Topic 1 - Foundations: Human Structure & Function PDF

Topic 1 - Foundations Human Structure & Course Function Confidence Not Confident Last Edited @August 8, 2024 12:44 PM Week 1 Osmosis...

Topic 1 - Foundations Human Structure & Course Function Confidence Not Confident Last Edited @August 8, 2024 12:44 PM Week 1 Osmosis and Diffusion Fluid Compartments of the Body Total 60% of body mass is water Extracellular Fluid 20% BW 33% body fluid Outside of cells (Low K+, High Na+) 1. Interstitial fluid: fills space between cells (little proteins) — 80% of ECF 2. Plasma: fluid portion of blood (high protein and ions) — 20% of ICF Intracellular Fluid 40% BW 67% body fluid Topic 1 - Foundations 1  Inside of cells (Low Na+, High K+) Cytoplasm Barriers Restrict movement of substances across membranes Capillary wall separates plasma from interstitial fluid Cell membrane separates interstitial fluid from intracellular fluid Osmosis and Diffusion Diffusion Passive movement of solutes from high to low solute concentration until concentrations on either side of the membrane are about equal No additional energy required Particle identity specific Osmosis Water (solvent) movement across a semi-permeable membrane from low to high solute concentration to make conc. equal Identity of particles is irrelevant Concentration vs Osmolarity vs Tonicity Concentration Number of specific dissolved particles in a volume of solution mol/L = M (mM in biology) Osmolarity Topic 1 - Foundations 2  Number of all dissolved particles in a volume of solution (penetrating and non- penetrating solutes) Osmol/L = OsM (mOsM in biology) 300 OsM in cells OsM aims to be equal on both sides of the membrane Tonicity Cell behaviour depending on concentration of non-penetrating solutes Measure of the osmotic pressure gradient between 2 solutions Isotonic is where solute concentration is equal on either side and net water flow is 0 Hypertonic is where solute concentration is greater in solution, and so water leaves the cell Hypotonic is where solute concentration is lower in solution, and so water enters the cell Oncotic Pressure Large molecules have large osmotic pressure Examples Topic 1 - Foundations 3  Important Principles of Body Function Introduction Physiology Studies the way cells, organs, and the whole body function, and how these functions are maintained in a changing environment Topic 1 - Foundations 4  Homeostasis Maintenance of a stable internal environment in response to changes in the external environment Self-regulatory Homeostatic Reflexes Negative Feedback Closed loop/Self-regulating 1. Stimulus 2. Sensor/receptor detects change 3. Afferent pathway carries message to the integrating/control centre 4. Integrating/control centre compares the actual value to the intended value 5. Efferent pathway carries message to the response system 6. Effector/target is the response system 7. Response to help return variable back to homeostatic conditions Topic 1 - Foundations 5  Example - Body Temperature High body temperature → Body temperature receptors → Hypothalamus → Blood vessels and sweat glands → Vasodilation and increased sweating Low body temperature → Body temperature receptors → Hypothalamus → Blood vessels and sweat glands → Vasoconstriction and decreased sweating Positive Feedback Open loop Feedback amplification Example - Birth Contractions Topic 1 - Foundations 6  Head against cervix → Stretch receptors → Brain → Pituitary gland secretes oxytocin → Uterus → Uterine contractions → Repeat Control of Homeostasis Chemical signals Endocrine cell: Form secretory vesicles that secrete into blood stream to deliver to target cells (that have the correlating receptor for hormone) Neuro-secretory cell: Transmits hormone molecules into blood stream to deliver to target cells Nerve cells: Transmits neurotransmitter signals to other nerve cells Hypothalamus Topic 1 - Foundations 7  Brain region that integrator for homeostatic reflexes Regulates autonomic nervous systems Releases neuro-secretory cells Oxytocin producing cells ADH/vasopressin producing cells Tropic releasing hormone Posterior