dehydrogenase.

This tumor marker is found in what tumor types? human chorionic gonadotropin

Trophoblastic tumors, nonseminomatous testicular tumors.

SMAD2, SMAD4 Mode of activation in tumor, and associated human tumor?

Tumor Suppressor gene SMAD2, SMAD4 Function: Component of the TGFB signaling pathway, repressors of MYC and CDK4 expression, inducers of CDK inhibitor expression Familial syndromes: Juvenile polyposis Sporadic cancers: Frequently mutated (along with other components of the TGFB signaling pathway) in colonic and pancreatic carcinoma. (Inhibitors of Mitogenic Signaling Pathways)

PTCH Mode of activation in tumor, and associated human tumor?

Tumor suppresor gene Patched Function: inhibitor of hedgehog signaling. Familial syndromes: Gorlin syndrome (basal cell carcinoma, medulloblastoma, several benign tumors). Sporadic cancers: Basal cell carcinoma, medulloblastoma. (inhibitors of mitogenic signaling pathnways)

CDKN2A Mode of activation in tumor, and associated human tumor?

Tumor suppression genes p16/INK4a and p14/ARF Function: P16- negative regulator of cyclin-dependent kinases. P14- indirect activator of p53. Familial syndromes: Familial melanoma Sporadic cancers: Pancreatic, breast, and esophageal carcinoma, melanoma, certain leukemias. (Inhibitors of cell cycle progression)

What is the main function of RB?

Tumor suppressive "pocket" protein that binds E2F transcription factors in its hypophosphorylated state preventing G1/S transition; also interacts with several transcription factors that regulate differentiation.

What is the main function of P53

Tumor suppressor altered in the majority of cancers; causes cell cycle arrest and apoptosis. Acts mainly through p21 to cause cell cycle arrest. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. Levels of p53 are negatively regulated by MDM2 through a feedback loop. P53 is required for the G1/S checkpoint and is a main component of the G2/M checkpoint.

APC Mode of activation in tumor, and associated human tumor?

Tumor suppressor gene Adenomatous polyposis coli protein. (Gardner syndrome) Function: inhibitor of WNT signaling. Familial syndromes: Familial colonic polyps and carcinomas. Sporadic cancers: Carcinoma of stomach, colon, pancreas; melanoma. (Inhibitors of mitogenic signaling pathways)

NF2 Mode of activation in tumor, and associated human tumor?

Tumor suppressor gene Merlin Function: Cytoskeletal stability, Hippo pathway signaling. Familial syndromes: Neurofibromatosis type 2 (acoustic schwannoma and meningioma). Sporadic cancers: Schwannoma, meningioma.

NF1 Mode of activation in tumor, and associated human tumor?

Tumor suppressor gene Neurofibromin-1 Function: Inhibitor of RAS/MAPK signaling. Familial syndromes: Neurofibromatosis type 1 (neurofibromas and malignant peripheral nerve sheath tumors). Sporadic cancers: Neuroblastoma, juvenile myeloid leukemia. (inhibitor of mitogenic signaling pathways)

PTEN Mode of activation in tumor, and associated human tumor?

Tumor suppressor gene Phosphatase and tensin homologue Function: Inhibitor of PI3k/AKT signaling Familial syndromes: Cowden syndrome (variety of benign skin, GI, and CNS growths; breast, endometrial, and thyroid carcinoma). Sporadic cancers: Diverse cancers, particularly carcinomas and lymphoid tumors. (Inhibitors of mitogenic signaling pathways).

VHL Mode of activation in tumor, and associated human tumor?

Tumor suppressor gene Von Hippel Lindau (VHL) protein Function: Inhibitor of hypoxia-induced transcription factors (e.g., HIF1a). Familial syndromes: Von hippel lindau syndrome (cerebellar hemangioblastoma, retinal angioma, renal cell carcinoma.) Sporadic cancers: Renal cell carcinoma. (Inhibitors of "pro-growth" Programs of metabolism and angiogenesis).

