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IMMS 1 Revision (part 1). Nick Richards & Byron Haywood-Alexander. Topics. Cells Homeostasis Molecular building blocks DNA/RNA Mitosis/Meiosis Genetic disease. 1. Cells.
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IMMS 1 Revision (part 1) Nick Richards & Byron Haywood-Alexander
Topics • Cells • Homeostasis • Molecular building blocks • DNA/RNA • Mitosis/Meiosis • Genetic disease
1. Cells Functional unit of the body, compartmentalised by a cell membrane, containing intracellular organelles and cytoplasm. Many cellular metabolic processes occur here including those that allow molecules into and out of the cell.
Organelles Nucleus - cell ‘brain’, double nuclear membrane, DNA, nucleolus produce rRNA Mitochondria - cell ‘battery’, oxidative phosphorylation, mtDNA, double membrane (inner highly folded) • Outer membrane - lipid synthesis and fatty acid metabolism • Inner membrane* - Respiratory (electron transport) chain ATP production • Matrix - Tricarboxylic acid (Krebs’) cycle • Intramembranous space - nucleotide phosphorylation Endoplasmic reticulum - flat folded sheets of membrane, nuclear pores • Rough - protein production • Smooth - membrane lipid production, protein processing
Organelles Golgi apparatus - parallel membrane sheets - process and modify ER products • Cis (nuclear) face - receive smooth ER vesicles, protein phosphorylation • Medial Golgi - modify products by adding sugars • Trans Golgi Network - proteolysis of peptides into active forms, sorting of molecules into vesicles Vesicles - spherical membrane bound organelles to transport and store material • Cell surface derived: pinocytotic and phagocytic vesicles • Golgi-derived transport vesicles • ER-derived transport vesicles • Lysosomes • Peroxisomes
Organelles Lysosomes (waste disposal system) - contain many acid hydrolases. H+ATPase on membrane creates optical pH 5 environment for enzymes. Peroxisomes - contain enzymes that break down long-chain fatty acids D-amino acid oxidase, Catalase, Urate oxidase Cytoskeleton - filament proteins supporting structure of the cell • Microfilaments - Actin forms a mesh (cell cortex) to inner cell membrane • Intermediate filaments - differ from cell to cell - spread tensile forces • Microtubules - Tubulin arise from centromere (2 centrioles) - not RBC
Cell membranes • Phospholipid bilayer • Contain glycolipids, glycoproteins, cholesterol and embedded proteins. Proteins: Transmembrane (integral), Catalytic, Structural (pumps, gates, receptors, adhesion molecules, energy transducers).
Cell membrane function ? • Barrier the external environment and compartmentalise the cell • Semi-permeable: • absorb nutrients and expel waste • maintain intracellular ionic balance • Cell response to signals • Molecules for intercellular adhesion • Insulate - myelin sheath
Cell Junctions Occluding junctions - prevent molecule leakage • Tight junctions Anchoring junctions • Actin filament sites • cell-cell junction (adherens junctions) • cell-matrix junctions (focal adhesions) • Intermediate filament sites • cell-cell junction (desmosomes) • cell-matrix junction (hemidesmosome) Communicating • Gap junctions • Chemical synapses
Endocytosis Energetic process to absorb/engulf molecules into cell. Phagocytosis* (eating) - macromolecules/ entire cell to form phagosomes Pinocytosis (drinking) - dissolved solutes Receptor mediated* - specific, depressed areas: coated pits.
