Histo 2015 (rojo) *check*

Pain and Temperature Receptors

• They are free (nonencapsulated) nerve endings
• They are located in the epidermis, dermis, and cornea
• Are associated with A delta(group III) and C (group IV) fibers
• Are receptors that adapt very slowly

Cutaneous Mechanoreceptors

Merkel Tactile Disks

• Nonencapsulated nerve endings, found in the basal layer of hairy and glabrous skin
• Primarily transduce light and crude touch (e.g., stroking skin with a cotton swab)
• Use Group II fibers
• Receptors adapt very slowly

Meissner Corpuscles

• Encapsulated nerve endings, located in the dermal papilla of glabrous skin
• They transduce fine, discriminative tactile sensations
• Use Group II fibers
• Receptors are fast-adapting

Pacinian Corpuscles

• Located in dermis, mesenteries, and periosteum
• Respond to pressure and vibration
• Use Group II fibers
• Receptors are very fast-adapting

Muscle and Tendon Receptors

• Encapsulated mechanoreceptors and proprioceptors

Muscle Receptors

• Use group 1a afferent fibers
• Are involved in the muscle stretch reflex (MSR)
• Form part of the myotatic reflex (e.g., patellar reflex)
• Measure primarily muscle length

Gamma Motor Neurons

• Consist of static and dynamic motor neurons
• They modify the sensitivity of muscle spindles
• Are coactivated along with alpha motor neurons

Golgi Tendon Organs (GTOs)

• Are found at the junction of the muscle and its tendon, and are connected with the muscle fibers in series
• Respond to muscle tension during muscle stretch and contraction
• Are sensitive to the velocity of tension development
• Use group 1b fibers

Langerhans Cells

• The epidermis consists of 4 cell types: keratinocytes, melanocytes, Langerhans (dendritic) cells, and Merkel cells (receptors)
• Specialized dendritic cells, located predominantly in the skin, that present antigens to naive T cells
• Derived from bone marrow monocytes
• Contain Birbeck granules that have a tennis racket appearance on electron microscopy

Mitosis and Meiosis

• Mitosis results in two diploid daughter cells
• Meiosis results in four haploid daughter cells.

Growth Factors and Tyrosine Receptors

• Intrinsic tyrosine kinase is activated through ligand binding, which leads to autophosphorylation of tyrosine residues

• Autophosphorylation of tyrosine residues leads to activation of GRB2, then SOS proteins, then RAS, and finally downstream signaling kinases (Raf, MAP), resulting in the activation of transcription factors

• Insulin and growth factors like EGF and PDGF are ligands

• Receptor-associated tyrosine kinase is activated through ligand binding, which leads to dimerization

• Dimerization recruits JAKs, leading to cross-phosphorylation of the dimer and activation/dimerization of STAT

• STAT translocates into the nucleus to activate transcription

• Cytokines, growth hormones and prolactin are all ligands

Cells with Nuclei

• The stratum granulosum is the last layer of skin which contains cells with nuclei

Pulmonary Surfactant

• Type II pneumocytes include cytoplasmic inclusions called lamellar bodies which secrete pulmonary surfactant

• Type II pneumocytes can undergo mitotic division

• They replace damaged Type I and Type II pneumocytes

Lung Zones and Respiration

• Upper zone: more air, less blood (apex)
• Middle zone: air and blood are approximately equal
• Lower zone: more blood, less air

Sertoli and Leydig Cells

• Anterior pituitary: FSH (follicle stimulating hormone) and LH (luteinizing hormone)
• FSH acts on Sertoli cells to maintain spermatogenesis
• Sertoli cells secrete inhibin, which inhibits FSH secretion as part of a negative feedback loop
• These cells also produce androgen-binding protein (ABP), which binds testosterone in the blood
• LH acts on Leydig cells, stimulating androstenedione and testosterone synthesis
• Testosterone acts through an intratesticular paracrine mechanism to reinforce the spermatogenic effects of FSH in Sertoli cells, constituting Negative Feedback Control
• Testosterone (from Leydig cells) forms a negative feedback loop with the hypothalamus and pituitary
• This decreases GnRH and LH release
• Leydig cells regulate the release of its own hormone, testosterone
• Sertoli cells down-regulate FSH release by secreting inhibin

