Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Magnesium in biology wikipedia , lookup
Biochemical cascade wikipedia , lookup
Lipid signaling wikipedia , lookup
Western blot wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Oxidative phosphorylation wikipedia , lookup
Biochemistry wikipedia , lookup
Evolution of metal ions in biological systems wikipedia , lookup
NORMAL and ABNORMAL CELLULAR FUNCTION Lois E Brenneman, MSN, ANP, FNP, C INTRODUCTION - Structural and functional unit of body - Building blocks for tissue, organs, organ systems - Functions of cells - Obtain O2 and nutrients - Metabolize nutrients - Eliminate CO2 - Synthesize proteins, other biomolecules - Respond to changes in environment - Regulate movement between external and internal cellular environments - Replicate - Agents which harm cells disrupt basic survival - Cells have specialized functions (in addition to basic functions - Kidney cells maintain fluid and electrolyte balance - Myocardial cells: contraction - Processes which control of cellular components - Regulation of availability of cellular components (gene expression) - Altering rate at which cellular components carry out physiologic functions CYTOPLASM and CELL ORGANELLES - Cell organelles - Cytosol: fluid medium (mostly water with some electrolytes, proteins, CHO) - Intracellular fluid (ICF): all fluid inside cell - Cytosol and nucleoplasm (fluid inside nucleus) - Chemical composition of organelles differs from cytosol - Electrolyte balance differs from extracellular fluid - Proteins: - Structural strength, form - Muscle contractility - Transport agents - Enzymes, hormones - Lipids: small portion most cells - Combine with proteins to keep cell membrane soluble in water - CHO - small portion of cell - used to form ATP - ATP- high energy phosphate compound required by cells to function * * Contraction, secretion, conduction, transport, etc. - Membrane bound compartments with specific functions - Plasma membrane also considered organelle - Nucleus is largest organelle © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 1 Mitochondria: Inner membrane forms transverse folds called cristae where enzymes needed for final step in ATP production The Cell: Shows nucleus, cytoplasm and organelles ORGANELLES 1. Mitochondria - Site of ATP synthesis - Double membrane - inner membrane folded into cristae - ATP formed from enzyme reactions on cristae - Highly active cells have high energy requirement (skeletal muscle) - More active cells have more mitochondria - Mitochondria can replicate - contain DNA` CLINICAL EXAMPLES Cyanide kills by interfering with final step in Krebs cycle It interferes with oxidative phosphorylation and resulting in inability to form ATP 2. Endoplasmic reticulum - Tubular, sac-like interconnected channels - cisternae - Net-like structure with membranes continuous with nuclear membrane - Surface covered with RNA granules which synthesize protein - Granules called ribosomes - Granular ER - contains ribosomes - production of cellular proteins - Smooth ER: no ribosomes - production of nonproteins Fat-soluble triglycerides, fatty acids, steroids, phospholipids - Functions to provide surface for chemical reactions © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 2 3. Free ribosomes - Not bound to ER - Linked together in chain called polyribosome - varying lengths - Synthesize protein molecules - most for use within cell Endoplasmic Reticulum: 3-D view of endoplasmic reticulum (ER) with attached ribosomal RNA and smooth endoplasmic reticulum - ER serves as surface for chemical reactions. Ribosomes serve as site of protein molecule synthesis CLINICAL EXAMPLES Many antibiotics operate by interfering with the ribosomes of certain bacteria hence the bacteria cannot synthesize necessary proteins and die. Antibiotic resistance often develops as the bacteria synthesize “ways around” this ribosomal issue. 4. Golgi complex - Golgi complex or Golgi apparatus - Concentric flattened sacs with membranes - Sometimes connected to ER or even a part of it - Membrane-bound vesicles in close approximation - Packaged chemicals for exocytosis - Active in various secretory cells e.g. pancreatic acinar - Role in secretion via vacuole formation for exocytosis - Other functions: - Produce polysaccharides - Chemical modification - activate enzymes - Store synthesize molecules - Produce lysosomes Golgi Complex: Concentric flattened sacs with membranes sometimes connected to ER; Functions to package chemicals for exocytosis; active in secretory cells. Produce lysosomes Hormone Synthesis and Secretion: Hormone synthesized by ribosomes attached to endoplasm reticulum (ER). Moves from rough ER to Golgi complex where it is stored as secretory granules. Granules stored within cytoplasm until released from cell in response to appropriate signal © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 3 5. Lysosomes - Membrane bound, spherical - contain digestive enzymes - Intracellular digestion - Hydrolytic enzymes: proteins, nucleic acids, CHO, lipids - Endocytosis - lysosomal enzymes digest contents - Digest worn-out/damaged cell components via autophagy - Autolysis: cell death releases lysosomes which self-destruct cell - Phagocytosis: lysosome process - Granulocytes: WBCs: lysosomes numerous - gives granular appearance - Remove dead/injured tissue in inflammatory process Lysosomes: The process of autophagy and heterophagy, showing primary and secondary lysosomes, residual bodies, extrusion of residual body contents from cell, and lipofuscin-containing residual body CLINICAL EXAMPLESBy products of W BC death in a septic knee can destroy cartilage as d ead W BC liberate lysoso m es. A cco rdingly septic k nee s m ust be dra ined (asp irated) q 24 hou rs. Abscess destroys good tissue as W BCs/phagocytes - attracted to the area to fight the infection - die and liberate lysosomes which destroy other tissue (besides the bacteria) 6. Peroxisomes - Contain oxidative enzymes which form H202 (peroxide) - Peroxide detoxifies harmful substances esp in liver/kidney CLINICAL EXAMPLES Peroxide is very toxic to many organisms esp anaerobic organisms which is why cellular liberating peroxide would be effective in fighting infection. Dentists sometimes recomm end peroxide rinses or peroxide toothpaste (M entad ent) to control anaerobic bacteria which are resp onsible for tooth plaque and gingiv itis. Unfortun ate ly peroxide also destroys good tissue which is why it stings on wounds and also why we now discourage its use on decu biti © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 4 7. Cytoskeleton - Network of proteins providing for cellular shape and/or movem ent - M icrofilamen ts and microtubules - Microfilam ents : rod-like stru cture s of a ctin an d m usc le filam ents Occ ur in both m uscle and non-m uscle cells - Microtubules- non-membranous cylindrical organelles contain tub ulin - Functions Structural support Inte rnal conduit for m ovem ent m ate rials within cells Provide for locomotion e.g. cilia Cytoskeleton: The microfilaments associate with the inner surface of the cell and aid in cell motility. The microtubules form