TP53 Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes P53 protein Function: Cell cycle arrest and apoptosis in response to DNA damage. Familial syndromes: Li-fraumeni syndrome (diverse cancers) Sporadic cancers: Most human cancers. (Enablers of genomic stability)

BRCA1, BRCA2 Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes Breast cancer-1 and breast cancer-2 (BRCA1 and BRCA2) Function: Repair of double-stranded breaks in DNA. Familial syndromes: Familial breast and ovarian carcinoma; carcinomas of male breast; chronic lymphocytic leukemia (BRCA2). Sporadic cancers: rare (DNA repair factors)

CDH1 Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes E-cadherin Function: Cell adhesion, inhibition of cell motility. Familial syndromes: Familial gastric cancer. Sporadic cancers: Gastric carcinoma, lobular breast carcinoma. (Inhibitors of invasion and metastasis).

STK11 Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes Liver kinase B1 (LKB1) or STK11 Function: Activator of AMPK family of kinases; suppresses cell growth when cell nutrient and energy levels are low. Familial syndromes: Peutz-Jeghers syndrome (GI polyps, GI cancers, pancreatic carcinoma, and other carcinomas.) Sporadic cancers: Diverse carcinomas (5-20% of cases, depending on type). (Inhibitors of "pro-growth" Programs of Metabolism and Angiogenesis)

MSH2, MLH1, MSH6 Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes MSH1, MLH1, MSH6 Function: DNA mismatch repair. Familial syndromes: Hereditary nonpolyposis colon carcinoma (lynch syndrome). Sporadic cancers: Colonic and endometrial carcinoma. (DNA repair factors)

MEN1 Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes Menin Function: Transcription factor Familial syndromes: Multiple endocrine neoplasia-1 (MEN1; pituitary, parathyroid, and pancreatic endocrine tumors).

RB Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes Retinoblastoma (RB) protein Function: Inhibitor of G1/S transition during cell cycle progression Familial syndromes: Familial retinoblastoma syndrome (retinoblastoma, osteosarcoma, other sarcomas). Sporadic cancers: Retinoblastoma; osteosarcoma, carcinomas of breast, colon, and lung. (Inhibitors of cell cycle progression)

SDHB, SDHD Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes Succinate dehydrogenase complex subunits B and D Function: TCA cycle, oxidative phosphorylation. Familial syndromes: Familial paraganglioma, familial pheochromocytoma. Sporadic cancers: Paraganglioma. (Inhibitors of "pro-growth" programs of metabolism and angiogenesis.)

WT1 Mode of activation in tumor, and associated human tumor?

Tumor suppressor genes Wilms tumor-1 (WT1) Function: transcription factor. Familial syndromes: Familial wilms tumor (kidney cancer/nephroblastoma). Sporadic cancers: Wilms tumor, certain leukemias. (Unknown mechanisms)

Glutaminase

Turns glutamine to glutamate in the kidneys producing NH4+ in the process to be directly excreted in the urine (instead of turned into urea and then excreted). Turns glutamine to glutamate in liver to make urea. Glutamine used as energy in intestines.

Type 1 vs type 2 vs MODY diabetes

Type 1: -Autoimmune destruction of b-cells -Almost undetectable [insulin] in blood Type 2 (insulin resistant) -Skeletal muscle and liver "resist" action of insulin -Insulin level can be normal in these patients MODY (maturity onset diabetes of the young) -decreased glucokinase activity -requires ↑ [glucose] to cause ↑ [ATP] therefore insulin release only at ↑ [glucose]

Type I fibers vs Type IIA vs Type IIB

Type I fibers: Slow-twitch (slow speed of contraction) Slow-oxidative (low glycogen content) High myoglobin content (appear red). Small fiber diameter Increased concentration of capillaries surrounding muscle (greater oxygen delivery) High capacity for aerobic metabolism High resistance to fatigue Used for prolonged aerobic exercise. Type IIA: Intermediate-twitch (fast speed of contraction) Fast-oxidative glycolytic fibers (intermediate glycogen levels) High myoglobin content (appear red) Intermediate fiber diameter Increased oxidative capacity on training Intermediate resistance to fatigue. Type IIB: Fast-twitch (fast speed of contraction) Fast-glycolytic (high glycogen content) Low myoglobin content (appear white) Large fiber diameter Limited aerobic metabolism, low mitochondrial content. More sensitive to fatigue compared with other fiber types Least efficient use of energy, primarily glycolytic pathway. Used for sprinting and resistance tasks.