Spermatogonia and Spermatocytes

• Sperm development: spermatogenesis

• Analogous to female oogenesis

• Diploid primordial germ cells undergo meiosis to form haploid gametes, and male and female gametes combine during fertilization to form a diploid zygote

• Spermatogenesis takes 64 days and occurs in the seminiferous tubules in the testes

• This process begins in puberty

• Type A and Type B spermatogonia are present, and are both diploid (46, 2N)

• Type A divides mitotically to maintain the pool of spermatogonia

• Type B divides mitotically to duplicate its DNA

• Become primary spermatocytes (46, 4N)

• Primary spermatocytes undergo meiosis I to form two secondary spermatocytes (23, 2N)

• Secondary spermatocytes undergo meiosis II to produce four spermatids (23, 1N)

• Spermiogenesis is the process by which the sperm's final architecture is formed

Menstrual Cycle Phases

• The menstrual cycle lasts approximately 28 (21-35) days

• Divided into the follicular phase and the luteal phase

• The follicular phase marks the beginning of the cycle and starts during menses

• While the length of the follicular phase can vary, the luteal phase always precedes the onset of menses by 14 days

Follicular Phase (Proliferative Phase; Days 1-14)

• Histology: primordial follicle becomes a primary follicle, then a secondary follicle, and finally a Graafian follicle
• There is atresia of neighboring follicles
• Sensitivity to the pituitary hormones LH and FSH increases as receptors are upregulated on the surface of theca and granulosa cells
• Estradiol levels increase and cause proliferation of the uterus
• FSH and LH are suppressed by the negative feedback effect of estradiol on the anterior pituitary
• Progesterone, FSH, and LH levels are low
• Follicular growth is fastest during the second week of the follicular phase

Ovulation

• Occurs 14 days before menses, regardless of menstrual cycle length
• A burst of estradiol synthesis at the end of the follicular phase reverses the feedback relationship of estradiol, stimulating positive feedback on the secretion of FSH and LH, leading to the LH surge
• ↑ Estrogen levels induce the LH surge and ovulation
• Estrogen levels decrease just after ovulation, but rise again during the luteal phase
• Cervical mucus increases in quantity, becoming less viscous and more penetrable by sperm
• During ovulation, blood from the ruptured follicle or swelling of the follicle can cause peritoneal irritation

Luteal Phase (Secretory Phase; Days 15-28)

• After the developing egg is ovulated, the remaining follicle regresses and forms the corpus luteum, which synthesizes and secretes progesterone
• Progesterone causes proliferation of the tortuous spiral arteries as well as glandular secretions from the endometrial lining
• This prepares the endometrium for receipt of a fertilized egg
• Basal body temperature increases because of the effect of progesterone on the hypothalamic thermoregulatory center
• If fertilization does not occur, the corpus luteum regresses at the end of the luteal phase, and estradiol and progesterone levels decrease abruptly
• This causes shedding of the endometrial lining and the onset of menses
• If fertilization occurs, hCG and progesterone from the trophoblast cells will maintain the endometrial lining

Sarcomere

• Extends from one Z-line to another Z-line

• Muscle contraction brings the Z-lines closer together

• Shortening of the H band and I band (“HI”) occurs

• The A band maintains its length during contraction

Membrane Potential

• Most cells in the human body possess a membrane potential
• There is a differential charge between the outside and inside of the cell
• Some cells, like nerve and muscle cells, are excitable, meaning a signal can cause a rapid change in potential, and this current is harnessed to do work in the form of muscle contraction or signal conduction
• The resting potential of muscle cells is -90mV, while that of nerves is -70mV

Excitation-Contraction Coupling

• Connects the membrane depolarization to muscle contraction

• Each of the three muscle fiber types—smooth, skeletal, and cardiac—require some way to accomplish this

• Similar to nerves, there is also a summative process in muscles

• ↑ Signal leads to ↑ Ca2+ influx, which then leads to ↑ recruitment of muscle fibers

• Muscle recruitment leads to more sustained cross bridging and variable degrees of muscle tension

