Foundations Summary-Maddee Tweel Class of 2024 PDF

BIOCHEM: LECTURE 1 – GENE EXPRESSION DNA Transcription - Nucleotides: base + sugar + phosphodiester linkage - RNA polymerase binds NTPs to antisense strand of DNA - 5’ > 3’ -...

BIOCHEM: LECTURE 1 – GENE EXPRESSION DNA Transcription - Nucleotides: base + sugar + phosphodiester linkage - RNA polymerase binds NTPs to antisense strand of DNA - 5’ > 3’ - Addition of 5’ cap helps protect from degradation DNA replication - Addition of poly A tail protects from cytosolic enzymes - DNA pol III recognizes RNA primer and extends w DNA Translation Genome - 20 AA specified by three base codons Exome: coding portion of genome - Code is degenerate - Organism complexity related to number of protein - AUG initiation coding genes and number of genes involved in communication Gene expression Microbiome = bigger than genome - Controlled most importantly through initiation of transcription RNA Euchromatin: loose, transcriptionally permissive - contains 2’ hydroxyl on sugar Heterochromatin: condensed - Histone acetylation promotes transcription - DNA methylation inhibits transcription BIOCHEM: LECTURE 2 – PROTEINS Proteins Post translational modification Proteome: entire compliment of proteins that can be 1. Phosphorylation (metabolism and signal transduction) expressed by a cell a. Protein kinases/ removed by phosphatases - Protein sequences written from amino (N) to carboxy 2. Glycosylation (protein stability, targeting, recognition) (C) terminus a. Attachment of carbs to Asn/Ser 3. Proteolysis (activation of proteases/hormones) Amino acids a. Enzymatic cleavage - At neutral pH: amino + and carboxy – - Classification based on side chain (polarity, ionizability) Protein denaturation: loss of 2-4 structure (irreversible) o Hydrophobic: protein interior (stabilize) o Polar: protein exterior (binding/catalysis) Enzymes - Decrease activation energy by binding to transition Peptide bonds state and providing correct orientation - Planar, no longer charged groups, cleaved by proteases - Mass spectrometry used to identify proteins in sample Biomarkers - Diagnostic for disease/response to therapy - Isozymes: proteins generated from diff genes but same function Conformational diseases - Alzheimer disease: beta-amyloid fibril - Mad cow disease: prions BIOCHEM: LECTURE 3 – CELL STRUCTURE AND DYNAMICS Protein traffic roadmap Cytoskeleton Gated transport Transmembrane transport Vesicular transport Provides structure and support, intracellular Nucleus: internal Mitochondria: N-terminal ER retention: C-terminal transport, contractility and mobility and basic sequence amphipathic helix KDEL sequence spatial organization Peroxisome: C-terminal SKL Lysosomal targeting: - Main elements: microtubules, actin (Ser, Lys, Leu) sequence attachment of M-6-PO4 filaments and intermediate filaments ER import: N-terminal hydrophobic sequence* this Cytoskeletal disease pathogenesis will be on any protein that - Impaired Keratin: Epidermolysis bullosa travels through ER (affects dermal-epidermal junction) - Cytosol: no signal - Mutated Lamin A gene causes a variety of - Proteasomal degradation: sequences rich in Pro, Glu, Ser, Thr disease - Some cancer treatments inhibit microtubules Lysosomal targeting Lysosomal hydrolase enters cis-Golgi from ER > M6P is added Membrane transporters & channels > binds M6P receptor and buds-off in Clathrin coated vesicle Unfacilitated: diffusion of hydrophobic molecule (passive) > vesicle fuses with acidic pre-lysosomal endosome resulting Facilitated: in dissociation of M6P > M6P receptors bud-off in vesicle and - Channel protein mediated (passive) return to trans-Golgi o Fast, non-stoichiometric - Transporter mediated (passive or active) Niemann Pick Disease o Slower, stoichiometric Cholesterol trafficking disorder NPC1 transports cholesterol from endosomes and lysosomes to ER and Golgi. When NPC1 is mutated, endosomes and Protein trafficking lysosomes are flooded w cholesterol Gene transcribed in nucleus to mRNA -> ribosomes Therapies: translate mRNA to polypeptide/protein -> vesicles w - Miglustat: reduce lysosomal congestion by decreasing protein bud-off RER and fuse at cis-Golgi -> Golgi sorts synthesis of glycolipids and adds carbohydrate chains -> lysosomes & secretory - Cyclodextrins: synthetic cholesterol carrier vesicles bud-off trans-Golgi -> vesicles exocytose proteins - Histone deacetylase inhibitors: increase healthy NPC1 Fabry disease X-linked lysosomal disorder Mutated GLA gene causes glycosphingolipids to accumulate in lysosomes leading to cell damage and abnormal ocular features (retina and lens cells) Therapy: - Enzyme replacement therapy: receptor leak from endosome to PM and can bind to injected enzyme replacement therapy BIOCHEM: LECTURE 4 – METABOLIC BIOCHEM Thermodynamics 1st law: energy intake = energy expenditure DG < 0 = favourable (exergonic); DG > 0 = endergonic Metabolic pathways Catabolic pathways: breakdown macromolecules (oxidation) - Provides energy by reducing NAD+/FAD to Glucose metabolism NADH/FADH2 Glycogen is a branched polymer of glucose in the cytosol and Anabolic pathways: build macromolecules (reduction) serves as short term storage form of cellular