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The important bit of meiosis

The important bit of meiosis. Cells divide twice First step is essentially mitosis but then they divide again First time there is replication so you end up with a normal number of chromosomes after division – you have 46 pairs which is reduced to 23 pairs

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The important bit of meiosis

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  1. The important bit of meiosis • Cells divide twice • First step is essentially mitosis but then they divide again • First time there is replication so you end up with a normal number of chromosomes after division – you have 46 pairs which is reduced to 23 pairs • From the second division there are now half the number of chromosomes -23 left • Things can go wrong with either step – termed meiosis I and II

  2. Nondisjunction in Meiosis I Paired chromosomes fail to separate. Nondisjunction in Meiosis II Sister chromatids fail to separate.

  3. Monosomy? • Turner’s (XO) • AutosomalTrisomy? • Down’s (Trisomy 21) • Chromosome 21 has a small amount of info on it thus this is compatible with life (also 13,18) • Sex chromosome trisomy • Klinefelters (XXY)

  4. Other genetic abnormalities? • Translocation (Chronic Myeloid Leukemia) • Chromosomes mingle when the meet which can cause errors • Triplet repeats (Huntington’s) • Excess repeats create too much protein e.g. glutamine • Substitution (Sickle cell) • AT subsitution results in abnormal cells • Insertion (Muscular Dystrophy)

  5. What are the 5 pedigrees? • Autosomal Dominant • Autosomal Recessive • X-linked Dominant • X-linked Recessive • Y-linked

  6. Deciphering pedigrees • Look if both sexes equally effected • If no… look if it skips a generation • If it skips a generation, it’s X linked recessive • If not, it’s X linked dominant (affected males don’t have affected sons) • If yes… its autosomal • Look at chances of getting the disease from a diseased parent • ½ = dominant • ¼ = recessive

  7. X-linked dominant • Sex differences • No affected males have affected sons • 1:1 ratio of affected:unaffected daughters

  8. Pedigrees • Autosomal Dominant • BOTH SEXES EQUALLY AFFECTED • Unaffected  normal offspring • Affected  1:1 affected:non affected

  9. Autosomal Recessive • BOTH SEXES EQUALLY AFFECTED • Affected individuals usually produce normal (carrier) offspring

  10. X-linked Recessive • Only males effected (pretty much) • Skips a generation

  11. Y-linked • Exclusively affects males • Effected males ALWAYS produce effected males

  12. Complications • (Should probably know two) • Mosaicism • Late onset • Incomplete penetrance • Mitochondrial inheritance

  13. A and a are alleles. p and q are frequencies. A (p) a (q) A (p) AA (p2) Aa (pq) a (q) Aa (pq) aa (q2) Hardy-Weinberg principle Population with an autosomal gene with two alleles (A and a). Frequency of wild type allele A is represented by p. Frequency of defective allele a is represented by q. Since there are only two alleles, p + q = 1. Consider the F1 generation when two heterozygotes (Aa) mate. Chance that offspring is AA is pxp = p2. Chance that offspring is Aa is (pxq) + (pxq) = 2pq. Chance that offspring is aa is qxq = q2.

  14. Applying the Hardy-Weinberg equation p + q = 1 A (p) a (q) A (p) AA (p2) Aa (pq) a (q) Aa (pq) aa (q2) Consider an autosomal recessive that affects 1 in 1600 births. Incidence is q2 = Frequency of allele a is q= Frequency of allele A is p= Carrier (Aa) frequency is 2pq= • 1/1600 • 1/40 • 1-1/40=39/40 • 2x39/40 x 1/40=1/20

  15. Factors required for Hardy-Weinberg equilibrium (know four) • Population is large. • No migration into or out of the population. • Random mating. • Mutation rate remains constant. • No selection of alleles (neither negative not positive).

