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

The important bit of meiosis

Nondisjunction in Meiosis IPaired chromosomes fail to separate.

Nondisjunction in Meiosis IISister chromatids fail to separate.

Monosomy?◦ Turner’s (XO)

Autosomal Trisomy?◦ 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)

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) AT subsitution results in abnormal cells

◦ Insertion (Muscular Dystrophy)

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

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

Deciphering pedigrees

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

Autosomal Dominant◦ BOTH SEXES EQUALLY AFFECTED◦ Unaffected normal offspring◦ Affected 1:1 affected:non affected

Pedigrees

Autosomal Recessive◦ BOTH SEXES EQUALLY AFFECTED◦ Affected individuals usually produce normal

(carrier) offspring

X-linked Recessive◦ Only males effected (pretty much)◦ Skips a generation

Y-linked

Exclusively affects males Effected males ALWAYS produce effected

males

(Should probably know two)◦ Mosaicism◦ Late onset◦ Incomplete penetrance◦ Mitochondrial inheritance

Complications

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.

AA (p2)A (p)

a (q) Aa (pq)

A (p) a (q)

Aa (pq)

aa (q2)

A and a are alleles.p and q are frequencies.

Chance that offspring is AA is p x p = p2.Chance that offspring is Aa is (p x q) + (p x q) = 2pq.Chance that offspring is aa is q x q = q2.

Consider the F1 generation when two heterozygotes (Aa) mate.

Since there are only two alleles, p + q = 1.

Applying the Hardy-Weinberg equation

AA (p2)A (p)

a (q) Aa (pq)

A (p) a (q)

Aa (pq)

aa (q2)

p + q = 1

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

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).

3 types◦ Voltage gated◦ Ligand gated◦ Mechanically gated (e.g. touch)

◦ Passive, facilitated or active

Transporters

ATPADP

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

Cl- HCO3-

Learn this!!

Simplified Nernst equation at 37°C

Eion

61 mV

Zlog

[ion]out

[ion]in

=

Ratio of Ca outside to in is 10,000:1EXCLUDES Ca in sarcoplasmic reticulum – it is only the ions next to the membrane that affect the membrane potential

C

Changing K/Na concentration Ca influx E.g. Ach nicotinic receptor

Action potential

id

4

3

21

0Na+ in K+ out

Na+ outK+ in

0

-90

K+ outCa2+ in & K+ out

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

Signal types

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

Second messengers

DAG, IP3 and Ca2+ and the activation of protein kinase C

CN

ACTIVEDAG

CHCH2 CH2OH

O

C=O

O

C=O

IP3

POH

OH HOP

P

IP3-gated Ca2+ channelin intracellular stores

Ca2+

N

C

Regulatorydomain

Catalyticdomain

INACTIVE

PKC

Adenylate cyclase converts ATPcAMP Guanylate cyclase converts GTPcGMP 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. cAMPATP) is done by phosphodiesterase

Drugs can impact by inhibiting this process

cNMP’S

Intracellular (e.g. steroids) act on the nucleus NOT membrane receptors

Or they may be receptors in the cytoplasm (e.g. NO guanylate cyclase – note NO is a vasodilator)

Ion channels change membrane potential◦ Na/K

Receptors may haveintrinsic function

Receptor types

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

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 adenylate cyclase.

Gi inhibits adenylate cyclase.

Gt stimulates cGMP phosphodiesterase.

Gq stimulates phospholipase C.

G protein coupled receptors

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 adenylate

cyclase. PLUS the nicotinic acetylcholine receptor (Na+/K+

channel)

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

Calcium channels

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)

Proteins

Why is this graph this shape?

Postive allosterism Relaxed haem binds O2 more readily This is essential for it to be able to unload O2

at tissues

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 dexoygenated Hb CO2 is converted to HCO3 and binds to Hb

(‘carbamation’) - stabalises deoxygenated Hb

CO2+H2O H2CO3 HCO3- + H+

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

Acid-base balance

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

Collagen

1: Synthesise alpha chains of pre-pro collagen (Pre and pro are both precursors)

2: Hydroxylate proline 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

Post translational steps

5: Assemble 3 chains to form procollagen

6: These zipper together into the triple helix

7: Remove the globular ends by procollagen peptidase, so that fibrils can be formed

(lack of this ethlers danlos (hyper mobile joints, stretchy skin)

8: Cross link fibrils (lysines and hydroxlysines) to form collagen.