Pituitary Gland Neuro-secretory region (Oxytocin and ADH) Anterior Pituitary Gland Hormone secretion Negative Feedback - Thyroid Hormone More TH, lower TRH and TSH release Hypothalamus secretes TRH → Anterior pituitary secretes TSH → Thyroid gland secretes TH → Stimulates target cells and inhibits the hypothalamus and anterior pituitary Neuro-secretions of the Hypothalamus into the A. Pituitary Releasing hormone stimulates tropic hormone release from the A. pituitary Topic 1 - Foundations 8  Inhibitory factor inhibits release of tropic hormones from the A. pituitary ( _ statin) Tropic hormones stimulate hormone release in other glands Diffusion Across Membranes Diffusion - Passive Topic 1 - Foundations 9  Fick’s Law of Diffusion Concentration gradient 1. Larger gradient → Faster diffusion Barrier permeability 1. More permeable molecule → Faster diffusion 2. Permeability = Lipid solubility/molecule size Distance of travel 1. Thinner barrier → Faster diffusion 2. Diffusion = 1/Change in distance Surface area 1. Larger surface area → Faster diffusion 2. Change in diffusion = Change in SA Drugs Introduction Definitions Drugs Medicine or other substance that has a physiological effect when introduced into body Topic 1 - Foundations 10  A chemical substance of known structure, other than nutrients or an essential dietary ingredient, which when administered to living organism produce a biological effect Medicines Mixtures of active ingredients and excipients that enhance clinic use (storage, preparation, tolerance) Sources and uses Sources: Synthetic (made in a lab) or natural Uses: Recreation, stimulants, medication, doping, research Example — Sarin Targets enzyme at neuromuscular junction Disrupts communication between nerve cells and skeletal muscle fibres Drug Names and Classes Drugs have generic and trade names Drug classes relate to their mechanism of action Drug Targets Receptors: Receive and transduce responses to chemical mediators 1. E.g. Beta 2 adrenoceptor: Adrenaline (hormone) binds→ Elicit cellular responses 2. For acute asthma Ion channels: Allows passage of ions across cell membrane Topic 1 - Foundations 11  1. Eg. Voltage gated Na+ channels: Opening of gate allows movement down the electrochemical gradient 2. Tetra toxin blocks voltage gated sodium channel Enzymes: Biological catalyst 1. Eg. Acetylcholinesterase 2. Sarin: Inhibitor Carrier molecules: Transports fixed number of substances across cell membrane 1. Eg. Na+/K+ATPase pump: 3 Na+ out, 2 K+ into cell (transport fixed number) 2. Dioxin: Inhibitor of pump Drug Selectivity and Safety Drugs will only act on cell with the specific receptor Drugs have more than 1 function, and function is dependent on dosage Correct dosage is required to elicit the desired function and response (achieved through regulation and gaining better understanding) Body’s Effect on Drugs Drug movement in is affected by body absorption and distribution Drug movement out is affected by metabolism and excretion Pharmacokinetics looks at administering the right amount of drug to elicit the desired response for the right duration to minimise risk of adverse effects Topic 1 - Foundations 12  Pharmacology Studies the uses, effects, and modes of action of drugs Drug Targets — Receptors Cell Signalling Chemical signalling allows for cell communication via molecule-receptor interactions Bound receptors interact with effectors to activate a cellular response Drugs can disrupt or mimic cell communication Drug receptors are usually on cell surfaces Types of Receptors Ligand-Gated Ion Channels Protein subunits arranged forming ion-conducting pore Ligand binding → Conformational change → Allows movement of ions through pore Chemical signal to electrical signal (Change in cell excitability) Acts as receptor and effector → Rapid effect after signalling (msec) Eg. Nicotinic acetylcholine (NACh) receptor Topic 1 - Foundations 13  G-Protein Coupled Receptors Transmembrane proteins (7 domains) Ligand binding → Conformational change → G-protein activation → Secondary messenger → Cellular response Intermediate speed (sec) E.g. Muscarinic acetylcholine (MACh) receptor Catalytic Receptors Extracellular domain binds ligands Transmembrane domain Intracellular domain has catalytic activity (Tyrosine kinases) Topic 1 - Foundations 14  Ligand binding → Dimerisation and phosphorylation → Enzymatic activity Slow speed (hours) E.g. Growth factor receptors Nuclear Receptors Ligand activated transcription factors that regulate transcription Nucleus or cytoplasm, but both function in nucleus Slow speed (hours) E.g. Steroid receptors (Androgen and oestrogen receptors) Amplifiers Secondary messengers can amplify and direct signals from bound receptors, triggering downstream effects Secondary messenger concentration and localisation is tightly regulated Topic 1 - Foundations 15  Rapid generation when needed Inactivation mechanisms when unneeded Drugs can target these and alter cellular responses Embryological Origins Introduction & Early Cell Divisions Embryology Studies adult anatomy and development from the embryo Congenital disorders are structural or functional defects inherited at birth Genetic, infection, nutrition, and environment Periods of Human Embryology Conceptus: Fertilisation to end of 2nd week Embryo: Beginning of 3rd week to end of 8th week Foetus: 3rd month to birth Early stages 1. Ovulation: Secondary oocyte released from ovary into the oviduct Topic 1 - Foundations 16  2. Fertilisation: Single sperm penetrates the secondary oocyte, forming the zygote 3. Cleavage: Zygote undergoes equal divisions, no growth 4. Morula: Ball of cells that enter the uterus 5. Blastocyst: Becomes a fluid-filled cavity with a single-cell layer 6. Implantation: Blastocyst implants on the uterine lining, and germ layers form Embryonic Disc Development Blastocyst Developed from morula via differentiation and cavity formation Trophoblast (outer epithelial layer) forms extra-embryonic structures (placenta) and inner cell mass forms embryonic structures Implants into uterine wall between 5-10 days Topic 1 - Foundations 17  Two Germ Layer Stage Inner cell mass splits into epiblast and hypoblast (differentiation), forming 2 different cavities (cavity formation) Formation of the embryonic disc Gastrulation Forms primitive streak that defines body axes Formation of the 3 germ layers Formation of the Primitive Streak Line of cells appear on the epiblast Invaginates to form the primitive groove Never reaches the cranial end Topic 1 - Foundations 18  Embryonic Body Axes 3 Layer Stage Epiblast cells move medially and into the primitive groove First cells move into the hypoblast into the middle, pushing hypoblast cells and forming the embryonic endoderm Later cells move into the space between the epiblast and endoderm, forming the embryonic mesoderm Remaining epiblast cells form the embryonic ectoderm Topic 1 - Foundations 19  Asymmetry Topic 1 - Foundations 20  Primitive node at the end of the primitive streak/groove contains cilia Cilia rotate left, directing fluid movement Cilia on the left edge bend due to fluid movement, causing left cells to release Ca2+ — left Cilia on right do not bend, nor release Ca2+ — right Situs invertus is a congenital disease where some organs are mirrored, causing other problems Notochord and Neural Tube Formation of the Notochord Cartilage-like, transient structure Involved in beginning the formation of the neural tube Cranial (anterior) midline extension from the primitive node to form a hollow tube, growing in length by using mesodermal primitive node cells Primitive streak shortens, with teratomas arising in newborns when primitive streak cells are retained Topic 1 - Foundations 21  Formation of Neural Plate and Neural Tube Ectoderm cells above the notochord thicken and differentiate, forming the neural plate — neuroectoderm Extension and folding gives rise to the neural folds and groove, and convergence of the folds gives rise to the neural tube — neuralation Neural Crest Cells Cells that are released during neuralation Epithelial-Mesenchymal Transition (EMT) Migrate to give rise to specific cell types: Topic 1 - Foundations 22  Dorsal root ganglia