the cytoskeleton and maintain position of the organelles 8. Centrosomes and centrioles Centromere: dense area of cytoplasm within nucleus Centriole: two hollow cylindrical structures within centrosome Function in non -dividing : organize microtubules Function in dividing cells: form spindle apparatu s for m itos is © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 5 PLASMA AND INTRACELLULAR MEMBRANES A. Introduction - Surrounds cells; sep arate s intracellular-extrace llular com partm ents - Organelles have mem branes - Primary role is to regu late pa ssa ge b etwe en c om partm ents - Role in cellular com m unication - selective b arriers - Composition Lipid bilayer: double layer of lipid molecules - polarity Phospholipids, glycolipids, cholesterol Amphipathic phospholipid m olecules - polar end and nonpolar end Polar end points toward interior of cell - hyd rop hillic Nonp olar buried in interior of mem brane - hyd rop ho bic Polarity allows m em brane to act as ba rrier - restricting loss and e ntry Mem brane exists in fluid sta te at body temp Structure is dynam ic - fluid mosaic m od el of m em brane structure Protein bound to eac h layer and within layers Anchored in or on lipid bilayer - forms structural component Proteins may have other structures attached to them CH O attache d outer surface - glycoproteins CHO attached to polar region - glycolipids Proteins also function to transport/ex change m ate rials - trans port Proteins function as enzymes Cell Membrane: Hydrophillic (polar) heads and hydrophobic (fatty acid) tails. Note positions of the integral and peripheral proteins in relation to interior and exterior of cell as well as the pores through which various substances pass CLINICAL EXAMPLE: Certain drugs which are said to be lipophilic can penetrate the cell membrane better than other drugs in the same class hence have better tissue levels and sometimes better efficacy. Certain ACE-inhibitor agents used to control hypertension are more lipophilic then others in the class and have increased tissue penetration with a long half-life (permitting once day dosing). Similarly older antihistamines (Benadryl -diphenhydramine) cross the blood-brain barrier causing sedation while newer - 2 ND generation antihistamines do not cross the blood brain barrier and have little or no sedation (Claritin - loratadine) © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 6 B. Functions of membrane components Lipid bilayer gives membrane its physical characteristics - Forms structure of membrane - Barrier (hydrophobic interior) to water-soluble substances: ICF - ECF - Gives membrane its fluidity Proteins give membrane its biologic features - “Gated channels” protein ion channels - ion passage - Protein channels across lipid bilayer - Channels permit passage of water-soluble substances - Ions are example of water-soluble substance - Channels are specific to ion; vary in number kind or type pending cell - Some channels are regulated - “open” or “closed” to specific ions - “Carrier molecules” - transport materials unable to transverse on their own - Bind with specific molecules - hormones or neurotransmitter - Orchestrate signal transmission to interior of cell - Catalyze biochemical reactions - ATP synthesis - energy production in mitochondria - Cellular structure - specialized membrane junctions CLINICAL EXAMPLES An entire class of antihypertensive drugs - calcium channel blockers - is based on the effects these molecules have on the calcium ion pores within the cell membrane. The issue is further complicated by so called fast-channel and slow channels Glucose requires protein molecules to “carry” the molecule across the cell membrane e.g. from the intestine where it is absorbed © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 7 MEMBRANE TRANSPORT - Passive movement: diffusion, osmosis, filtration, carrier-mediated facilitated diffusion - Active: energy driven carrier-mediated transport; endocytosis, exocytosis A. Diffusion - movement of a substance - Net movement of a substance from higher concentration to lower - Movement down a concentration gradient - Diffusion equilibrium: substance equally distributed between 2 compartments - No movement if substances equally distributed between two regions - Rate of movement - rate function of concentration gradient - Amount of substance; kinetic movement, size of membrane pores - Other factors: ability to dissolve in lipids; electrical charge - Plasma membrane presents barrier 1. Dissolve in fluid structure of plasma membrane and pass through 2. Pass through pores (channels formed by proteins) Na+, K+, Ca++, chloride, bicarbonate, water - Example: movement of O2 molecules; CO2, N2, steroids, fat-soluble vitamins Diffusion: Particles move from areas of higher concentration to areas of lower concentration so as to become equally distributed across membrane Osmosis osmotically active particles induce the flow of water across membrane CLINICAL EXAMPLES Ethyl alcohol (ETOH) readily diffuses across cell membranes and rapidly enters all body compartments accounting for the fact that it can affect a wide variety of body systems and functions. Oxygen and carbon dioxide readily diffuses across the cell membrane even in avascular areas such as the cornea or synovial joints B. Osmosis - movement of water - Net diffusion of water through selectively permeable membrane - Membrane separates two aqueous solutions with different solute concentrations - Membrane is impermeable to one or more of the solutes - If concentration on non-diffusable solute is greater on one side then net diffusion of water occurs (osmosis) through membrane toward area of higher solute concentration - Movement occurs until concentrations solute/solvent equal on both sides - Water molecules move from area of greater concentration to lower concentration - Pressure is created on membrane - Osmotic pressure - pressure created on membrane during water movement Magnitude of pressure is function of number of solute particles Greater the number of non-diffusible solute particles; greater is the pressure © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 8 CLINICAL EXAMPLES Clinical examples: brain swelling and use of osmotically active compounds like mannitol to pull water out of brain tissue and into blood Edema and anasarca when proteins is low - fluid flows out of blood vessels and into surrounding tissue Magnesium citrate is used as laxative because it osmotically pulls water into the colon causing loose stool. Similarly diabetic has polyuria because the osmotically active glucose pulls water into vessels which in turn are filtered by kidney into the urine - Isotonic - Fluids containing osmotically active particles in the same concentration as plasma (example sodium chloride 0.9%) - RBCs neither string nor swell in isotonic solutions - Water volume of cell remains constant - neither shrinks nor swells - Cells shrink in hypertonic solutions - water diffuse out of cells Higher concentration of osmotically active particles - Cells swell (burst) in hypotonic solutions - water diffuses into cells Lower concentration of osmotically active particles