1. *Hyaline*- Type II collagen - Fetal skeleton, synovial joints, cartilages of nasal cavity, costal cartilages, and tracheal rings. 2. *Elastic*- Elastic fibers - External ear, external acoustic meatus, epiglottis 3. *Fibrocartilage*- Type I collagen - Intervertebral discs, pubic symphysis, articular discs.

Types of cartilage (3)

I. *Motor (efferent) Neurons*: - CNS/ganglia -> cells - Voluntary & Involuntary impulses II. *Sensory (afferent) Neurons*: - Receptor -> CNS - Pain, temperature, touch, pressure, & proprioception III. *Interneurons (intercalated neurons) - Between sensory & motor

Types of neurons

Which 2 amino acids can sometimes be considered essential?

Tyrosine and cysteine are conditional nonessential because essential amino acids phenylalanine (makes tyrosine) and methionine (makes cysteine) needed to synthesis in the body.

Urea cycle and pyrimidine synthesis related how?

Urea cycle defect in OTC (Ornithine transcarbamylase deficiency) defect (mitochondria enzyme 2) results in accumulation of carbamoyl phosphate, which means some ends up in cytosol where it is available to enzymes in pyrimidine synthesis pathway, leading to increased orotate production (which ends up in urine). This is different from hereditary orotic aciduria.

NAD+ and FAD+ used for?

Used as electron carriers that capture electrons from oxidized fuel. NAD+ picks up electrons as H:- (hydride anion), whereas FAD+ can pick up free radicals (H●). Both reduced to NADH and FADH2 respectively.

Ketone bodies

Used by brain in prolonged fast, muscles in brief fasting (stop after 3 days). Not used at all by liver (synthesized by liver). Ketone bodies are converted to 2 acetyl coA to be used in TCA cycle. So b-oxidation makes acetyl coa which goes into liver to make ketones. Ketones can then travel in blood to tissues and once inside the cells get converted back into acetyl coa and used in TCA cycle.

Triglycerides transported in blood via?

VLDL and chylomicrons

VLDL vs chylomicrons transport

VLDL transports endogenous lipids. Chylomicrons transport exogenous lipids (dietary lipids)

Major forms of underlying cancer and casual mechanism behind the paraneoplastic syndrome nephrotic syndrome

Various cancers Tumor antigens, immune complexes.

TCR (T cell receptor) vs B cell receptor rearrangement

Very similar. Heavy chain in B cells = Beta chain in T cells Light chain in B cells = alpha chain in T cells. Both heavy/beta have V,D,J and are the first ones to rearrange. Both Light/alpha have V and J and second to rearrange. T cells have multiple D segments, B cell only 1 D segment. Tdt is active during both beta and alpha chain rearrangement in T cells, only Heavy chain rearrangement in B cells.

How do (NADH) electrons from glycolysis reach the inner mitochondrial space?

Via Malate shuttle. Oxaloacetate picks up the H and turns to malate then malate travels to the electron transport chain and drops off the H to NAD+ (which turns to NADH) and in turn (malate) converts back into oxaloacetate.

How are amino acids absorbed into the intestinal epithelial cell.

Via cotransport of Na+ and amino acids at the brush border. - different carriers, overlapping specificity (different transporters depending on the amino acid). - Bidirectional transport. (Na+/K+ ATPase allows for low intracellular Na+ concentration which allows the cotransport)

How are amino acids transported from epithelial cell to blood (portal vein)

Via facilitated transporter on the serosal side.