Enteric ganglia Schwann cells Melanocytes (pigment cells) Sympathetic and parasympathetic ganglia Dentine Segmentation of the Neural Tube Cranial end swells, forming vesicles that eventually develop into the brain Remainder becomes the spinal cord Embryo Folding & the Mesoderm Embryo Folding End of 3rd week: Flat disc 4th week: Rapid growth of the embryonic disc and amion due to differentiation Little growth in the yolk sac Folding to generate body form Topic 1 - Foundations 23  Mesoderm Development Paraxial Mesoderm Next to neural tube Somite formation in the trunk region, which later produces muscle, bone, and dermis Somitogenesis Form in pairs below the head region — cranial → caudal Mesenchymal cells undergo MET, enclosing to form a somite, with some mesenchymal cells remaining inside each somite, repeating regularly Topic 1 - Foundations 24  Somite splits into outer dermamyotome and inner sclerotome Dermamyotome splits into dermatome and myotome Dermatome → Dermis, Myotome → Muscle, and Scelerotome → Skeletal elements Different dermatomes and myotomes give rise to different structures depending on their position on the embryo spinal cord Topic 1 - Foundations 25  Intermediate Mesoderm Gives rise to the urogenital system (kidneys, gonads, and associated ducts) Pronephros degenerates Mesonephros (mesonephric tissue and tubules) tissue differentiates to form gonads and ducts Genital ridge forms either testes (SRY → SOX9 ←→ FGF9) or ovaries (WNT4/RSPO1, FOXL2) — gonadal sex determination FGF9 and WNT4/RSPO1 suppress each other DMRT1 and FOXL2 suppress each other Undifferentiated mesonephros degenerate Metanephros gives rise to the kidney Topic 1 - Foundations 26  Lateral Mesoderm Somatic/Parietal and Splanchic/Visceral Forms the ventro-lateral body wall (connective tissue), bones of limbs, heart and vasculature, and the gut wall Development of the Cardiovascular System Vasculogenesis Blood vessel formation from mesodermal cells During embryogenesis 1. Haemangioblasts migrate Topic 1 - Foundations 27  2. Differentiate into angioblasts and haematopoetic cells to form blood island 3. Cells differentiate into endothelial cells and blood cells 4. Pericytes are recruited to stabilise Angiogenesis Blood vessel formation from existing blood vessels During embryogenesis and in adults Can occur to promote tumour metastasis 1. Hypoxia, causing release of VEGF-A 2. Triggers outgrowth and tube formation 3. Stabilisation by pericytes Topic 1 - Foundations 28  Development of the Heart 1. Primitive blood vessels form the endocardial tubes 2. Fuse to form primitive heart tube 3. Swelling, rotation and formation of the septum give rise to the left and right atriums, and arteries 4. Further partitioning gives rise the the ventricles, and the heart Summary Topic 1 - Foundations 29  Development of the Endoderm Gut tube Formed by lateral folding of the embryo Parietal/Somatic mesoderm folds laterally and fuses, lining the embryonic coelom Visceral/Splanchnic mesoderm becomes the mesodermal lining of the gut Regions of the Gut Tube Topic 1 - Foundations 30  Development of the Stomach Dilation and enlarging of the distal foregut ventro-dorsally Dorsal part grows faster, curving the stomach Rotation 90° left and superiorly (up) bends the duodenum into C-shape Development of Other Endodermal Organs Endoderm thickens Cell proliferations forms buds Lengthening and bifurcation/branching Topic 1 - Foundations 31  Lungs Ventral out-pocketing of the endoderm forms the respiratory diverticulum (forms the trachea) Ventro-caudal growth 1st bifurcation (split) → Right and left primary tracheal buds → Bronchi 2nd bifurcation→ Secondary bronchial buds (3 right, 2 left)→ Lung lobes 3rd bifurcation→ Tertiary bronchial buds→ Bronchopulmonary segments 14 more branching → Terminal bronchioles Other Derivatives Topic 1 - Foundations 32  Development of the Head Head structures Skeletal structures formed from neural crest cells rather than the mesoderm Pharyngeal Arches 4 main arches in the human embryo Covered by ectoderm (pharyngeal cleft) Mesenchymal core from mesoderm and neural