• The general mechanism relies heavily on depolarization stimulated Ca²⁺ release from the sarcoplasmic reticulum

• First ACh is released at the NMJ

• ACh then binds to ligand-gated Na⁺ channels on the muscle fiber, causing local depolarization

• This depolarized potential travels along the membrane into deep invaginations called T-tubules

• The sarcoplasmic reticulum (muscle's equivalent of the ER) runs along and between muscle fibers

• It coalesces into cisternae beside the T-tubules

• When the T-tubules are depolarized, this causes Ca²⁺, stored in high concentrations in the SR, to be released

• Calcium release floods the actin and myosin filaments with calcium

• Ca²⁺ levels initiates cross bridging

• The SR continually pumps Ca²⁺ back into its lumen, so contraction is only present as long as depolarization continually triggers its release

• In skeletal muscle, calcium binds to the troponin C subunit of troponin

• This moves tropomyosin out of the way to expose the myosin binding site on actin

• In smooth muscle, calcium binds to calmodulin

• Together, they activate myosin light chain kinase (MLCK), which phosphorylates myosin, allowing it to bind to actin

• Once calcium accomplishes this, the cross bridge cycle is the same

• The myosin head binds to actin

• Pi generated from the previous contraction cycle is released, initiating the power stroke, where the myosin head pulls the actin filament towards the M-line

• Then, ADP is released

• Addition of a new ATP molecule to the myosin head causes its release

• Hydrolysis of the ATP causes it to return to its elongated high-energy conformation

• Rigor mortis occurs in death because ATP is required for cross bridge release

• ATP stores are depleted following death, muscle tone increases until decay and protein degradation begins

Bladder Epithelium

• The urinary bladder is lined with transitional epithelium, also known as urothelium
• Cells are highly distensible to accommodate changes in bladder size and shape
• The tissue serves as the mucosal lining of the ureters, urinary bladder, and proximal urethra
• It is adapted to withstand and protect underlying tissues from hypertonic and potentially cytotoxic urine

Blood-Brain Barrier (BBB)

• Formed by tight junctions between nonfenestrated capillary endothelial cells, a basement membrane, and CNS astrocyte processes

• Nonpolar/lipid-soluble particles (CO2, O2, EtOH) can rapidly cross the BBB by diffusion

• Glucose and amino acids cross the BBB slowly, requiring carrier-mediated transport

Blood-Testis Barrier

• A physical barrier in the testis between blood vessels and the seminiferous tubules that avoids autoimmune response
• Tight junctions between Sertoli cells form the barrier
• The basal compartment of the blood-testis barrier comprises the tight junctions and spermatogonia
• The adluminal compartment of the seminiferous tubules comprises the primary spermatocyte, secondary spermatocyte, and spermatid

Insulin and Glucagon

• Insulin is the major anabolic hormone of the body

• Glucagon, whose actions antagonize those of insulin, is the major catabolic hormone of the body

• Insulin is a peptide hormone consisting of an A chain and a B chain linked by two disulfide bonds

• Insulin is produced in pancreatic β cells in the islets of Langerhans

• Insulin is first synthesized as preproinsulin in the rough endoplasmic reticulum

• Proinsulin is formed when the signal peptide is cleaved in the rER, and it is also in the rER that the nascent insulin peptide folds into its native conformation

• The disulfide bonds are formed

• Proinsulin is then transported to the Golgi, where it is cleaved to insulin and C-peptide

• Insulin and C-peptide are stored in secretory granules until exocytosis is stimulated

• Increased glucose concentration inside β-cells is the primary stimulus for insulin release

• Glucose enters the pancreatic β cell through the GLUT2 (insulin-independent) transporter by facilitated diffusion

• Inside the cell, glucose is oxidized in glycolysis to ATP

• ATP closes ATP-sensitive potassium channels on the plasma membrane

• Closure of these potassium channels leads to membrane depolarization

• Depolarization opens voltage-gated [Ca²⁺] channels, leading to [Ca²⁺] influx

• Increased intracellular [Ca²⁺] leads to exocytosis of insulin secretory vesicles, causing increased insulin in the blood