CLINICAL EXAMPLES Drowning in salt vs fresh water is readily apparent on autopsy due to (among other things) the effect of the hypertonic (sea water) presenting with shrunken lung cells vs hypotonic (fresh water) presenting with swollen lung cells. Normal saline (0.9%) causes neither shrinking nor swelling of erythrocytes or other body cells hence it is widely used in clinical therapy. There are select circumstances where hypertonic or hypotonic solutions would be used clinically but for the most part we tend to use isotonic solutions in clinical practice. C. Filtration - Substances move across membrane due to pressure differences - Move from areas of greater pressure to lower pressure - Example: Renal formulation of glomerular filtrate Large particles remain in capillaries due to size and impermeability of basement membrane CLINICAL EXAMPLE INFLAMMATION: Intercapillary fluid pressure - capillary filtration pressure forces water through pores and into interstitial spaces. Capillary filtration is a function of the arterial pressure, venous pressure and also the effects of gravity. Edema (swelling) which occurs when inflammation results histamine release which, in turn, causes dilation of precapillary sphincters and arterioles in the affected area. DVT: Venous thrombosis obstructs venous flow thereby producing increased venous and capillary pressures. Normally, the lower pressures would facilitate movement of fluid into the capillaries where it is pushed back to the heart to be re-circulated. In this case the increased venous pressure results in an outward flow (flow from capillaries into tissue) hence the associated swelling to the affected area. Typically DVTs present with swelling, redness and pain. © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 9 D. Carrier-mediated transport systems Certain molecules need carrier to travel down gradient - Molecule is too large to pass unaided - Molecule is not lipid soluble hence needs carrier Examples: glucose, amino acids, inorganic ions (Na+, Cl-, K) Some require energy (active) some require no energy in put (facilitate diffusion) Specificity - specific for a particular solute Example: glucose transport system will not transport other molecules (aa) Saturation: maximum rate (transport maximum) at which solute can be transported System is saturated if more solute is present Saturated system transports at maximum rate; can’t handle additional solute Below saturation level rate is proportional (linear) to solute concentration Higher the solute faster the rate of transport Competition Same carrier system transports two different molecules Rate of transport for each will diminish by presence of other Solutes compete for carrier; some of each transported at maximum rate Energy Dependency Many carrier systems require energy Metabolic inhibitors (interfere with energy-producing reaction) stop transport Speed Substances transported by mediated transport usually more rapid than simple diffusion 1. Facilitated diffusion Carrier protein - facilitates movement of molecule which otherwise can’t diffuse - Energy not required because movement is down the gradient - Subject to protein-binding - System is saturable - Subject to competition - Example: glucose across membranes of RBCs, muscle, adipose - Molecule is too large to pass unaided; not lipid-soluble - Combines with carrier - conformational changes Insulin increases number of transport proteins Insulin also increases rate of glucose metabolism Facilitated Diffusion: carrier system required to move molecules across gradient. Moves down gradient thus no energy requirement © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 10 CLINICAL EXAMPLE Glucose in urine (glycosuria) of diabetic. Excess blood glucose saturates carrier system in kidney which normally re-absorbs all of the glucose presented. Kidney cannot keep up and glucose “spills” into urine. Glycosuria creates osmotic gradient which in turn increases water content of urine and results in polyuria Certain drugs - aspirin for one - are carrier mediated. Blood levels (and toxicity) are directly related to increased dosing (linear) to a point then toxicity sharply rises (nonlinear) with small increases in dosing after the point when carriers become saturated. - tinnitus, GI toxicity 2. Active transport - Carrier-mediated process against concentration gradients - Energy (ATP) is required because movement is against gradient - Reverses the effects of diffusion - Always requires energy; reverses diffusion - All body cells capable of active transport - Depends on energy derived from metabolism - Two classes depending on how system derives energy Active Transport: selected molecules transported across membrane against gradient thus require using energy driven ATP pump a. Primary active transport systems - Same protein which binds is also capable of hydrolyzing ATP - Uses energy released to move against gradient FOUR PUMPS - Sodium-potassium adenosine triphosphatase (Na+,K -ATPase)* - Calcium ATPase (maintains lower conc Ca++ in cytoplasm) - Hydrogen ion ATPase (energy transduction; acid-base balance) - Hydrogen-potassium ATPase (acid-secreting cells stomach, kidney) * Na+,K -ATPase pump is important for cell volume regulation - Prevents accumulation of Na+ ions in cell - Water follows Na+ (osmosis); pump prevents H20 influx - Accumulation of Na+ in ICF causes osmosis of H20 into cell - Pumping Na+ out counteracts tendency of water to enter cell CLINICAL EXAMPLE: hypoxia causes decreased/ceased cellular metabolism (no ATP is generated) hence pump does not operate. Na+ is not removed from cell and water follows resulting in cellular swelling © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 11 b. Secondary active transport systems - Many organic molecules transported via this method - Uses ion gradient created by primary active transport as energy source - Concept is similar to kinetic energy of a dam Water is allowed to build; when dammed-up water is released, the energy released can be harnessed for other purposes - Ions allowed to flow down gradient create energy - Energy so created used to drive another reaction against the gradient - Energy is stored in ion gradient - can be used in 2 ways - Phosphorylate ADP to ATP for purposes of energy storage - Coupled to the pumping of another solute molecule - Most common ion used is sodium - sodium binds to transport protein - Result is change in affinity of binding site for transported solute - Allosteric modulation - Binding of ligand to a protein - Changing conformation of protein - Sodium moves down gradient - transported substance moves against gradient Cotransport or symport - both molecules move in same direction Counter-transport - molecules move in opposite directions through common carrier mechanism CLINICAL EXAMPLE: There is a coupled ratio of glucose-sodium in a 1:1 molar ratio in the intestine via a sodium-glucose cotransporter. This discovery (early 1960s) led to the formulation of oral rehydration solutions for the treatment of diarrhea particularly for infants/children. The glucose in these oral rehydration solutions acts through a sodium-coupled