crest cells Inner lining of endoderm (pharyngeal pouch) Each arch has a cartilaginous skeletal element from neural crest, muscle from head mesoderm, cranial nerve, and arch artery from mesoderm derived endothelial cells Topic 1 - Foundations 33  Birth Defects Topic 1 - Foundations 34  Biological Basis of Membrane Potential Properties of Cell Membranes Key Rules Things travel down gradients, at greater speeds for steeper gradients — passive Opposites attract, and like charges repel The Cell Membrane Selective entry and maintenance of the intracellular and extracellular (different solutes) aqueous environment Occurs due to hydrophilic/hydrophobic interactions, simple diffusion, and facilitated diffusion Transmembrane proteins connect the intracellular and extracellular environment Ions are hydrophilic and can’t cross passively — must use selective gated channels (proteins) to enter in the presence of a stimulant K+ and Na+ distribution Topic 1 - Foundations 35  High Na+ outside cell and high K+ inside due to Na+/K+ ATPases — diffusion gradients Membrane is more permeable to K+, and leaves via specific K+ leak channels (always open) that can’t transport anions out (mainly phosphate and proteins) Whilst the leak channel is bi-directional, the concentration gradient favours K+ efflux Negative charge on inner membrane, and so some K+ re-enters the cell Negative membrane potential when K+ movement in and out is equal (concentration gradient out and electrical gradient in) Membrane Potential Membrane Potential Charge difference across membrane (mV) Cations leave the cell (K+) Resting Membrane Potential Topic 1 - Foundations 36  Resting when cell permeability is due to leak channels, i.e. closed gated channels Charge difference at rest More permeable to K+, more negative RMP due to K+ leak channels in the membrane and efflux due to concentration gradient Shifts in Membrane Potential from RMP Depolarisation is a shift toward 0 mV Repolarisation is a shift toward RMP Hyperpolarisation is a shift lower than RMP The Equilibrium Potential of an Ion Equilibrium Potential Chemical concentration gradient (stored/potential energy) and electrical charge difference drive ion membrane movement When these forces are balanced, net ion movement is 0 — equilibrium K+ leaves the cell via chemical concentration gradient, leaving anions behind, giving rise to a negative MP, so K+ also enters via electrical charge difference Topic 1 - Foundations 37  Membrane permeable to cations but not anions Each Ion has Equilibrium Potential Predicted equilibrium potential from Nernst eq. (Eion) Ions move in the direction that brings MP closer to Eion E.g. Vm = -65mV, EK = -80mV, so since Vm > EK, K+ will flow out of the cell Cations entering depolarise the membrane, cations exiting hyperpolarise Na+/K+ ATPase prevents MP from just sitting at K+ Eion Topic 1 - Foundations 38  The Nernst Equation Purpose is to predict the equilibrium potential of any ion given the concentrations of the ion Driving Force Sum of all force on an ion, pushing or pulling the ion The further away Vm is from Eion, the greater the driving force E.g. E.g. Topic 1 - Foundations 39  ECl is close to RMP because there is no Cl transporter NACh nACh typically depolarises the membrane when activated because Na+ has a higher driving force than K+ and RMP is further away from ENa than EK Goldman-Hodgkin-Katz Eq. Used to predict membrane potential, given the ion distribution across the membrane and permeability Excludes Ca2+ since concentrations small compared to the other ions Not all cells have the same ion permeability and concentration, and so RMP is cell- type specific During an Action Potential Topic 1 - Foundations 40  RMP is positive and closer to ENa due to increased sodium permeability and therefore influx into the cell — depolarised Monovalent Cation Channel Opening Equally permeable to Na+ and K+ RMP is close to 0, little potential energy and therefore membrane movement Signifies that polarisation is important for membrane movement Na+/K+ ATPase maintains negative membrane potential Topic 1 - Foundations 41