  16. Transporters • 3 types • Voltage gated • Ligand gated • Mechanically gated (e.g. touch) • Passive, facilitated or active ATPADP

  17. Cl- HCO3- • Be aware of exchangers and anti porters • With vs. anti concentration gradients • May require ATPase – may transfer two ions • Important ones: Cl/HCO3 in RBCs, Ca/Na membrane antiporter, Na/K pump • Or just one: • Ca ATPase extruded out of the cell, Ca ATPase into SR j

  18. Simplified Nernst equation at 37°C 61 mV [ion]out Eion = log [ion]in Z Learn this!! Ratio of Ca outside to in is 10,000:1 EXCLUDES Ca in sarcoplasmic reticulum – it is only the ions next to the membrane that affect the membrane potential

  19. id K+out Ca2+in & K+out 1 2 0 0 Na+in 3 K+out Transmembrane Potential mV -90 4 Na+out K+in Action potential • C • Changing K/Na concentration  Ca influx • E.g. Ach nicotinic receptor

  20. Signal types • Paracrine • Endocrine • Autocrine • Direct contact • With three effects: • Change ion balance cascade of effects (e.g.Ca) • Alter gene transcription • Alter existing enzymes via phosphorylation

  21. Second messengers • Learn these ones… • Phospholipase C is activated by G-coupled proteins (Gq alpha units), hydrolyses PIP2 IP3 and DAG • IP3 opens Ca channels on the SR • IP3 is also converted to IP4 to open another Ca channel on the membrane • And this Ca acts to activate further Ca SR release • PLC IP3 IP4 Ca • PIP2 DAG PKC

  22. N C ACTIVE P P OH IP3 OH HO Regulatory domain P N PKC Ca2+ C Catalytic domain INACTIVE IP3-gated Ca2+ channel in intracellular stores DAG, IP3 and Ca2+ and the activation of protein kinase C C=O C=O O O CH2 CH CH2OH DAG

  23. cNMP’S • Adenylatecyclase converts ATPcAMP • Guanylatecyclase converts GTPcGMP • cAMP acts on protein kinase A (amongst others) • cGMP acts on protein kinase G (amongst others) • cGMP and cAMP are common second messengers • The reverse (e.g. cAMPATP) is done by phosphodiesterase • Drugs can impact by inhibiting this process

  24. Receptor types • Intracellular (e.g. steroids) act on the nucleus NOT membrane receptors • Or they may be receptors in the cytoplasm (e.g. NO guanylatecyclase – note NO is a vasodilator) • Ion channels change membrane potential • Na/K • Receptors may have intrinsic function

  25. It’s important to know that this is how ras is activated by growth factors (cancer)

  26. G protein coupled receptors • Ligand binds and stimulates the alpha subunit (all you really need to know) • The alpha subunit has a set function based on its classification • Gs stimulates adenylatecyclase. • Gi inhibits adenylatecyclase. • Gt stimulates cGMPphosphodiesterase. • Gq stimulates phospholipase C.

  27. Acetylcholine – parasymathetic ns • There are five muscarinic acetylcholine receptor subtypes. • M1, M3 and M5 couple through Gq to stimulate phospholipase C. • M2 couples through Gi to open a K+-channel. • M4 couples through Gi to inhibit adenylatecyclase. • PLUS the nicotinic acetylcholine receptor (Na+/K+channel)

  28. Calcium channels • Ca in… • Voltage gated Ca channels (membrane) • IP4 gated Ca channels (membrane) • Ca gated Ca channels (sarcoplasmic reticulum) • IP3 gated Ca channels (sarcoplasmic reticulum) • Ca out… • Plasma membrane ATPase • Sarcoplasmic reticulum ATPase • Ca/Na exchanger

  29. Proteins • Haemaglobin is a quaternary struture • 4 globins and a haem • 2 alpha/2 beta structure • Only two things bind to the haem… • O2 • CO (NOT CO2 – this binds to the globin)

  30. Why is this graph this shape?

  31. Postiveallosterism • Relaxed haem binds O2 more readily • This is essential for it to be able to unload O2 at tissues