transport mechanism to promote fluid absorption in the small intestine even during diarrheal episodes. Accordingly the glucose-sodium solutions reduce (potentially dangerous) fluid loss from diarrhea. Gatoraide and Pedialyte are mildly sweet and salty at the same time. E. Endocytosis and exocytosis Endocytosis: process of bringing particles into cell and releasing into interior Exocytosis: process releasing secretions to exterior of cell Pinocytosis: Exocytosis: membrane engulfs particle forming vacuole transporting it inside cell. Exocytosis: membrane surrounds particles within cell forming vacuole which subsequently transports contents across membrane and releases them into extracellular fluid © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 12 Endocytosis: bringing in protein an other substance through cell wall invagination Pinocytosis - movement in of water or ECF adhering to cell membrane Phagocytosis: ingestion of particulate material or macromolecule (commonly refers to engulfment of bacteria) Receptor-mediated endocytosis Movement of substances through cell-surface receptors that stimulate endocytotic process Cell membranes have cell-surface receptors Substances - ligands - bind selectively - taken into cell Example LDL which provide cholesterol for membrane synthesis LDL = low-density lipoprotein Exocytosis - reverse pinocytosis - active release of products into ECF - Secretion granules formed by Golgi apparatus - Formed granules move to inner surface of membrane causing outpouching - Outpouching ruptures and releases contents - Secretory process necessary for digestion, glandular secretion, neurotransmission Endocytosis: Membrane engulfs particles forming vacuole which is taken into the cell Exocytosis: Particles engulfed within vacuoles then expelled from cell through membrane CLINICAL EXAMPLE Monocytes (type of WBC) and macrophages (tissue monocytes) are large cells which function to engulf bacterial and viral organisms (phagocytosis). Killer lymphocytes also function in this manner. While some WBCs “die in combat” e.g. neutrophils (type of granulocyte) generally die at the site of infection releasing microbe-toxic substances in the process, monocytes very often survive the phagocytotic process. Subsequently, they may expel the remains of the organism(s) so destroyed (exocytosis) Low density lipoprotein (LDL) is a necessary molecule to facilitate cholesterol import into the cell for membrane synthesis. Too much LDL however (very endemic in cultured societies) results in hyperlipidemia and the associated sequelae of atherosclerotic cardiovascular and cerebrovascular disease © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 13 F. Epithelial transport Molecules cross epithelial cells via one of two routes Paracellular pathway: molecules pass through extracellular spaces Transcellular pathway (more common) - pass through cell Molecule must cross both basal and luminal pathways May involve active and passive processes Epithelial Structure: Arrangement of epithelial cells in relation to underlying tissues and blood supply. Epithelial tissue has no blood supply of its own relying instead on vessels in underlying connective tissue for nutrients (N) and elimination of wastes (w) © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 14 ELECTRICAL PROPERTIES OF CELLS Membrane potentials - Differences in electrical potential across membrane - Characteristic of all living cells - Exists due to unequal ion distribution on either side of membrane - Factors maintaining unequal distribution - Differences in membrane permeability to various ions - Active transport systems - Membrane with potential said to be polarized - Inside of cell is more negative than outside Cell Membrane Potential: negative charge along cell membrane. Electrical potential is negative on the inside of cell membrane relative to the outside Cells are “excitable” when they can generate action potential (AP) Can generate impulses along their membrane Impulses so generated transmit signals along membrane Resting membrane potential normally -70 to -85 mV from inside to outside Small excess of negative ions in the intracellular fluid (ICF) Small excess of positive ions in the extracellular fluid (ECF) Opposite charges attracted to one another - membrane separates them Graph of Action Potential Potassium (K+) higher concentration in intracellular fluid Sodium (Na+) higher concentration in extracellular fluid © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 15 Potassium and sodium ions are the major determinants of resting membrane potential Membrane at rest is more permeable to potassium than sodium More potassium leaks out of cell 50-70 times more potassium channels than sodium channels Potassium moves down concentration gradient Some of positively charged K+ ions move into cell due to electrical gradient Equilibrium potential: occurs when electrical and concentration gradient are equal - Value is function of concentration gradient of ion across membrane - Larger the concentration gradient, the greater equilibrium potential Equilibrium potential value varies with cell type Average cell : K+ = -90 mV; Na+ = +60mV Nerve cell: -70 mV Some positively charged Na+ ions are leaking into cell making it slightly more positive than usual potassium equilibrium potential Nerve cell excitability - Neither K+ nor Na+ are at equilibrium so flow of ions continues - Resting membrane potential is closer to potassium equilibrium potential - Gradients maintained via Na+, K+ -ATPase - Pumps Na+ - which has leaked into cell - back out of cell - Pumps K+ - which has leaked out of cell - back into cell - Pump is unequal resulting in a net charge across membrane Pumps 3 Na+ ion out for every 2 K+ ions in Results net movement of charge across membrane creating potential Accounts for name “electrogenic pump” - Transient changes in membrane permeability to ions - Alter voltage across membrane - Major mechanism by which cells can communicate CLINICAL EXAMPLE excess potassium (K+) given IV can stop the heart - mimicking an MI due to its effect to decrease membrane reactivity. Done intentionally, it may not be readily apparent and has, at times, become a forensic issue where “foul-play” is suspected. Similarly, during open heart surgery, the heart is bathed in a potassium solution - the so-called cardioplegic - to stop the heart. The solution is then flushed away with normal saline after surgery is completed to allowing the heart to resume beating. Cell excitability - changing or altering electrical potential across cell membrane - Nerve and muscle cells are considered excitable - Can change membrane potential - Effect an action or response - Return to resting state - Excitable cells rapidly change resting potential in response to stimulus - Graded potential - local potentials that vary in amplitude - conducted decrementally - Action potential: rapid reversal of polarity in electrically excitable cells © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 16 A. Action potentials Effect responses in target cells mainly skeletal muscle and next neuron After AP cell returns to normal resting state - re-establishes resting membrane potential Process occurs in wave which spreads down neuron - Entire membrane does not depolarize at once - Results in propagation of a nerve impulse Nerve impulse is wave of depolarization followed by wave of repolarization Depolarization-repolarization travels along nerve away from point of stimulation Once generated - impulse conducted in identical manner without change No change in magnitude or velocity Stimuli (individual or collective) which fail to generate AP produce no nerve impulse Response of nerve to stimuli is per all-or-none law (maximal or zero) Nerves don’t generate weak or strong impulses as a function of stimuli intensity At axon terminal- AP activates voltage-sensitive Ca++ ion channels Located in presynaptic membrane Ca++ ions diffuse into cell Ca++ diffusion stimulates vesicles containing neurotransmitters - Vesicles fuse with membrane and release contents into synapse - Neurotransmitters diffuse across synapse Neurotransmitters cross synapse - bind to postsynaptic neuron receptors Ultimately trigger response on target cell (tissue) Refractory period: minimum amt of time after AP before cell can be restimulated Length of refractory period determines conduction frequency - Maximum number of impulses which can be conducted per second - Fibers with shorter refractory periods have higher conduction frequency - Fibers with longer refractory periods have lower conduction frequencies Nerve fibers conduct impulses at higher frequency than myocardial fibers Neuron Showing cell body, axon and dendrite Synapse: Shows rupture of vesicles with diffusion of neurotransmitter across synapse to another neuron (left) and to neuromuscular endplate (right) © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 17 CLINICAL EXAMPLE: The SA node of the heart is called the pacemaker. This is because it is the first area to depolarize and initiate and action potential which spreads throughout the heart via the normal conduction pathway (SA node to AV node to bundles etc.). The end result is atrial and ventricular contraction when the action potential spreads to the respective muscle fibers which then depolarized and contract. Similarly, the SA node it has the shortest refractory period hence it is the first area capable of depolarizing again Occasionally arrhythmias occur when there is a portion of the heart (outside of the AV node) - spontaneous pacemakers - which spontaneously depolarizes and aberrantly takes over the role of the pacemaker. Calcium ions decrease membrane permeability to sodium and vice versa. With insufficient calcium (hypocalcemia), permeability to sodium increases and membrane excitability increases which results in spontaneous muscle movement known as low-calcium tetany Local anesthetics (procaine, lidocaine, cocaine, etc.) operate via decreasing membrane permeability to sodium and preventing an action potential from occurring STAGES OF ACTION POTENTIAL 1. Adequate positive stimulus to neuron causes rapid and marked change in membrane potential (MP) - Sodium permeability increases - Na+ enters faster than it can be pumped out 2. Membrane potential less negative as more Na+ passes through - Potential is reduced to critical value called threshold - Gated Na+ channel open at -45 mV - rapid infusion of Na - Membrane is more permeable to Na+ than K - Na+ equilibrium - inside of membrane becomes more positive 3. Depolarization Positively charged Na+ reverses polarity of membrane potential -> AP - AP when inside of cell becomes positive to outside of cell - Increase in membrane permeability is transient (less 1 msec) - Inactivation gates of sodium channel begin to close 4. At peak of AP K channels open thus increasing permeability to K+ ions - Increase in K+ diffusion out begins - it accelerates movement of Na+ - Causes inside of membrane to become positive - K+ leaves cell for same reasons Na+ entered - Favorable electrical and chemical gradient - Increased membrane permeability 5. Diffusion of Na+ inhibited by decrease in K+ permeability - Net loss of K+ from inside causes MP return to zero then become positive - Reestablishment of resting membrane potential - More K+ leaves cell than is actually required to restore resting MP © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 18 6. Hyperpolarization: inside of membrane briefly more negative than normal resting state - Sodium-potassium pump returns normal membrane resting potential - Pump exchanges internal Na+ for external K+ - Restores normal internal/external ratios of the ions 7. Repolarization - activities which restore resting membrane potential CELLULAR ENERGY METABOLISM - Sum of all biochemical reactions - anabolic (building) and catabolic (breaking down) - Many reactions require energy - would not occur spontaneously - ATP is major cellular energy unit - required for many functions - adenosine triphosphate - Nucleic acid derivative containing high energy phosphate bonds - Release energy when bonds are broken - All cells generate ATP from catabolism of energy (fuel) sources - Energy generated as ATP is transferred to cellular functions - Energy is released during breakdown of ATP to ADP (adenosine diphosphate) - ATP production via three metabolic pathways - glycolysis, Krebs cycle, oxidative phosphorylation A. Glycolysis - Breakdown of glucose (hexose) into two 3-carbon pyruvate molecules - Lactic acid is byproduct - diffuses out into tissue and plasma - Enzymes for the breakdown in cytoplasm - requires 10 enzymes - CHO are only fuel molecules involved (only carbohydrates can be used) - Generates 4 molecules ATP for each glucose but 2 used in process - net of 2 ATP - Anaerobic system - inefficient but can keep cell viable for short periods - Forms less than 5% of ATP needed - Occurs during intense muscular exertion where O2 demand exceeds supply - Produces oxygen debt requires deep breathing afterwards to restore debt - Process of restoring called recovery oxygen consumptions (minutes to hours) - Lactic acid in muscle reconverted to glucose or pyruvic acid in presence of oxygen - Lactic acid leaving cell during exercise travels to liver and changed to C02 and glycogen ATP - adenosine triphosphate Storage form of cellular energy. Energy released from hydrolysis of highenergy bonds fuels cell metabolism © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 19 CLINICAL EXAMPLE On vigorous exercise (or not-so-vigorous if one is “out-of-shape”) the person begins to feel muscle pain as the lactic acid accumulates. Eventually pain increases to a point where exercise must stop. With conditioning, more and more exercise can be performed prior to pain making further movement intolerable. Figure skaters, for example, will report leg muscles aching as they near the conclusion of their programs. When experiencing lactic-acid induced pain, they are then less able to perform the more demanding athletic feats as compared to earlier in the program prior to the build-up. They frequently schedule “rest periods” between jumps where they simply glide around the ice. Skaters (and other athletes) are observed to be breathing heavily at the end of their performances (often while seated and waiting for their scores) as they repay the oxygen debt during so called recovery oxygen consumption. Similarly, deep knee bending or holding prolonged muscle positions in ballet exercises will often cause the muscle quivering as lactic acid levels build. Cell Metabolism Glycolysis: anaerobic process which is less efficient (2 ATP). Uses glucose as energy source and generates lactic acid as a byproduct Krebs Cycle: first step in aerobic metabolism - uses CHO, lipids or proteins as energy source - End products enter oxidative phosphorylation to form ATP © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 20 Krebs cycle - First step in aerobic metabolism - Also known as citric acid cycle - Aerobic process - requires oxygen - Several products can be used as fuel (carbohydrates, lipids, proteins) - Required enzymes located in mitochondrial matrix - Acetyl coenzyme A (acetyl CoA) is major substrate (from pyruvate) - Pyruvate (from glycolysis) is major fuel molecule as converted to Acetyl CoA - Pyruvate is converted to acetyl CoA in mitochondria - Lipids and proteins also form acetyl CoA which enters cycle - Acetyl CoA from lipid and protein metabolism also enters - Amino acids are capable of entering at certain points (can thus be used as fuel) - First step is combination of 2 acetyl groups with 4 carbons forming citrate - Eight sequential steps follow - each cycle produces the following end products - 2 molecules of CO2 - 4 coenzymes formed from transfer of 4 pairs of H+ atoms Flavin adenine nucleotide (FAD) to form 1 FADH2 Nicotinamide adenine dinucleotide (NAD) to form 3 NADH - 1 Guanosine triphosphate (GTP ) from phosphorylation of guanosine diphosphate (GDP) - Transfer of H+ ions to coenzymes represents transfer of energy - These transferred H+ ions subsequently used in oxidative phosphorylation - End products of Krebs cycle used in oxidative phosphorylation to form ATP Oxidative Phosphorylation: Last step in aerobic metabolism - Uses H+ electrons to transfer energy via reduced coenzymes formed in glycolysis and krebs - Results in energy release and formation of 38 molecules of ATP in combination with Krebs © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 21 C. Oxidative phosphorylation - Last step in aerobic metabolism - Synthesis of ATP from ADP - Uses energy released when molecular O2 combines with H+ to form water - Enzymes located in inner mitochondrial membrane - Uses hydrogen atom (H+) electrons to transfer energy - Transfers of H+ is via the reduced coenzymes formed from glycolysis and Krebs - H+ electrons transferred to series of metal-containing enzyme complexes - Metal-containing enzyme complexes known as electron transport chain (ETC) - Molecular oxygen is the final acceptor molecule in the chain - As electrons flow through complex, series of energy transfer occurs - Each protein complex in ETC has greater affinity for electrons than previous protein - Electrons flow from higher to lower energy states - thus energy is released - Energy so released is used to pump H+ across mitochondrial membrane - Pumped into intermembrane space - Sets up an ion gradient - Flow of ions back down electrochemical gradient provides energy - Energy so provided used for oxidative phosphorylation of ATP - Chemiosmotic model - Protons pass through enzyme protein channel known as ATP synthetase - Energy released as protons diffuse across membrane - Released energy from ATP synthetase use to phosphorylate ADP to ATP - ATP output is 38 molecules for Krebs-oxidative phosphorylation - 3 ATP for each NADH - 2 ATP for each FADH2 - Aerobic process much more efficient than anaerobic pathways CLINICAL EXAMPLES ATP DEFICIENCY: A variety of relatively rare diseases - collectively known as oxidative phosphorylation diseases - present with muscle weakness and multi-organ system dysfunction. All of these diseases are related to an inability of the mitochondria to produce adequate amounts of ATP. List is quite extensive and comprises mostly rare or little-known diseases, however, some of the more well known diseases on this list include Frederick’s ataxia, pigmentary retinopathies, certain sequelae of diabetes, and neuropathy syndromes. DIABETIC KETOACIDOSIS: The Krebs cycle uses pyruvate (from glycolysis) as the major fuel molecule from which the end products (CO2, FADH2, NADH, GTP) are produced. These end products are subsequently acted upon via oxidative phosphorylation to produce 38 molecules of ATP for energy. Lipids and proteins can also be used as an fuel source although in the normal, non-diabetic individual, they are used to a much lesser extent as compared to pyruvate (from glucose). Due to the diabetic’s insulin deficiency, glucose is not available as a fuel source resulting in excess breakdown of adipose stores which, in turn, result in increased levels of free fatty acids. These free fatty acids are oxidized within the liver via acetyl CoA producing ketone bodies (acetoacetic acid and beta-hydroxybutyric acid). Oxidation is accelerated by glucagon. The ketone bodies so formed exceeds the rate at which they can be utilized by muscle and other tissue. Accordingly, ketonemia and ketonuria develop. Dehydration will further compromise urinary excretion of ketones resulting in increased plasma hydrogen ion (H+) and systemic metabolic ketoacidosis. Ketogenic amino acid from protein catabolism further increases the ketotic state. Infections commonly precipitate ketoacidosis in the diabetic because the stress of the infection increases insulin requirements © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 22 THE NUCLEUS AND REGULATION OF GENE EXPRESSION - Nucleus: large membranous organelle - frequently centrally located within cell - Large quantities deoxyribonucleic acid (DNA) which forms genes - Genes control synthesis of proteins which, in turn, controls cellular function - Nuclear envelope separates nucleus from cytoplasm - large membranous envelope - Two distinct membranes (in contrast to plasma membrane) - Fused together periodically to form circular pores Materials pass in and out of nucleus via pores Pores 10X larger than plasma membrane pores Proteins pass through pores with relative ease - Ions-water move easily between nucleus and cytoplasm - Nucleolus - collection of dense fibers and granules within nucleus Most visible when cell is not in mitosis Primarily RNA and proteins Granules are precursors of ribosomes (sites of protein synthesis) - Chromatin: long molecules of DNA in association with protein Non-visible with light microscope except during mitosis Coil and condense during mitosis into chromosomes - Chromosomes - X-shaped structures (condensed chromatic during mitosis) 22 pairs of autosomes - different in size and shape from each other 1 pair sex chromosome - XX or XY A. Genes Entire cellular activity controlled via genes Linear sequence of nucleotides on DNA Code for production of a single protein Sequence divided into units of 3 nucleotides - each called codon (triplet) Exact sequence of codon codes for single amino acid Nucleotide bases: guanine, thymine, cytosine, adenine Genes determines specific code that