• Insulin has a short half-life of about five minutes, so C-peptide, with its longer half-life, is a good indicator of insulin production and secretion

• Insulin release occurs in two phases

• Glucagon is cleaved from a larger peptide chain in pancreatic α cells of the islets of Langerhans The main stimulus for glucagon release is hypoglycemia

Glucocorticoids

• Hormones produced by the cortex of the adrenal gland

• Includes glucocorticoids, mineralocorticoids, and weak androgens

• Catecholamines like epinephrine and norepinephrine are secreted by the adrenal medulla

• Glucocorticoids (e.g., cortisol) are essential for the body to respond to stressful situations

• The effects of glucocorticoids can be remembered using the mnemonic "Cortisol is BBIIG” (Bone formation, Blood pressure, anti-Inflammatory/Immunosuppression, Insulin, and Gluconeogenesis)

• Glucocorticoids decrease Bone formation through the inhibition of osteoblast activity, and the inhibition of intestinal Ca²⁺ absorption

• They regulate Blood pressure through the upregulation of α₁ receptors on arterioles

• Cortisol excess causes an increase in arterial pressure, while cortisol deficiency causes a decrease in arterial pressure

• Glucocorticoids are anti-Inflammatory/Immunosuppressive

• Increase insulin resistance, leading to a diabetogenic effect.

• Increase Gluconeogenesis, lipolysis and protein catabolism

• Mineralocorticoids (e.g., aldosterone) secreted from the adrenal cortex

Protein and Lipid Digestion

• Digestive products of protein can be absorbed as amino acids, dipeptides and tripeptides
• Proteins are denatured by HCl in the stomach, preparing them for digestion by proteases in the small intestine
• Pepsin, which is secreted as pepsinogen by chief cells of the stomach, begins to degrade proteins to peptides in the stomach
• The main pancreatic enzymes that further degrade peptides to amino acids and di- or tri-peptides are trypsin, chymotrypsin, elastase, carboxypeptidase
• This occurs primarily in the ileum
• Amino acids cross the luminal membrane via Na⁺-dependent co-transporters
• They then traverse the basolateral membrane into the blood by facilitated diffusion
• Four separate carriers for amino acids: neutral, acidic, basic and imino amino acids
• Dipeptides and tripeptides use a H⁺-dependent cotransport mechanism to cross into enterocytes, and cytoplasmic peptidases in the enterocyte hydrolyze the di- and tripeptides to amino acids
• Absorption is faster for di- and tripeptides than for free amino acids

Lipid Digestion

• Lingual lipase initiates partial digestion of lipids in the mouth
• Mixing in the stomach breaks lipids into droplets to increase their surface area for digestion by pancreatic enzymes
• Pancreatic lipases degrade lipids to free fatty acids and monoglycerides
• Cholesterol and bile acids combine to form micelles

Lipid Absorption

• FFAs (Free fatty acids), monoglycerides and cholesterol diffuse out of micelles into enterocytes at the luminal border, which is a passive process
• Inside the enterocyte, the lipid digestion products are re-esterified to make triglycerides, cholesteryl esters, and phospholipids
• Apoproteins combine with the re-esterified lipid products and form chylomicrons, which are exocytosed across the basolateral membrane into the lymph vessels, rather than the blood vessels
• Hereditary absence of apoprotein B (abetalipoproteinemia) results in the inability to absorb dietary fats

Actin

• Microfilaments within the cytoskeleton, and part of the contractile apparatus in muscle cells
• G-actin (globular) or F-actin (filamentous)
• Essential for mobility and contraction of cells during cell division
• Participates in muscle contraction, cell motility, cell division, vesicle and organelle movement, cell signaling, and the formation of cell junctions
• Alpha, beta, and gamma actins identified in vertebrates.
• Alpha actins = major part of contractile apparatus
• Beta and gamma actins= components of the cytoskeleton

Tubulin

• To form microtubules, the dimers of α- and β-tubulin bind to GTP
• GTP-Bound to dimer --> assembles on (+) ends of microtubules while in the GTP-bound state
• Dimers bound to GTP assemble into microtubules, while dimers bound to GDP tend to fall apart

Myosin

• Binds actin to facilitate muscle contraction