energy - Storage in liver (control blood glucose) and muscles (for Key principles: energy) - Every metabolic pathway has a committed step (highly exergonic/reversible) Glycogenesis: glucose > glycogen (insulin) - Catabolic and anabolic pathways must differ (at least Glycogenolysis: glycogen > glucose (glucagon) one step needs different catalyst) - Accumulation or decrease of metabolites can provide Glycolysis: glucose breakdown (central catabolic pathway) biomarkers for onset and progression of disease Glucose + 2ADP + 2NAD > 2 pyruvate + 2ATP + 2NADH - only source of ATP outside of mitochondria Macromolecules: Storage form Glycogen, proteins, triglyceride Kreb’s cycle: carbon enters as acetyl-CoA and produces up to Glucose, amino acids, fatty acids Transport form 32 ATP per glucose oxidized Pyruvate, acetyl-CoA Coupled to ATP Synthesis* Gluconeogenesis: primarily in liver to replenish blood glucose * NADH/FADH2 are oxidized to NAD+/FAD in electron during a longer fasting period transport chain coupled to ATP synthesis - Use pyruvate, lactate, glycerol, some AA to make glucose ATP: highly exergonic w two high energy phosphoanhydride Glycolysis: glucose breakdown (triggered by insulin) bonds (short lives and non-membrane permeable) Gluconeogenesis: glucose synthesis (triggered by glucagon) Metabolic toolkit: the core pathways Absorptive/post-absorptive states Triacylglycerol Glycogen Protein Glycogen Absorptive/fed Post-absorptive/fasting TG Glycogenolysis synthesis Anabolic period Catabolic period hydrolysis Glycerol Glucose Fatty acids Amino acids ­ insulin ¯ glucagon ¯ insulin ­ glucagon Glycolysis Gluconeogenesis NADH, ATP Muscle Glycogen synthesis Glycogen break/d Fatty acid synthesis Pyruvate Protein synthesis Protein break/d Fatty acid oxidation Liver (Nutrient Glycogen synthesis Glycogen break/d Acetyl-CoA distribution centre) Triglyceride synthesis Ketone synthesis H2O Oxygen CO2 Adipocytes Triglyceride synthesis Triglyceride break/d ATP ATP Oxidative NADH TCA cycle ATP FADH2 ATP phosphorylation ATP Main sources of blood glucose during fasting: 2020-09-02 31 1) Short - Glycogen breakdown 2) Long - Gluconeogenesis (in liver) Glucose can be synthesized from: - Lactate (muscles) - Glycerol (fat) - a-keto acids (amino acids, in liver) - Glycogen (liver) Type I diabetes leads to hyperglycemia, hypertriacylglycerolemia, and ketoacidosis BIOCHEM: LECTURE 5 – SIGNAL TRANSDUCTION AND CELL FATE Themes in signal transduction 1. Ligands bind to specific cell receptors Cell cycle Three types membrane receptors: Consists of interphase (G1, S, G2) and M phase (mitosis, cytokinesis) - G protein coupled receptors (epinephrine, glucagon) M phase: prophase > prometaphase > metaphase > anaphase > - Ion channel coupled receptors (acetylcholine) telophase + cytokinesis - Enzyme coupled receptors (insulin, EGFR, cytokines) - Coordinates DNA replication and cell division w checkpoints o Receptor tyrosine kinases - Regulated at molecular level by expression and degradation of cyclin proteins (controlling CDKs) 2. GTP hydrolysis by G proteins acts to regulate the activity and timing of many signal pathways G proteins act as switches to turn pathways on/off Signal transduction - G activating protein (GAP): GTP > GDP (inactivate) Extracellular signal molecule > receptor protein > intracellular - G exchange factor (GEF): GDP > GTP (activate) signalling molecules > effector proteins > cell response Two types G proteins: - Altered protein synthesis (slow) - Heterotrimeric: activated by GPCRs - Altered protein function (fast) - Monomeric: cell processes Extracellular signals: can be classified chemically, by system or by 3. Signals are often propagated within the cell by transient nature of transmission (contact dependent, paracrine/local, synaptic, formation of second messengers endocrine) Second messengers kept at low intracellular levels until needed, then generated from abundant cell precursors Receptor tyrosine kinases - Adenylate cyclase > cAMP Ligand binds RTK > receptors joins and dimerize > dimerization - Ion channels > increase intracellular Ca+ activates RTK domains > receptor phosphorylates tyrosine residue > - Hydrolysis of phospholipids intracellular signaling proteins bind phosphorylated tyrosine’s > signalling pathway 4. Signals are amplified and regulated using protein - Tyrosine kinase is highly conserved among RTKs phosphorylation cascades Phosphorylation can modify activity or provide docking sites Activation of RAS for signaling protein RAS is a molecular switch that can turn on cell proliferation when - Protein kinases: add P (using ATP) bound to GTP - Protein phosphatases: remove P 1. Activated RTK activates RAS GEF PK pathways highly conserved and regulated and slower than 2. RAS GEF (GDP > GTP) activating RAS Ca+ signaling RAS oncogene 5. Assembly of signaling complexes are facilitated using a Mutations impair GTPase activity and leave RAS constitutively ON limited repertoire of modular protein domains leading to cancer Intracellular signaling complexes enhance the speed, - KRAS: codon 12 efficiency and specificity of the response - NRAS: codon 61 - Scaffold proteins can act as docking site on activated - HRAS: intermediate