Requires lysyl oxidase: defect lathyrism (curved spine, aortic aneurysm, dislocations)

Osteogenesis Imperfecta◦ Glycinebulky amino acid, so type 1 collagen

(bone) can’t fold correctly and is unstable◦ Fractures◦ NOT a post translational disease (primary

structure)

Haematocrit is just the red blood cell cell content (usually 40-45%)

Blood

EPO driven (produced by the kidney)

Haematopoiesis (making blood)

Lots of causes Can be a symptom of bleeding anywhere in

the body (ulcers, malignancy) Symptoms:

◦ Pallor (sign?)◦ Tiredness◦ Fainting◦ Light headedness◦ Dyspnoea

Anemia

2,3 BPG Redistribute blood to important places Produce reticulocytes (immature RBCs,

limited use – note LARGER)

How does the body respond?

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!

3 Classifications

1: Vascular constriction◦ Near instant contraction◦ Due to inhibited local production of NO and

prostacylcin◦ Usual, relaxed state comes back to pathways…

4 stages following vascular injury

Just note the NOPKG and ProstaglandinPKA pathways

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…

Remember that PLA2 is activated…

PLA is converted to PI – COX1 converts this to thromboxane… which does what?

Aspirin inhibits COX1 blood thinner. Why is this permanent?

3: Clotting Collagen starts intrinsic clotting Thromboplastin/tissue damage starts

extrinsic (slower) Both of these activate factor X Which converts ProThrombinThrombin Which converts Fibrinogen Fibrin Forms the clot

4: Clot lysis (have to get rid of it) Process is ‘fibrinolysis’ (-lysis = degrade) Plasminogen is converted to plasmin which

leads to fibrinolysis Activation of plasminogen plasmin is by

agents such as tPA and streptokinase (‘clot busters’)

Fed 0-4 hours post prandial◦ Insulin release muscle/adipose uptake◦ Brain uses glucose independent of insulin◦ Stimulates protein, lipogenesis, glycogen synthesis◦ Stimulates glycolysis

Fasted 4-12 hours◦ Glucagon>insulin◦ Break down glycogen, and triglycerides into FFA◦ Muscle uses up glycogen

Starved >12◦ Proteolysis, lipolysis◦ Gluconeogenesis◦ FFA ketones

Metabolism

Remember insulin does the opposite of glucagon and insulin is released after eating

These regulate glucose uptake Hexokinase is found in the brain – where

affinity is much higher than (usual) glucose levels

Converted to G6P – inhibitive Glucokinase is found in the liver – much

lower affinity – except after eating G6P is NOT inhibited – glucose is stored (as

glycogen) and released as required

Hexokinase and Glucokinase

For generating energy (ATP)

Just need to note that phosphofructokinase conversion is irreversible and activated by AMP, inhibited by ATP

Glycolysis

The next step splits fructose 1,6 biphosphate into 2 x gylceraldehyde (by isomerase – reorganises it)

This is converted into pyruvate – but this is not a efficient payoff in terms of ATP

Under AEROBIC conditions, this is converted into acetyl-CoA

Under anaerobic conditions it lactate

It is this that produces ATP In mitochondria Lots of things input Driven by AMP, inhibited by what it

produces: ATP, NADH

Citric Acid Cycle

6-4 carbon Acetyl CoA drives it by adding two carbons

This allows the synthesis of necessary products – especially NADH

NADH donates its H (becomes NAD) The H is used to drive proton pumps Lots of H results in ADPATP by oxidative

phosphorylation

This is the real pay off stage of glycolysis – without oxidative phosphorylation (i.e. in anaerobic conditions) ATP yield is low

Lots of glucose lots of insulin lots of glycolysis lots of acetyl coa

Fatty acids are synthesised which creates more available acetyl-coa

So lots to drive the cycle This just means you can make more things

you wouldn’t usually e.g. purines, GABA

Back to the fed state…

Low acetyl-coa means the cycle isn’t driven FFA are broken down to feed in. A fatty acid is just lots of acetyl units –

which contain carbon So these are harvested for their carbon and

bound to coa so they can be fed into the cycle

Which is why you get lipolysis and FFA breakdown but this also creates ketones which are acidic… so lead to what…?