How does aspartate provide source of NH4+

Via purine nucleotide cycle in the brain and muscles that convert aspartate to fumarate and release NH4+ in the process to go to urea cycle in liver.

How is alanine formed from other amino acids?

Via transamination reaction with PLP cofactor. In the muscle: Amino acid -> a-keto acid giving its NH3 to a-ketoglutarate in the process and making glutamate. Glutamate then gives the NH3 to pyruvate (pyruvate made via glycolysis) to form alanine. Alanine is then transported in blood to liver to serve as a carbon skeleton to make glucose with the nitrogen group going to urea cycle in liver.

Vimentin marker for

Vimentin is a cytoskeletal protein that is predominantly found in cells of mesenchymal origin, including cells of the musculoskeletal system (i.e., osteoblasts, chondroblasts, fibroblasts, adipocytes, endothelial cells) and cells of lymphatic and circulatory systems. Therefore, immunostaining with vimentin would be positive for mesenchymal tumors such as sarcomas. Sarcomas typically resemble the tissue of origin on histology (e.g., adipocytes in liposarcoma). This image shows monomorphic cells arranged in a rosette pattern characteristic of a carcinoid tumor. Since it is not of mesenchymal origin, it would not stain with vimentin.

What is the associated neoplasm and etiologic agent in lichen sclerosis

Vulvar squamous cell carcinoma

I. Neurons II. Supporting Cells (Neuroglia) III. Extracellular Matrix

What 3 things makes up the composition of nerve tissue?

Epithelial cells that lack a free surface. Is typically seen in most endocrine glands such as the interstitial cells of Leydig in the testis, the lutein cells of the ovary, the islet of Langerhands in the pancreas, the parenchyma of the adrenal gland, and the anterior lobe of the pituitary gland. Epithelioreticular cells of the thymus also may be included in this category. Epithelioid patterns are also formed by accumulations of connective tissue macrophages in response to certain types of injury and infections as well as by many tumors derived from epithelium.

What are epithelioid tissues?

Most slides seen with light microscope are formalin-fixed, paraffin-embedded, hematoxylin and eosin (H&E)- stained specimens.

What are most slide sets given to each student to study with the light microscope consistent of?

Tissues are composed of cells, organs are composed of multiple tissue types.

What are organs composed of?

Actin filaments

What are stereocilia and microvilli made of

1. Occluding junctions 2. Anchoring Junctions 3. Communicating junctions

What are the 3 junctional complexes between epithelial cells?

Lateral interdigitations between the two cells.

What are the arrows pointing to?

Terminal bar- junctional complexes that attach adjacent epithelial cells on their lateral surfaces: the Zonula Occludens, Zonula Adherens, Macula Adherens and Gap Junctions.

What are the arrows pointing to?

Cuboidal

What are the deeper layers of epithelium typically (cell type).

Chondrosarcomas. Slow growing Found in the axial skeleton Hyaline cartilage infiltrates bone marrow Rarely metastasize.

What are the second most common matrix producing tumors of bone?

H-band gets smaller. I- band gets smaller. Z lines get closer together. A band doesn't change. M band, M line doesn't move.

What changes size during skeletal muscle contraction?

Hematoxylin alone = blue Eosin alone = red H&E = purple

What color is hematoxylin and eosin (H&E) staining

Connective tissue underlies or supports the other three basic tissues (Epithelium, Muscle, and Nerve), both structurally and functionally. *Connective tissue is characterized by its extra-cellular matrix* Examples of connective tissue include bone, cartilage, blood, fat, bone marrow, and lymphoid tissue

What does connective tissue do and examples of connective tissue?

Mesoderm: Torso and limbs Neuroectoderm (neural crest) for head.

What gives rise to connective tissue?

Mesoderm: vascular endothelium. Endoderm: epithelium of structures derived from yolk sac (gut, airway) Ectoderm: epidermis, ependyma (thin membrane of glial cells lining the ventricles of the brain and the central canal of the spinal cord.)