receptor - The receptor itself can act as docking site while activated Oncogenes and tumour suppressor genes G-protein pathway: activated alpha subunit G protein (GTP Oncogene Tumour suppressor bound - conformational change) > activated adenylyl cyclase > Constitutively active (gain Knocked out (loss of function) activated cAMP > activated PKA > phosphorylated protein function) ½ alleles mutated (dominant) Both alleles mutated (recessive) Somatic mutation (not Somatic or germ mutation (can inherited) be inherited) Mutated TSG results in: - Accelerated cell growth - Reduced apoptosis - Mitosis before DNA repair - Reduced DNA repair - Abnormal gene expression  Oris (mouth) Mentis (chin) ThoracisMamma human body. The study Shoulder Dorsum of anatomy can be by body Axilla (armpit) (thorax,(breast) (back) TABLE 1-1 Terms of Relationship region or by body organ Dorsum systems. Generally, courses chest) Brachium (arm) Mamma Abdomen Loin of anatomy in the United States approach anatomical Axilla (armpit) (breast) (back) Antebrachium Umbilicus TERM DEFINITION study by regions, integrating Loin Olecranon all applicable body Brachium (forearm)(arm) Abdomen (navel) (back of Antebrachium Umbilicus systems into the study elbow) Anterior (ventral) Near the front (back of that region. Hence, this Pelvis (forearm) (navel) Olecranon Carpus (wrist) of textbook1 is arranged regionally but, by way of intro- Posterior (dorsal) Near the back CarpusANATOMY: LECTURE 2 – HISTOLOGY Pelvis elbow) Pollex duction for someone studying anatomy for the first Superior (cranial) Upward or near the head (wrist) Palm Manus (hand) (thumb) (palmar) Groin time,Upper this limb initial chapter Gluteuswill briefly introduce you to Pollex Digits (thumb) Thigh Palm (fingers) (palmar) Pubis Manus (hand) Inferior (caudal) Downward or near the feet Terms Thighof relativePubis position Groin (buttocks) Digits Patella (kneecap) (fingers) the major Upper limb body systems Gluteus that you will encounter in Medial Toward the midline or your study of anatomy. You will find it extremely median plane (buttocks) Medial Patella (kneecap)> intermediate > lateral Lower limb Popliteus (back of knee) > middle > posterior helpful to refer back Popliteus to this introduction as you Lateral Farther from the midline or Crus (leg) Lower limb Anterior Calf encounter various Calf body systems in your study of (back of knee) Crus (leg) median plane Superior Tarsus (ankle) (cranial) > middle > inferior (caudal) regional anatomy. (heel of foot) Calcaneus Proximal Near a reference point Proximal Tarsus(toes) Digits (ankle) > middle > distal Pes (foot) By convention,Calcaneus anatomical Plantus (heel of foot) descriptions of the Distal Away from a reference on a person in the anatomical Hallux (great toe) Pes (foot) Superficial > deep human body are based (sole of foot) FIGURE Hallux Digits (toes) 1-1 Anatomical Plantus Position and the Terminology Used to Describe Various Body Regions point position (Fig. 1-1): (sole of foot) (great toe) FIGURE 1-1 Anatomical Position and the Terminology Used to Describe Various Body Regions Superficial Closer to the surface Superior Deep Farther from the surface Frontal plane Standing Superior Right erect Leftand facing forward Median plane Divides body into equal Frontal plane ArmsRight hanging Cranial Left at the sides with palms facing right and left parts forward Cranial Medial Lateral Mid-sagittal plane Median plane Legs Medial placed together Proximal with feet facing forward Proximal Lateral Sagittal plane Divides body into unequal Terms of Relationship and Body Planes right and left parts Frontal (coronal) plane Divides body into equal or Anatomical descriptions Proximal often are referenced to one unequal anterior and Transverse plane or more of three Proximal distinct body planes (Fig. 1-2 and posterior parts Table 1-1): Transverse plane Caudal Distal Transverse plane Divides body into equal or unequal superior and Sagittal plane: vertical plane that divides the Caudal Distal inferior parts (cross body into equal right and left halves (median or sections) Dorsal or mid-sagittal plane) or a plane parallel to the posterior 1 Dorsal or Sagittal plane posterior Sagittal plane Distal Distal Ventral or anterior Inferior Ventral or anterior FIGURE 1-2 Body Planes and Terms of Relationship Inferior 2 FIGURE 1-2 Body Planes and Terms of Relationship 2 ANATOMY: LECTURE 2 – HISTOLOGY 1 Epithelial cells Characteristics: Epithelial tissue Can be simple, stratified and glandular Epithelial cells are closely aggregated w a very small amount Shape: squamous, cuboidal & columnar of extracellular matrix Polarity: apical (top) & basal (bottom) Principle functions: Adhesion: - Covering, lining and protecting surfaces (ex: epidermis) - Tight junctions - Absorption (ex: intestinal lining) - Adhesion junction - Secretion (ex. Parenchymal cells of glands) - Firm adhesion/desmosome - Specialized sensory (ex: neuroepithelium) - Gap junction (communication) Apical surface specialization: Is not innervated by blood vessels - Microvilli (increase cell surface for absorption) - Stereocilia (longer microvilli, absorption in male reproductive tract) - Cilia & flagella (movement) Basement