Exocytosis • Vesicles from the Golgi complex • Fuse with the plasma membrane • Expulsion of waste OR Secretion of enzymes/hormones
Movement across membranes Movement types • Passive diffusion • Facilitated diffusion through protein channels with(out) carrier proteins • Active transport Examples • Gaseous exchange along chemical gradient • Glucose - protein assisted which is upregulated by insulin. Voltage gated channels activated by action potentials. • NaK ATPase pump - going against chemical and electrical gradients
Receptors Gateway to intracellular signals • open a channel • activate an intracellular enzyme • induce second messenger • migrate to nucleus as receptor-ligand complex
2.Homeostasis ? Control of the internal environment
Communication Types • Endocrine - hormones • Nervous - currents and neurotransmitters • Immune - antibodies, cytokines, interleukins Receptor and ligand required
Cell to cell signaling Endocrine system - hypothalamus, pituitary, thyroid, parathyroid, thymus, pancreas, kidney, gonads, adrenals Immunity - T lymphocytes secreting IL2, cytokines Neuro synapses, neuromuscular junction, clotting
Types of hormone Peptide - insulin, growth hormone, TSH • From short chain of AA to small proteins • Some glycoproteins • Hydrophilic - receptors Steroid - testosterone, oestrogen, cortisol • Synthesised from cholesterol • Different enzymes produce hormones • Lipid soluble - cross membranes but require transport proteins Amino-acid derivative - adrenaline, T4, T3 • synthesised from tyrosine
Feedback Positive feedback - amplification of signal Negative feedback loop - centre of homeostasis • Clotting cascade • Oxytocin during childbirth • Blood sugar regulation • Temperature regulation • Blood pressure regulation • Metabolism/thyroid regulation
Water Distribution Total body water ~ 42L 60% of body weight Cl- K+ HCO3- 40% of body weight intracellular fluid - 28L 20% of body weight extracellular fluid - 14L Na+ Transcellular - 1L -CSF -Digestive juices -Mucus Interstitial - 10L Plasma - 3L
Water Homeostasis • Fluid compartments are in osmotic equilibrium • Solutes (osmotically active) in ICF and ECF create osmotic gradients • Any change in solutes in any compartment results in a water movement ECF ICF K+ Na+ Urea Glucose
Regulatory hormones Antidiuretic hormone Aldosterone Atrial natriuretic peptide ? Water Homeostasis Water intake: • Drink - thirst, social • Diet • IV fluid Water loss: • Kidneys • Insensible losses • sweat • breath • vomiting • faeces
Definitions Osmosis - net movement of solvent molecules through a semipermeable membrane to a higher solute concentration. Osmolality - measure of the number of dissolved particles per kg of fluid. Osmolarity - measure of the number of dissolved particles per L of fluid. Osmotic pressure - pressure applied to a solution, by a pure solvent, required to prevent inward osmosis. Through a semipermeable membrane. Oncotic pressure - form of osmotic pressure exerted by proteins that tends to pull fluid into its solution.
Water homeostasis mechanisms Water loss from ECF • ↑ solute or ↓ fluid results in an ↑ osmolality • Detected by osmoreceptors in hypothalamus • Release of antidiuretic hormone (ADH) from posterior pituitary • ADH acts by increasing water reabsorption in the kidneys • Dilutes solute and returns ECF water to normal Decreased renal blood flow • ↓ water in ECF results in ↓ circulating volume results in ↓ renal blood flow • Kidney release of Renin and activation of RAAS • Angiotensin II and aldosterone increase Na+ reabsorption (exchange K+ and H+) bringing water. Also stimulates ADH.
Water deprivation Vomiting Diarrhoea Burns Heavy Sweating Diabetes insipidus Diabetes mellitus Drugs Dehydration • Low intake • Excess loss • Low ADH
Hyponatraemia Cerebral over-perfusion headache confusion convulsions Water excess • High intake • Decreased loss • Excess ADH
Oedema Oedema - excess water in the intercellular tissue space. • inflammatory (leakage) • Venous (increased end pressure) • Lymphatic (blocked) • Hypoalbuminaemic Serous effusion - excess water in a body cavity.