What gives rise to epithelium?

Mesoderm

What gives rise to muscle

Neuroectoderm

What gives rise to nerve

(Basophil) Histamine and Heparin

What is contained in the granules?

A reversible conversion of one mature epithelial cell type to another mature epithelial cell type. Metaplasia is generally an adaptive response to stress, chronic inflammation, or other abnormal stimuli. The original cells are substituted by cells that are better suited to the new environment and more resistant to the effects of abnormal stimuli. Metaplasia results from reprogramming of epithelial stem cells that changes the patterns of their gene expression. Most common type: columnar to squamous- occurs in glandular epithelium, columnar cells replaced by stratified squamous epithelium. Squamous metaplasia occurs in pseudostratified respiratory epithelium of the trachea and bronchi in response to prolonged exposure to cigarette smoke. Also in cervical canal in women with chronic infections (simple columnar replaced by stratified squamous nonkeratinized epithelium). Squamous-to-columnar: Gastroesophageal reflux (Barrett's esophagus), stratified squamous nonkeratinized epithelium of lower part of esophagus can undergo metaplstic transformation in an intestinal-like simple columnar epithelium containing goblet cells If abnormal stimuli persists for a long time, squamous metaplastic cells may transform into squamous cell carcinoma. Cancers of the lungs, cervix, and bladder often originate from squamous metaplastic epithelium. Squamous columnar epithelium may give rise to glandular adenocarcinomas.

What is epithelial metaplasia?

Chondrocytes and 3 major classes of molecules Collagen Proteoglycans - Contribute to the ground substance - GAG's Multiadhesive glycoproteins - Fibronectin Water

What is hyaline cartilage matrix composed of?

Elastic materials, reticular fibers, basement membranes, and lipids.

What is not seen on H&E stain?

Cilia BB stands for basal bodies C for cilia

What is the apical modification?

Microvilli

What is the apical modification?

Black arrow: Epithelium Red arrow: Connective tissue Epithelium lines the GI

What is the black arrow? Red arrow?

Support, protection, hematopoiesis stem cells, and calcium homeostasis

What is the purpose of bone?

NADH-TR stain The deeply stained, smaller muscle fibers exhibit strong oxidative enzyme activity and correspond to the type I slow oxidative fibers. The lighter staining, larger fibers correspond to the type IIb fast glycolytic fibers. *Stains mitochondria*

What is this stained with ?

ATPase stain The darkest ones are type I, the lightest ones are type IIb

What is this stained with?

Simple columnar epithelial tissue

What is this tissue

Stratified squamous epithelial tissue

What is this tissue

Stratified squamous

What kind of cells found in keratinized skin?

Bone (connective tissue)

What kind of tissue is this?

Ciliated pseudo-stratified simple columnar epithelial tissue

What kind of tissue is this?

Dense connective tissue

What kind of tissue is this?

Fat (connective tissue)

What kind of tissue is this?

A. Skeletal muscle B. Cardiac muscle C. Smooth muscle

What kind of tissue is this? A, B, and C?

A. Gray matter (nervous tissue, spinal cord). B. Ganglion (nervous tissue) C. Nuclei in neuron axons (nervous tissue).

What kind of tissue is this? A, B, and C?

Has a free surface, basal lamina, and specialized cell to cell junctions. Covers surfaces, lines cavities, and forms glands. Upper left: H&E stained section showing a pancreatic duct lined by a single layer of contiguous cuboidal epithelial cells. Lower left: An H&E stained section showing the wall of the esophagus lined by stratified squamous epithelium. Upper right: An H&E stained section showing a single layer of tall columnar epithelial cells lining the gallbladder.

What makes epithelium special? Identify the upper left, lower left, and upper right pictures.

A. Hematoxylin only B. Eosin only C. Hematoxylin and Eosin

What stain is A, B, C?

ATPase stain and NADH-TR stain (stains mitochondria)

What stains do you use to see the 3 fiber types of skeletal muscle?