membrane: composed of basal lamina (collagen IV, laminin, proteoglycans) and fibrous reticular lamina Glandular: Endocrine - Paracrine - Autocrine Exocrine - Merocrine (exocytosis, serous & mucous) - Holocrine (sebaceous) - Apocrine (mammary) Exocrine glands can be simple (unbranched) or compound (branched) and can be acinar/alveolar or tubular in shape. ANATOMY: LECTURE 3 – HISTOLOGY 2 Basic connective tissue Bone Cells of the connective tissue include: Cells in the bone consist of: - Fibroblasts (most common; synthesize extracellular - Osteoprogenitors > osteoblasts > osteocytes matrix; healing and scar formation) - Osteoclasts (from bone marrow) - Adipocytes (store fat) Extracellular matrix: collagen I, proteoglycans, glycoproteins - Macrophages (ECM turnover; phagocytosis) - Mast cells (inflammatory/immune response) Clinical correlations - Plasma cells (produce antibodies) Paget’s disease: uncontrolled osteoclast/osteoblast activity - Other leukocytes (in inflammatory response) leading to large disorganized bones Osteoporosis: osteoclast reabsorption exceeds osteoblast Fibers of the connective tissue include: deposition (bone fractures) - Collagen fibers (structural proteins) Rickets: Insufficient calcium - Reticular fibers (very thin delicate collagen III fibers) Scurvy: vitamin C deficiency - Elastic fibers (elastin and fibrillin proteins) Muscle tissue Ground substance of the connective tissue: Epimysium > perimysium > endomysium - Glycosaminoglycans (GAGs) Skeletal muscle: groups of thick (myosin) and think (actin) - Proteoglycans (proteins + GAGs) myofilaments - Glycoproteins (proteins + carbohydrates) - Multinucleated w satellite cells - Striated (actin & myosin) Specialized connective tissue includes cartilage, bone and Cardiac muscle: cell to cell attachment via intercalated discs blood forming cardiac muscle fibers (gap junctions create functional syncytium) Cartilage - Centrally located nuclei All cartilage consists of chondrocyte cells, but the EM differs - Striated The perichondrium diffuses nutrients from blood Smooth muscle: fusiform cells (no striations) - Hyaline (collagen II, proteoglycans, chondronectin) communicating via gap junctions - Elastic (collagen II, elastic fibers) - Centrally located nucleus - Fibrocartilage (collagen I, collagen II) Nervous tissue Cells of the nervous system include: Neurons: motor, sensory, interneurons Glia (CNS): - Oligodendrocytes (form myelin sheaths) - Astrocytes (support) - Microglia (immune defense, phacogytosis) - Ependymal cells (line ventricles and central canal) PNS supporting cells: - Schwann cells (form myelin sheaths) - Satellite cells (found in sensory cranial ganglia and autonomic spinal ganglia) ANATOMY: LECTURE 4 – DEVELOPMENTAL BIO Embryonic development Week 1: Developmental processes 1. Fertilization takes place in ampulla of uterus Cell proliferation: increase in number of cells 2. The zygote undergoes cleavage forming a 16-cell morula - Mitotic cell division 3. Morula gradually develops into blastocyst which hatches - Stimulated by induction (growth factors) from zona pellucida - Inhibited during differentiation Week 2: - Regulated by cyclins and cyclin-dependent kinases 4. Trophoblast cells of blastocyst implant into the uterine wall with proliferating syncytiotrophoblasts Cell differentiation: generates a diversity of specialized cells 5. Syncytiotrophoblast continues to expand into the decidua - Specification (reversible) and commitment (irreversible) 6. Inside the blastocyst, the embryoblast differentiates into - Governed by transcription factors/intracellular signaling epiblast (dorsal) and hypoblast (ventral) pathways a. Epiblast cells eventually become germ layers Week 3: Morphogenesis: development of form and structure 7. Blastocyst is fully embedded in decidua and undergoes - Cell condensation, migration, size, shape, apoptosis gastrulation and becomes a gastrula - Tissue movement (invagination, delamination, splitting, 8. The primitive streak establishes the first body axis and fusion, folding) triggers the epiblast layer to differentiate into the germ - Induction (one group of cells influences another group layers: ectoderm, mesoderm, endoderm (trilaminar disc) of cells) Week 4: 9. Mesoderm cells eventually create the notochord (transient structure) which runs along the craniocaudal Germ layers axis Ectoderm: dorsal layer 10. Mesoderm cells around the notochord differentiate into Neurulation > neural tube > CNS/PNS specialized types: Sensory epithelium of ears, nose, eyes, mouth a. Axial (notochord), paraxial (somites), cardiogenic Skin, hair nails (heart), intermediate (kidneys), lateral plate (pleura, pericard, peritoneum) Mesoderm 11. Notochord promotes neurulation where it stimulates Paraxial meso > somites > skin, muscle, bony tissue surrounding ectoderm cells to form the neural plate then Intermediate meso > adrenal tissue, gonads, kidneys, spleen neural tube (which becomes the CNS) Lateral meso > serous membranes, limb tissue, heart 12. The trilaminar embryonic disk undergoes folding to form a three-dimensional cylinder-shaped embryo Endoderm GI tract from pharynx to anus Experimental embryology Lining of urethra and bladder To