Hyponatraemia Artefactual Sodium loss Diuresis Addison’s disease Excess water IV fluids SIADH Excess water & sodium Oedema (CCF, liver disease) S+S: intracellular overhydration (headache, confusion, convulsions) Sodium Hypernatraemia • Water deficit • low intake • osmotic diuresis • DI • Sodium excess • mineralocorticoid excess S+S: cerebral intracellular dehydration (confusion, tremors, irritability), hypertension, oedema/serous effusion
Hyperkalaemia Decreased K+ loss renal failure diuretic/ACE-inhibitors Addison’s Redistribution acidosis S+S: risk of cardiac arrest Hypokalaemia Potassium loss D+V Diuretics Hypomagnesaemia Conn’s and Cushing’s Redistribution Alkalosis Refeeding syndrome S+S: Weakness, dysrhythmia Potassium Excretion from intestines and kidneys (Na/K ATPase pump controlled by aldosterone)
Hypocalcaemia Vit D deficiency Mg deficiency Renal disease Parathyroidectomy Intestinal malabsorption S+S: tetany, carpopedal spasm Calcium Hypercalcaemia • Hyperparathyroidism • Malignancy • Skeletal mets • PTH-like hormone from tumours • Vitamin D toxicity • Granulomatous disease (TB) S+S: Metastatic calcification Bones, stone, psychic groans, abdominal moans, thrones.
3. Molecular building blocks Simple molecules form complex, large macromolecules with functions: • Structure • Osmotic • Enzyme • Other specific
Carbohydrates/Saccharide/Sugars • Cn(H2O)n Mono, Di, Oligo, Poly • Groups • Hydroxyl • Aldehyde • Ketone • Carboxyl • OH group react with OH/NH = O/N-glycosidic bond • Polysaccharides: 1-4 and 1-6 bonding forming Glycogen, Starch
Lipids/Fatty acids • Straight hydrocarbon chain with carboxyl group • Eicosanoids - major biological function • derived from eicosanoic acid
Nucleotides • Sugar + nuclear base + single phosphate group • Purine derivative • Pyrimidine derivative
Aminoacids • Charge determined by all 3 groups • Change at different pH • Side chain determine polarity and non-polarity • Strong peptide bond CO-NH. Requires proteolytic enzymes.
Chiral centres Most sugars in the human body are D form, whereas protein take L-form!
Proteins • Long AA chains • Varied function - structure dependent • Structure • Primary • Secondary • Tertiary • Quaternary
Enzymes • Biological catalyst - bind but to not get used up • Speed-up and regulate reaction rate • Optimum temperature and pH • Activation, modification, inhibition • Isoenzymes - different structure, catalyse same reaction Disease marker! Drug target!
Co-enzymes • Organic structures (nonprotein) that help maximise organic enzyme active site • Cannot catalyse alone • Metal ions (Fe2+, Mg2+, Zn2+), vitamin derivatives (thiamine pyrophosphate) • Activation-transfer coenzymes • Oxidation-reduction coenzymes
Forces • Van der Waals - weak attractive/repulsive force between all atoms due to fluctuating electrical charge. • Hydrogen bonds - interaction between polar groups. Important in AA side chains, O/N in main chain and water. • Hydrophobic forces - as uncharged and non-polar side chain repel water, they tend toward a protein core. • Ionic bonds - between fully/partially charged groups • Disulphide bonds - very strong covalent bonding between sulphur atoms.
DNA/RNA • Base Nucleotides • Complementary Base Pairing • DNA Polymerase • Sense and Anti-Sense Strands • RNA
Maternal Chromosome Paternal Chromosome Gene locus Alleles
Replication of DNA • Double stranded -> Single stranded • Topoisomerase • DNA Helicase • DNA polymerase • Semi-conservative replication
Transcription ANTI-SENSE DNA • Double stranded -> Single stranded • Topoisomerase • DNA Helicase • RNA polymerase • Messenger RNA (mRNA)
Translation • mRNA -> Ribosome • Splicing • Introns • Exons • tRNA • Anticodon
Non-Sense Single nucleotide polymorphism (SNP) Premature stop codon Examples? Duchenne’s Muscular Dystrophy Mis-Sense and Non-Sense • Mis-Sense • Single nucleotide polymorphism (SNP) • Different amino-acid • Examples? • Sickle Cell (CAG -> CTG) GOWER’S SIGN