transcribed as RNA Gene is located on one of the two DNA strands - master strand template (pattern) Template for messenger RNA (mRNA) synthesis Transfer RNA (tRNA) or ribosomal RNA - formed from template on other parts DNA Genetic code (to ribosomes) allows formation of several thousand proteins Essential to function of organism Most proteins contain 100 to 1,000 amino acids DNA Double Helix: Showing sugarphosphate-sugar backbone supporting the paired four bases where cytosine pairs with guanine and adenine pairs with thymine © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 23 CLINICAL EXAMPLE Substitution of a single amino acid glutamic aid is replaced with valine resulting in the synthesis of an abnormal globulin chain causing the formation of hemoglobin (HbS) which results in sickle cell anemia. Whether the person has relatively asymptomatic sickle-cell trait or the actual disease, sickle cell anemia, depends on whether the individual is heterozygous (one abnormal gene and one normal gene) or homozygous (two abnormal genes) for the abnormal trait. Chromosomes are paired structures, made up of individual genes. Individuals inherit one chromosome (with its associated genes) from each parent . Variety of genetic combinations (and associated disease states) are possible depending on the genetic makeup of the parents B. RNA and protein synthesis Almost all chemical reactions are enzyme dependent All enzymes are proteins - synthesis is controlled by nuclear DNA Cellular activity regulated directly or indirectly by DNA DNA contains blue prints for other proteins - hormones, structural proteins DNA visualized as twisted ladder - double helix model RNA formed from DNA template and travels outside nucleus DNA-Directed Control of Cellular Activity - Synthesis of Cellular Proteins. Messenger RNA carries the transcribed message which directs protein synthesis from the nucleus to the cytoplasm. Transfer RNA selects the appropriate amino acids and carries them to ribosomal RNA where assembly of proteins takes place © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 24 1. Transcription: Synthesis of RNA from DNA (in the nucleus) DNA partially unwinds One strand acts as template on which mRNA is synthesized Other strand is noncoding DNA coding is carried via series of triplets (bases) Code is transferred to RNA via complementary pairing bases Only part of gene is transcribed Non-transcribed portions important for regulation of transcription RNA leaves DNA, leaves nucleus and forms template for protein assembly 2. Translation Translation (protein assembly) occurs in ribosomes (in cytoplasm) mRNA leaves by way of pores in nuclear envelope enters cytoplasm mRNA becomes associated with ribosomes - organelles which synthesize proteins Correct amino acids are joined in proper sequence to form a protein molecule Assembly process is called translation Once mRNA is associated with the ribosome, peptide (protein) synthesis rapidly occurs DNA Double Helix and Transcription of Messenger RNA (mRNA). Top panel: sequence of four bases (adenine, cytosine, guanine, thymine), which determines specificity of genetic information. The bases face inward from sugar -phosphate backbone and form pairs (dashed lines) with complementary bases on the opposite strand. Bottom panel: transcription creates a complementary mRNA copy from one of the DNA strands in the double helix CLINICAL EXAMPLE: Occasionally, a patient has an idiopathic reaction to a drug which is usually safely prescribed for most patients. Such idiopathic reactions are unpredictable and not dose-related. As an example, most people were able to troglitazone (Rezulin) - drug designed for Type II diabetes - without problems. Rarely, however, some patients experienced fatal liver toxicity; the drug was eventually withdrawn from the market. Human (animal) biochemistry is made up of thousands of enzyme reactions, leaving the potential for genetic variation in the form of spontaneous or inherited mutations. Many of these enzyme variations (mutations) are not clinically significant. However, the potential exists for clinical consequences where a particular drug interacts negatively with a here-to-fore unnoticed (clinically insignificant) enzyme variation. © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 25 CELLULAR REPRODUCTION - Mitosis - means of cellular reproduction; most cells can reproduce - Adult: new cells replace old, worn, damaged cells - Control - rigid control allows for replacement of only needed cells - Turnover is billions of cells per day - Specific controls produce the correct quantity of cells - Diminished stimulation or specific inhibition controls stops process - Neoplasia occurs when control process does not function CLINICAL EXAMPLE: RBCs reproduce at levels to maintain normal hemoglobin and hematocrit thereby prevented the individual from polycythemia (excess RBCs manifest by a high hemoglobin). Erythropoietin is a compound normally secreted by the kidney which functions to stimulate RBC production to maintain normal levels. Formulated as a drug, it is used to treat patients with anemia often secondary to renal or HIV disease. Athletes have been known to illicitly inject erythropoietin in an effort to stimulate RBC production in an effort to enhance sports performance via an increased oxygen-carrying capacity. The drug, a natural compound, is otherwise undetectable except that the athlete will have an abnormally high hematocrit simulating polycythemia. While a COPD patient would be expected to have polycythemia, an athlete would not normally present in this manner. Many sports associations disqualify athletes whose hematocrit is above 50%. This problem has presented in the Tour de France bicycle race as well as in the 2002 Winter Olympics wherein several athletes where disqualified. Regeneration of cells Regenerative capacity: ability of cells to reproduce Labile cells: regenerate frequently - life-span measured in hours or days Leukocytes Epithelial cells Stable cells: reproduce only under special circumstances - life-span years or even lifetime Osteocytes (bone), parenchymal cells (liver), glandular cells Mitotic figures rare but abundant after injury (liver can regenerate readily) Permanent cells - live for entire life of organism Nerve cells (neurons lose ability to reproduce after 6 months) Most muscle cells eg cardiac muscle does not regenerate - forms scar after MI Reproduction of cells The cell cycle Begins when cell is created from division of its parent cell Ends when cell divides forming two daughter cells Replication: chromosomes duplicate themselves in anticipation of mitosis Mitosis: process by which cell divides forming 2 identical daughter cells Meiosis: specialized form of reproduction which occurs only in gametes © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 26 STAGES OF CELL CYCLE G1 stage Time interval after cell formation which precedes replication of DNA S stage - time during which DNA replication occurs G2 stage - time interval after DNA replication; before beginning of M stage M stage - time period when cell division occurs Go stage - time interval during