express phenotype and decide cell fate, need a combo of: Liver, pancreas, gallbladder - Cell autonomous (instructions inside cell) Respiratory tract, tonsils, thyroid, parathyroid glands, thymus, ear - Conditional development (instructions outside cell) Induction: presence of cell influences development of others Competence: cells ability to become something Teratology: causes, mechanisms and manifestations of Potency: cells ability to differentiate into other cell types developmental deviations Teratogens - Chemical (environmental pollutants, drugs, hormones, vitamins) - Infectious (viruses, bacteria) - Physical (radiation, hyperthermia) - Maternal (diabetes, obesity, malnutrition) Developmental defects Congenital anomalies - Structural (macroscopic & microscopic) - Functional ANATOMY: LECTURE 5 – MUSCULOSKELETAL SYSTEM Appendicular skeleton: shoulder girdle, upper limb bones, pelvic girdle, lower limb bones Axial skeleton: skull, vertebral column, ribs, sternum Shoulder girdle: Skull: - Scapula (shoulder blade) - Bones connected by sutures - Clavicle (collar bone) – only bone connection of the - Mandible and small auditory ossicles are the only upper limb movable bones in skull Upper limb: Vertebral column: 33 vertebrae Arm: - 7 cervical – 2/lists head - Humerus - 12 thoracic - 1 Forearm: - 5 lumbar – 2/begins to walk - Radius (lateral) - 5 sacral (fused) - 1 - Ulna (medial) - 4 coccygeal (fused) Hand: Thoracic cage: - Carpal (8) - 12 thoracic vertebrae - Metacarpals (5) - 12 pairs of ribs - Phalanges (14) - Costal cartilage - Sternum Bones Long bones: humerus, radius, ulna, metacarpals, phalanges Short bones: carpels, tarsals Pelvic girdle: two hip bones and pubic symphysis (3 bones Flat bones: scapula, cranial bones, sternum, ribs fuse at acetabulum) Irregular bones: vertebrae, hip bone, face bones - Pubis Sesamoid bones: patella, in tendons - Ilium - Ischium Joints by function Synarthroses – immovable (sutures) Lower limb: Amphiarthroses – slightly movable (pubic symphyses) Thigh: Diarthroses – Freely movable (synovial joints) - Femur Leg: Joints by structure - Tibia (medial) Fibrous: - Fibula (lateral) - Suture (tightly bound fibrous tissue; only found in skull) Foot: - Syndesmosis (varied length fibrous tissue) - Tarsals (7) Cartilaginous: - Metatarsals (5) - Synchondrosis (hyaline cartilage; all synarthrosis) - Phalanges (14) - Symphysis (fibrocartilage) Synovial: most moveable in body; most joints - Plane - Hinge - Pivot - Condylar - Saddle - Ball and socket Skeletal muscle - Muscle fibers attached to bone by tendons - Bursa: fluid filled sac between bone & tendon - Tendon sheath: surrounds tendon - Muscles need to cross join to produce movement at the joint - Muscles in same compartments tend to have same function and innervation ANATOMY: LECTURE 6 – BODY CAVITIES AND VISCERA Cranial cavity and vertebral canal: Abdominopelvic cavity (lined by meninges) Abdominopelvic walls: - Brain (cerebrum, cerebellum, brain stem) - Superior: diaphragm - Spinal cord - Posterior: 5 lumbar vertebrae, iliopsas muscle and quadrant - Endocrine glands lumborum muscle - Floor: pelvic diaphragm - Anterolateral wall: flat muscles of abdominal wall Thoracic cavity: Thoracic wall Peritoneum - Ribs Parietal peritoneum attached to abdominal wall - Costal cartilage Visceral peritoneum attached to some organs - Sternum - Thoracic vertebra Intraperitoneal viscera: (held by mesentery) - Intercostal muscles - Esophagus - Jejunum - Transverse - Liver - Stomach - Illium colon - Gallbladder Parietal pleura attached to thoracic wall - Spleen - Appendix - Sigmoid - Biliary tree Visceral pleura attached to lungs colon - Air enters pleural space: pneumothorax Extraperitoneal viscera: - Fluid buildup in pleural space: effusion Primary Secondary - Adrenal glands - Duodenum Mediastinum (divided by sternal angle T4/T5) - Kidneys - Pancreas Superior: Inferior: - Ureter - Ascending colon - Thymus - Heart - Descending colon - Trachea - Esophagus - Esophagus - Great vessels - Great vessels Abdominopelvic cavity Pelvic inlet divides the greater and lesser pelvis Pericardial cavity Serous pericardium includes visceral (attached to Male pelvic organs Female pelvic organs organs) and parietal layers (attached to pericardium) - Ureters - Ureters Fibrous pericardium attached to diaphragm and great - Bladder - Bladder vessels (and parietal layer of serous pericardium) - Urethra - Urethra - Rectum - Rectum - Prostate - Uterus - Seminal glands - Uterine tubes - Ductus deferens - Ovaries  ANATOMY: LECTURE 7 – CARDIOVASCULAR AND LYMPHATIC SYSTEM The heart: Pericardium > myocardium > endocardium Valves: AV valves: tricuspid (R) & mitral (L) Semilunar valves: pulmonary (R) & aortic (L) Vasculature: Has L&R coronary arteries and cardiac vein Conducting system: SA node > AV node > AV bundle > ventricular bundle Circulation: R ventricle > pulmonary valve > pulmonary trunk > lungs > pulmonary veins > L aorta > mitral valve > L ventricle > aortic valve > aorta > body > sup/inf VC > R atrium Blood vessels: Lymphoid system: Arteries: elastic (large) > muscular (med) > arteries (small) Primary organs: thymus & red bone marrow (sites of spongy Veins: large > med > venules (small) bone: end of long bones, flat bones) - Veins have valves - Lymphocytes generated - Veins have thinner walls/bigger lumen than arteries Secondary organs: spleen, lymph nodes, mucosal associated Capillaries: continuous (min leak) > fenestrated (leak) > lymph tissue (MALT) sinusoid (max leak) - Lymphocytes interact with antigen Portal system: vein between two capillary beds (ex: hepatic) Lymphatic vessels: Venous return: return of blood to the heart aided by: Lymphatic capillaries > lymphatic trunks > lymphatic ducts (big) - Skeletal muscle contractions - Capillaries gather cells, debris and pathogens into - Pumping of blood in arteries to accompanying veins lymphatic vessels to lymph node and then back to blood - Venus angle: where lymph returns to veins (between Anastomosis: connection between two blood vessels internal jugular vein and subclavian vein) - Arterio-arterial: functional and true terminal arteries (true more prone to ischemia) - Veno-venous: superficial and deep veins (separated by fascia; superficial drains) - Arterio-venous: capillaries; sphincters can create arteriovenous shunt (maintain body temp) ANATOMY: LECTURE 8 – NERVOUS SYSTEM Brain Convolutions on cerebrum: gyri separated by sulci Convolutions on cerebellum: folia separated by fissures Brain structures: - Cerebellum (half of neurons in brain found here) - Brainstem (medulla, pons, midbrain) - Frontal, parietal, temporal, occipital lobes, limbic lobe - Diencephalon (thalamus, hypothalamus, epithalamus/pineal gland) Sulci: - Central sulcus separates frontal and parietal lobe - Lateral sulcus separates frontal/parietal from temporal - Parietooccipital sulcus separates parietal and occipital lobe Nerves Neurons Cranial nerves: 12 pairs Sensory (afferent): stimuli from periphery > CNS - Project from brainstem and exit through openings in Motor (efferents): CNS > periphery organs skull Interneurons: connect different regions of CNS (only in CNS) - CN 1, 2, 8: sensory - Form neural circuits enabling communication between sensory - CN 3, 4, 6, 11, 12: motor neurons, motor neurons and other interneurons in CNS - CN 5, 7, 9, 10: sensory and motor - Short/local: sensory directly to motor neuron (reflex) - Long/projection: cerebrum to spinal cord Spinal nerves: 31 pairs (8 cervical) - Connect w spinal cord and exit through openings of vertebrae (intervertebral foramina) PNS - Formed by combination of posterior and anterior roots Sensory Motor o Posterior roots: somatic and visceral sensory Somatic Conscious or unconscious Conscious or unconscious o Anterior roots: somatic and visceral motor Pain, temp, touch, senses Skeletal muscle (vision, smell, hearing balance) Neuroglial cells Proprioception Macroglia: Visceral Mostly unconscious Unconscious Astrocytes: Status of internal organs Innervation of smooth - regulate exchange of molecules between circulatory (heart, lungs, digestive muscle (gut, arteries), system and NS (contribute to blood brain barrier); form tract, etc.), taste glands limiting membrane on surface of CNS Autonomic nervous system - Increase blood flow/vasodilation (BOLD fMRI) - Clear away certain neurotransmitters - Maintain composition of extracellular fluid/contribute to structural integrity of nervous tissue Oligodendrocytes (CNS) and Schwann cells (PNS) for myelin Microglia: phagocytic role clearing debris at sites of damage PATHOLOGY: LECTURE 2 – CONCEPTS AND PRINCIPLES Key concepts Tissue/cellular response to injury Etiology: cause of disease (genetic or acquired) Hypertrophy: increase in cell size due to increased cellular - Single etiological agents (ex. Single gene mutation) protein - Multifactorial (genetic, environmental, etc.) Hyperplasia: increase in number of cells in an organ/tissue typically w increase in size/mass Pathogenesis: events occurring in response to etiologic agent Atrophy: reduced size of organ/tissue from decrease in cell size and number - Due to decreased work, denervation, decreased blood Causes of cell injury supply, inadequate nutrition, loss of endocrine Oxygen deprivation (hypoxia) stimulation, pressure - Ischemia – reduced blood flow Metaplasia: reversible change from one differentiated cell - Inadequate ox of blood type to another (ex. squamous to columnar mucosa) - Decreased ox carrying capacity in blood - Blood loss Physical agent (trauma, temp, radiation, electricity) Necrosis (messy, pathologic) Chemical agents (poison, environmental, medications) Coagulative Infectious agents (virus, bacteria) - Tissue architecture preserved (days) Immunologic reactions (inflammatory response) - Eosinophilic, ghost cells persist Genetic derangements (SNP) Liquefactive Nutritional imbalance (obesity, anorexia) - Tissue digested into liquid mass - Pus: liquefactive necrosis + neutrophils - Can result in abscess Apoptosis Gangrenous (coagulative) Intrinsic: - Limb with loss of blood supply (coagulative) - insults antagonize anti-apoptotic proteins, channels open Caseous (liquefactive) in mitochondrial membrane, activation of caspases - Cheese like “caseating granulomas” Extrinsic: Fat necrosis (coagulative) - Fas-Fas ligand, activation of caspases - Fat destruction Fibrinoid (coagulative) Causes: - Necrosis to blood vessel walls - Physiologic (embryogenesis, hormone withdrawal, tolerance, death of inflammatory cells) Injuries - Pathologic (DNA damage, misfolded proteins, infection) Ischemia-reperfusion injury: - after blood blow restored, reperfusion causes ROS, Ca+ overload, inflammation, activation of compliment > cell death Infarct: area of necrosis caused by ischemia PATHOLOGY: LECTURE 3 – INFLAMMATION & TISSUE REPAIR Killing mechanism of neutrophils: Phagocytosis Degranulation NET Acute inflammation reaction Engulf and Release enzymes Extrude nuclear 1. Increase in blood flow eliminate and free radicals contents to form - Vasodilation and increased permeability of nets/traps microvasculature slow blood flow and increase red blood cell concentration (producing localized redness). 