Van Gieson

What stains for collagen?

Pancreatitis

When enzymes secreted by pancreas (which should only be in GI tract) end up in blood. That's why you can find pancreatic lipase/amylase on blood tests. Can be caused by alcoholism

In diabetes, how does sorbitol and galactitol play a role in cataracts and peripheral neuropathy?

When glucose is high- the polyol pathway is pushed forward in the eye. The conversion of Glucose to Fructose is slow so increasing Sorbitol and galactitol (the intermediates) concentration leads to increased intraocular pressure. also, accumulation of sorbitol and galactitol (galactose to fructose) in muscle and nerve may contribute to peripheral neuropathy in diabetics.

How is hormone-sensitive lipase controlled.

When in a fasting/energy demanding (exercise) state- low insulin/high glucagon stimulates ATP -> cAMP which then phosphorylates (activates) protein kinase A. Protein kinase A activates hormone sensitive lipase which releases FA from adipose tissue into the blood

Co-expression of IgM and IgD on the same cell

When rearranged VDJ, mu is the very first heavy chain region that is on that chromosome that is why we always make IgM first. When you make IgD you use the same variable region but you essentially alternative splice and get IgD but you have the exact same variable region (haven't utilized a different polyadenylation signal) but different constant regions and that's as far as we can go until we come in contact with antigen. If you told me you found B cell in the periphery and it is expressing IgG, it is probably not a naïve cell prob memory cell because naïve cell that has never seen antigens only express IgM and IgD.

What what seen in mice when PPARa gene was knocked out?

Whenever fasting or on high fat diet- developed fatty livers, hypoglycemia, and hypoketosis. Used reverse transcription-PCR to ensure the gene was knocked out.

Mucous membrane: lines those cavities that connect with the outside of the body, namely, the alimentary canal, the respiratory tract, and the genitourinary tract Serous membrane: serosa, lines the peritoneal, pericardial, and pleural cavities

Where are mucous and serous membranes found?

Osteocytes reside in lacunae. Lacunae contain osteocytes.

Where do osteocytes reside?

The osteocyte extends processes into canaliculi (small tunnels) to communicate with adjacent lacunae

Where do the osteocytes extend their processes into in order to communicate with adjacent lacunae

Trachea and bronchial tree Ductus deferens Efferent ductules of epididymis

Where is pseudostratified found?

Small intestine and colon Stomach lining and gastric glands Gallbladder

Where is simple columnar found?

Small ducts of exocrine glands Surface of ovary (germinal epithelium) Kidney tubules Thyroid follicles

Where is simple cuboidal found?

Vascular system (endothelium) Body cavities (mesothelium) Bowman's capsule (kidney) Respiratory spaces in lung

Where is simple squamous found?

Epididymis and proximal part of ductus deferens (male reproductive system). Sensory (hair) cells of the inner ear.

Where is stereocilia found

Largest ducts of exocrine glands Anorectal junction

Where is stratified columnar found?

Sweat gland ducts Large ducts of exocrine glands Anorectal junction

Where is stratified cuboidal found

Epidermis Oral cavity and esophagus Vagina

Where is stratified squamous found?

Renal calyces Ureters Bladder Urethra

Where is transitional epithelium found?

1. Prolonged activity (endurance) Type I 2. Strength and power Type IIb 3. Strength and endurance Type IIa

Which fiber is prevalent in: 1. Prolonged activity (endurance) 2. Strength and power 3. Strength and endurance

Connective tissue: Mesoderm for torso and limbs - Benign tumors are fibroma, lipoma, chondroma, osteoma - Malignant tumors are -sarcomas Neuroectoderm (neural crest) for head.

Which germ layer can connective tissue tumors derive from?

Epithelium: Mesoderm- vascular endothelium - Benign tumors are -angiomas - Malignant tumors are -sarcomas Endoderm- epithelium of structures derived from yolk sac (gut, airway) - benign tumors are papilloma/adenomas - Malignant tumors are carcinomas Ectoderm- epidermis, ependyma - benign tumors are papilloma/adenomas - Malignant tumors are -carcinomas

Which germ layer can epithelium tissue tumors derive from?