  32. What lowers the affinity of haem for O2? (note this shifts the curve to the RIGHT) • 2,3, BPG • Stabilises deoxygenated Hb • H or CO2 – effect on pH? • Increases acidity – the Boer effect • H binds to Hb and stabilizes dexoygenatedHb • CO2 is converted to HCO3 and binds to Hb (‘carbamation’) - stabalises deoxygenated Hb • CO2+H2O H2CO3 HCO3- + H+

  33. Acid-base balance • Ventilation (breathing) excretes CO2 • Hence hyperventilation  respiratory alkalosis • And hypo ventilation  respiratory acidosis • You also get metabolic imbalance • Increased acid (e.g. ketones in diabetes)  metabolic acidosis • Increase HCO3  metabolic alkalosis • Either way, it comes back to this… • CO2+H2O  H2CO3 HCO3- + H+ • Lungs Kidney

  34. Collagen • Triple helix (Left handed) • Glycine: Proline/hydroproline • Or glycine:lysine/hydrolysine • Major part of the extra cellular matrix • Need to know steps of post-translational modification and diseases related to them

  35. Post translational steps • 1: Synthesise alpha chains of pre-pro collagen • (Pre and pro are both precursors) • 2: Hydroxylateproline to hydroxyproline • (requires vitamin C so problem = scurvy) • 3: Hydroxylate lysine residues to hydroxylysine • 4: Glycosylate some hydroxlysine • These steps are done to enable cross linking and glycosylation gives a more open structure

  36. 5: Assemble 3 chains to form procollagen • 6: These zipper together into the triple helix

  37. 7: Remove the globular ends by procollagen peptidase, so that fibrils can be formed • (lack of this  ethlersdanlos (hyper mobile joints, stretchy skin) • 8: Cross link fibrils (lysines and hydroxlysines) to form collagen. • Requires lysyloxidase: defect  lathyrism (curved spine, aortic aneurysm, dislocations)

  38. OsteogenesisImperfecta • Glycinebulky amino acid, so type 1 collagen (bone) can’t fold correctly and is unstable • Fractures • NOT a post translational disease (primary structure)

  39. Blood • Haematocrit is just the red blood cell cell content (usually 40-45%)

  40. Haematopoiesis (making blood) • EPO driven (produced by the kidney)

  41. Anemia • Lots of causes • Can be a symptom of bleeding anywhere in the body (ulcers, malignancy) • Symptoms: • Pallor (sign?) • Tiredness • Fainting • Light headedness • Dyspnoea

  42. How does the body respond? • 2,3 BPG • Redistribute blood to important places • Produce reticulocytes (immature RBCs, limited use – note LARGER)

  43. 3 Classifications • Normocytic, normochromic • Cells are the same, just less • So blood less – either Acute Blood Loss, or Anemia of Chronic Disease • Microcytic, hypochromic • Little girly cells • No iron • Menstruation • Macrocytic, normochromic • BIG cells (may be reticulocytes) • Vitamin B12/Folate deficiency • Intrinsic factor required for uptake – any question involving terminal ilium, think anemia!

  44. 4 stages following vascular injury • 1: Vascular constriction • Near instant contraction • Due to inhibited local production of NO and prostacylcin • Usual, relaxed state comes back to pathways…

  45. Just note the NOPKG and ProstaglandinPKA pathways

  46. 2: Platelet plug • Collagen and vWF exposed by damage • Platelets bind and activate • Reinforcing : bindingthromboxane A2 and ADP release (platelet activator/aggregators) • Again, we’ve done the pathways…

  47. Remember that PLA2 is activated…

  48. PLA is converted to PI – COX1 converts this to thromboxane… which does what? • Aspirin inhibits COX1  blood thinner. Why is this permanent?

  49. 3: Clotting • Collagen starts intrinsic clotting • Thromboplastin/tissue damage starts extrinsic (slower) • Both of these activate factor X • Which converts ProThrombinThrombin • Which converts Fibrinogen  Fibrin • Forms the clot

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