2. Edema Chronic inflammation - Exudate edema is caused by increased vascular Cause: persistent infection, hypersensitivity/autoimmune diseases, or prolonged exposure to toxic agents permeability. Extravascular fluid has high protein concentration & cellular debris. - Transudate edema is caused by decrease in osmotic Morphologic features: pressure. Extravascular fluid has little/no protein or - Infiltration w mononuclear cells cellular debris. o Lymphocytes o Macrophages 3. Eliminate offending agent - Leukocytes adhere to endothelium and migrate through o Plasma cells vascular wall into interstitial tissue. o Eosinophils (less common) (sometimes 2 nuclei) o Mast cells (less common) o Mediated by adhesion molecules and cytokines - Tissue destruction (chemokines) - Angiogenesis (vessel proliferation) - Most important leukocytes are phagocytotic that - Fibrosis (connective tissue replacement) ingest/destroy and produce growth factors for repair o Neutrophils (first 6-24 hours) o Macrophages (24-48 hours) Granulomatous inflammation Inflammation w a collection of activated macrophages (and T- lymphocytes) in an attempt to contain offending agent – leads Acute inflammation morphologic patterns to injury in normal tissue. Serous inflammation - Granulomas are multinucleated giant cells (Langhans) Typically, no infection, so edema fluid is cell-poor without many leukocytes 1. Foreign body granulomas: from inert foreign bodies - Ex: blister from burn 2. Immune granulomas: when inciting agent is difficult to irradicate Fibrinous inflammation Develops when vascular leaks are large and there is a local procoagulation stimulus (fibrin and fibrinogen release) Systemic effects of inflammation – “acute phase response” - Ex: inflammation in lining of body cavities like pleura 1. Fever (linings become granular) 2. Leukocytes (elevated WBC) 3. Elevated “acute phase proteins” (plasma proteins like Purulent (suppurative) inflammation/abscess fibrinogen) Typically, due to pathogen infection, edema fluid is full of neutrophils and liquified debris of necrotic cells. Can also lead Tissue Repair to enclosed collection of neutrophils (abscess) Regeneration: triggered by cytokines and growth factors, tissues replace damaged components and return to normal Acute inflammation outcomes state 1. Complete resolution (minimal damage) - Ex: mucosal linings (GI tract), skin, liver, bone marrow 2. Abscess formation 3. Scarring or fibrosis: healing by replacement w connective Connective tissue deposition/scar formation: replacement of tissue in tissues not capable of regeneration injured cells with connective tissue 4. Chronic inflammation 1. Cytokines/chemical mediators released 2. New blood vessels formed (angiogenesis) Cardinal signs of inflammation 3. Migration/proliferation of fibroblasts - Rubor (redness) 4. Granulation tissue (meshwork of fibroblasts and blood - Tumor (swelling) vessels) - Calor (heat 5. Maturation and remodelling of fibroblasts = mature scar - Dolor (pain) Wound strength: - Week 1: 10% of original - Month 3: 70-80% of original PATHOLOGY: LECTURE 4 - NEOPLASIA Cancer nomenclature: Epithelial tissue (skin, gut, resp tract, liver, kidney) Definitions: - -“carcinoma” Neoplasia: new cell growth/proliferation - -“adenocarcinoma” glands Neoplasm: a new growth (benign or Mesenchymal/connective tissue (bone, muscle, cartilage, fat) malignant) – also equated with tumor - -“sarcoma” Cancer: malignant neoplasm - -“angiosarcoma” endothelial (blood vessels) Clonal proliferation: tumor from one cell (Smooth muscle: Lei- & Striated muscle: Rha-) Carcinogenic agents: non-lethal DNA damagers “oma” is typically benign… but exceptions: Dysplasia: cells are mutated and growing Lymphoid tissue: “lymphoma” (crowded, disorganized) but not Melanocytes: “melanoma” invading/breaking basement membrane (pre- Bone marrow: “leukemia” cancerous state) Metastasis: to change place Paraneoplastic syndrome: disease/symptom Metastasis pathways: Carcinogenic agents from presence of cancer in body but not at - Lymphatics - Radiant energy (UV, DI) local presence of cancer cells - Blood stream/hematologic - Chemical (cigarette smoke) - Body cavities (pericardial, - Oncogenic viruses/microbes pleural, peritoneal) - Genetic predispositions - Chronic inflammation (IBD) Neoplasm macroscopic features Neoplasm microscopic features Benign Malignant Benign Malignant Size smaller larger Border Non-invasive Destructive invasive Border