Muscle: Mesoderm - Benign tumors are -myomas - Malignant tumors are -myosarcomas

Which germ layer can muscle tumors derive from?

Nerve: Neuroectoderm

Which germ layer can nerve tumors derive from?

Left picture is normal. Normal because it is myelinated. Right picture is demyelinated and can be found in diseases like Guillain-Barre syndrome.

Which is normal? Why is it normal? How does the difference effect the patient?

Energy storage, insulation, and cushioning for vital organs Few mitochondria, few blood vessels, limited sympathetic innervation *Locations*: a. Subcutaneous tissue b. Breast c. Abdominal cavity d. Bone marrow Adipocytes synthesize and secrete hormones, growth factors, and cytokines: - *Leptin* - Angiotensinogen - Adiponectin - Resisten - Steroid hormones

White adipose tissue

What is hyper-IgM syndrome?

X-linked failure to express CD40L on T helper cells. Is a T cell mutation but a B cell deficiency disease. IgM levels up to 10 times normal Deficiency of IgG, IgA, IgE (would still have IgD) Fail to make germinal centers Recurrent respiratory infections

Xenobiotic detoxication by the liver pathway

Xenobiotic or waste metabolite in the diet or peripheral circulation (RH) ---> Phase I reactions (Introduce/expose reactive groups for use in phase 2, includes reduction, oxidation, hydroxylation, hydrolysis) --> (primary metabolite) Phase II reactions (conjugate a negatively charged group to promote excretion, includes conjugation, sulfation, methylation, glucuronidation) --> (secondary metabolite, suitable for excretion)

Xenobiotics for excretion simple pathway

Xenobiotics enter, ligand send signals to nucleus for transciption of enzymes and transporters. Xenobiotics -> phase 1 oxidation enzymes -> phase 2 conjugation enzymes -> phase III elimination via transporters using ATP.

Couples the actin cytoskeleton to the plasma membrane at regions of cell-cell adhesion Major link protein: E-cadherin-catenin complex Cytoskeleton components: Actin filaments

Zonula adherens (Anchoring junction)

FA released into blood transported on?

albumin

What is the protein component of VLDL

apoB100

Most important control point for gluconeogenesis regulation?

between fructose 6 phosphate and fructose 1,6 BisPhosphate Insulin stimulates phosphofructokinase-1 (glycolysis) and inhibits fructose 1,6 bisphosphatase (gluconeogenesis) Glucagon stimulates fructose 1,6 bisphosphatase (gluconeogenesis) and inhibits phosphofructokinase 1 (glycolysis) (Insulin also stimulates glucokinase (glycolysis) and inhibits glucose 6-phosphatase (gluconeogenesis) - Glucagon does the opposite.

Essential fructosuria

deficiency of fructokinase benign genetic disorder

Which enzyme reactions are nad and fad found in

dehydrogenase reactions

What is the associated neoplasm and etiologic agent in reflux esophagitis, barrett esophagus

esophageal carcinoma gastric acid

Name 3 places iron is found (iron deficiency anemia)

iron is found in hemoglobin, TCA cycle enzymes, ETC complexes

Where is urea made, where most of the urea cycle enzymes active?

liver

This tumor marker is found in what tumor types? catecholamine and metabolites

pheochromocytoma and related tumors

This tumor marker is found in what tumor types? prostatic acid phosphatase

prostate cancer

Ketogenic diet can be used to treat what in children?

pyruvate dehydrogenase (PDH) deficiency.

What do anaplerotic reactions do?

replenish TCA cycle intermediates

Whats used in anaerobic metabolism to convert pyruvate to lactate?

the 2 NADH which were made earlier in glycolysis.

Isozymes

two or more enzymes with identical function but different structure

How many ATP made in ETC

~28


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