which no reproduction occurs Cells not destined for early reproduction can be arrested at Go stage Stable cells can be stimulated to go from Go to G1 to replace lost cells STAGES OF CELL CYCLE G1 Stage - time interval after cell formation which precedes replication of DNA S Stage - time during which DNA replication occurs G2 Stage - time interval after DNA replication; before beginning of M stage M Stage - time period when cell division occurs Go Stage - time interval during which no reproduction occurs • Cells not destined for early reproduction can be arrested at Go stage • Stable cells can be stimulated to go from Go to G1 to replace lost cells Replication Replication occurs during the S stage of interphase DNA strands uncoil and form template Each daughter cell inherits one new strand and one parent strand Chromatids: two identical double-stranded DNA molecule MITOSIS: reproduction processes for non-gamete cells - Process where cell splits into two daughter cells - Each cell has identical chromosomes to original - All cells except gametes (sperm/egg cells) divide in this fashion - Enables organism to grow while cell size remains small - Example: reproduction of blood cells in the bone marrow © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 27 PHASES OF MITOSIS Prophase - chromatin condenses into two distinct chromosomes Paired chromatids joined at centromere Nuclear membrane/nucleolus disappear Centrioles migrate to opposite poles; spindle fibers forms between them Metaphase Chromosomes align in plane along spindle midway between poles Plane called equatorial plane Equal pull from two poles Anaphase Centromere division Newly divided chromosome move to opposite poles of spindle V-shaped chromosomes pulled through cytoplasm by spindle Telophase Two sets of daughter chromosomes gather at opposite poles New nuclear envelope forms around each set Chromosomes gradually unravel and disperse Spindles disappear; centrioles remain, nucleolus reappears Cleft or cleavage forms in plasma membrane Cytoplasm divides equally during anaphase-telophase - cytokinesis Furrow deepens - cell splits © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 28 MEIOSIS Reduction division - special nuclear division which forms gametes Ova: 1 ovum and 3 polar bodies from each parent call Sperm: 4 sperm formed from parent cell 2 stage process resulting in 4 cells Produces daughter cells with ½ number of chromosomes as parent cell Enables cells to reproduce sexually Sexual reproduction creates organisms which are unique • Asexual reproduction (mitosis) produces organisms which are identical with the parent cell • Sexual reproduction results in production of new organism which is unique and contains genetic material from each of 2 parents Subsequent union of gametes form zygote which develops into new organism PHASES OF MEIOSIS Gametogenesis Meiosis 1 - Number of cells is doubled; chromosom e number unchanged - Results in ½ num ber of chrom osom es per cell - Prophase 1, metaphase 1, anaphase 1, telophase1 M eiosis 2 - Division is similar to mitosis - The number of chromosom es does not get reduced - Prophase 2, metaphase 2, anaphase 2, telophase 2 Oogenesis results in 1 ovum and 3 polar bodies after meiosis Spermatogenesis where meiotic division results in 4 spermatozoa from primary spermatocyte cells © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 29 PHASES OF MEIOSIS MEIOSIS I Prophase I - Events similar to those which occur during prophase I of mitosis - Chromosomes coil up; nuclear membrane disintegrates - Centrosomes move apart - Synapsis of homologous chromosomes produce tetrads (bivalents) - Crossing over: process whereby two chromosomes exchange fragments Likely to occur at several different points Results in chromosomes which are mixtures of original two chromosomes - Chiasmata (sing chiasma) areas where crossing over has occurred Hold chromosomes together until they separate during anaphase Chromosomes partially separate during late prophase - Kinetochore forms on each chromosome instead of on each chromatid in mitosis - Spindle fibers: attach to chromosomes and begin to move them to center of cell Crossing Over Occurs between homologous chromosomes at several different points. Results in mixtures of the original two chromosomes. Chiasmata: areas where crossing over has occurred (remain attached until anaphase). Crossing over and independent assortment promotes variation in gametes. Results in gametes with some genes from each of the two parents - Accounts for why various children from same parents are unique Metaphase I - Bivalents (tetrads) become aligned in center of cell - attached to spindle fibers - Independent assortment: random arrangement of pairs of chromosomes - Various alignment possibilities of chromosomes inherited from each parent - Random arrangement contributes to variability among gametes Anaphase I - homologous chromosomes separate Telophase I - Nuclear envelope reforms and nucleoli reappear (stage absent in some species) Interkinesis Interkinesis is similar to interphase except that DNA synthesis does not occur © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 30 MEIOSIS II - Similar to mitosis Prophase II - similar to prophase of mitosis Metaphase II - similar to metaphase of mitosis Anaphase II - similar to anaphase of mitosis Telophase II - similar to telophase of mitosis CLINICAL EXAMPLE Meiosis accounts for variation of the individual which in turn accounts for adaptation and ultimate survival of the species. Offspring of sexual reproduction are unique individuals having characteristics of each parent. Various combinations of genes (expressed and recessive) from each parent in addition to random mutations accounts for disease resistence, biologic differences which impact on the survival of any species. As an example, certain people who have been repeatedly exposed to the HIV virus have never seroconverted because these individuals genetically lack the binding site needed for the virus to enter the cell. Another example involves tolerance to measles which had evolved over centuries in Europeans who had long been exposed to this disease. Measles was not typically lethal for this group of people who normally recovered uneventfully from a childhood episode. By contrast, the native Hawaiian Islanders - a group never previously exposed to measles - were wiped out in huge numbers during the 1800s when they contracted this disease from European missionaries and colonizers who traveled to the Islands. Finally, one of the concerns regarding possible cloning of livestock or other animals is the lack of genetic variation would leave large numbers of individuals vulnerable to new diseases. In contrast to animals, most plants can reproduce both asexually (via rooting shoots, cuttings, etc) or sexually (via planting seeds). In the former case - the plant grown from a cutting - is identical (cloned) to the parent plant. In the latter case - the plant grown from seed - will likely show some degree of variation (color, disease resistence, type of fruit, etc.). © 2003 Lois E. Brenneman, MSN, CS, ANP, FNP all rights reserved - www.npceu.com 31