Encapsulated, Ill-defined, Cell Uniform Varied, altered polarity, well circled irregular morphology pleomorphic Adjacent tissue Compressed Infiltrated Nuclear Oval, thin Pleomorphic, prominent Appearance Homogeneous Heterogenous morphology membrane nuclei, clumped chromatin w necrosis Mitosis Few Many Necrosis None Often Invasion No Yes Essentials for malignant transformation: Have: - Own growth signal - Limitless replication - Angiogenesis (blood) Evade: - Inhibitory growth signals - Apoptosis - DNA repair Prognosis - Tumor stage: reflects spread (depth of invasion of tumor) - Tumor grade: o Low = well differentiated o High = poorly differentiated PHARMACOLOGY: LECTURE 1-4 Ligands and receptors Receptors targeted by drugs: Pharmacodynamics: what drugs do to the body - Ligand gated ion channels (milliseconds) - Relationship of drug concentration to drug effect - Enzyme linked receptors - Biological effect is proportional to drug/receptor - G-protein coupled receptors complex - Ligand-activated transcription factors (hours) - Ligands can be drugs or endogenous signaling molecules (hormones, neurotransmitters) Ligand/receptor interactions: - Vast majority are reversible bonds Drugs elicit effects by mimicking/blocking the actions of - Strength and/or number of bonds determines: endogenous signalling molecules o Affinity of ligand for receptor o Functional effect/outcome Sigmoidal Receptor Binding Curves Receptor binding curve Agonists: ligands that activate a receptor Bmax Antagonists: block Bmax the binding site and inhibit activation 1 1 Agonists Fraction of Receptors Bound (B) Fraction of Receptors Bound (B) Potency (ED50): amount of drug/dose needed to produce Semi-log transformation an effect of a given magnitude Agonist Types: Its All Relative Low Kd = high affinity 0.5 0.5 Efficacy (Emax): max effect achieved A: full agonist Kd 100 Kd high potency, A maximum efficacy C B: partial agonist Effect (%) B high potency, 0 5 10 0.1 50 1 10 reduced efficacy Ligand Concentration [L] Ligand Concentration [L] D C: full agonist Graded Dose-Response Curves Dose response curve reduced potency, maximum efficacy - Graded phenomena (infinite intermediate states) -Semi-logarithmic transformation D: partial agonist reduced potency, -Common representation 0.01 of pharmacological 0.1 data 1.0 10 100 Emax Emax reduced efficacy -Does not change value of Bmax and Kd Dose - Partial agonists: Failure of partial lower agonists to produce functional a maximal impact response is generally Kd can be identical for full and partial agonists not due toon receptor decreased receptor affinity 100 100 (not due to affinity for receptor (Kd)) Sinal – PHAC 3001 15 Partial agonists have a lower functional impact upon the receptor compared to full agonists Maximum efficacy is generally defined by the maximum effect achieved with the endogenous receptor agonist (e.g. Biological Effect (%) Biological Effect (%) Antagonism hormone or neurotransmitter) 50 50 Chemical: direct interaction; effect of one or both is lost 19 Emax: max response achieved by ligand ED ED50: dose at 50% Emax (ligand potency) 50 (acidic vs. basic) ED 50 Physiological: indirect interaction; opposing actions (vasodilation vs. vasoconstriction) 0 Quantal 5 Dose-Response 10 Curves 0.1 Pharmacological: 1 blocks10ability of agonist to bind/activate Ligand Dose a receptor (bind to receptor but does not activate signal Ligand Dose Quantal-the Emax dose Quantal Phenomena response curve maximum response achieved by the ligand transduction) Graded Phenomena “all-or-none” - Quantal phenomena: all or none (death, pregnancy) infinite number of intermediate states death, pregnancy, cure, pain relief, effect of a given magnitude - 50 Useful ED to describe -the ligand populations dose at which 50% of Emax is achieved e.g. vessel Competitive dilation, bloodantagonist pressure change, - also referred to as ligand potency 100 heart rateAffects change potency - Binds reversibly and can 16 be overcome w increasing Individuals responding (%) Emax dose-response curve agonist useful to describe population rather than concentration ED50 individual responses to -drugs Partial agonists can be competitive antagonists w 50 cumulative response respect to full agonists based on plotting cumulative frequency % of individuals Non-competitive distribution of responders versus the log dose antagonist who require this dose to respond Affects efficacy - Binds irreversibly to receptor or allosteric site 1.25 2.5 5 10 20 Ligand Dose Non-Competitive Antagonists: Effect on Agonist Dose Response Curves Antagonists can have potency, but they cannot have efficacy bc they have no Competitive functionalEffect Antagonists: impacton on receptor Agonist Dose Response Curves 17 100 Emax= 100% A A: agonist with NO antagonist 100 Emax= 100% A B agonist has maximum potency, maximum efficacy A: -agonist with NO antagonist Effect (%) -agonist has maximum potency, 50 maximum efficacy Effect (%) B: agonist with non-competitive antagonist 50 B agonist retains maximum potency, B: -agonist with competitive antagonist Emax = 50% ED50 = 0.1 but now exhibits reduced efficacy -agonist now has reduced potency, but ED50 = 0.1 ED50 = 10 retains maximum efficacy