But in the starved/fasted state…

Endocrinology Understand feedback… Produce something,

inhibits further production (usually – exception - oxytocin)

This can be at the level of the hormone being produced – or at the level of the stimulating hormone

Steroids◦ E.g. cortisol◦ Intracellular◦ Slow acting (have to activate

transcription factors)

Peptide/Catecholamines◦ Catecholamines are noradrenalin

and adrenalin◦ Fast acting – on pre-existing

enzymes◦ Act on membranes

Types of hormones

Know the ones that are released by the hypothalamus and what they release from the anterior pituitary

Then need to know the diseases associated with them – there’s always a problem with too much or too little

What hormones do you need to know?

Corticotrophin releasing hormone (CRH) from hypothalamus

Adrenocorticotrophin hormone from anterior pituitory

Cortisol from Adrenal gland Breaks down protein, causes lipolysis,

increases gluconeogesis/glycogen synthesis Effects:

◦ Immunosuppressive◦ Decreases bone density◦ Decreases muscle mass

CRH

Too much… Cushings◦ Central weight gain (strange)◦ Moon face◦ Bruising◦ Depression, loss of libido

Too little… Addison’s◦ Weight loss◦ Anorexia◦ Nausea and vomiting◦ Depression

Growth hormone releasing hormone and growth hormone inhibiting hormone from hypothalamus

Anterior pituitary then releases growth hormone

Does what you would expect- builds things up e.g. protein synthesis, stimulates IGF-1 ( growth), stimulates gluconeogenesis, stimulates glycogen synthesis

What are these actions the opposite of?

GHRH and GHIH

Excess... Acromegaly/gigantism◦ Distinction is age – acromegaly is after growth

plates form◦ Change in appearance◦ Headache◦ Visual deterioration◦ Poor libido/impotence◦ Goitre

◦ If you don’t have enough… You are just short

Thyrotropin Releasing Hormone from hypothalamus

Thyroid Stimulating Hormone from AP Releases T3 (Tri-idiothyronine) And T4 (Thryoxine)

◦ The major effect of these is to increase the basal metabolic rate

TRH

High… hyperthyroid◦ Increased BMR so…

Weight loss Increased appetite Diarrhoea Goitre

Low… hypothyroid◦ Low BMR so…

Weight gain Anorexia Constipation Goitre

Luteinizing hormone releasing =Gonadatrophin releasing hormone

From hypothalamus Stimulates AP to produce luteinizing

hormone and follicle stimulating hormone Important for when you do repro (act on

gonads to produce sex steroids – oestrogen, testosterone)

LHRH/GnRH

2 things released – ADH (vasopressin) and oxytocin

You will cover both of these in semester 2/3…

Just worth knowing hypothalamusposterior pituitary is neuroendocrine transmission unlike AP which is endocrine

This means low amounts have an effect◦ Oxytocin important in giving birth◦ ADH is anti-diuretic hormone – you retain water so it

regulates blood pressure

The posterior pituitary

Increased action:◦ Increased availability of substrate

Iodine excess in hyperthyoid◦ Immune response

Hyperthyroid caused by Graves Disease (antibodies stimulate thyroid gland)◦ Tumours

Pituitary/hypothalamas tumour – can cause excess secretion of any hormone

Decreased action:

◦ Decreased availability of substrate Iodine deficiency in hypothyroid

◦ Immune response Hypothyroid - Hashimotos – destruction of the thyroid gland

◦ Destruction of the gland Radiation, surgery (hypothyroid)

Why do things go wrong?