Human Bio Test 2

Protein Synthesis

Genome

total genetic info of organism

• 3 × 10⁹ base pairs of DNA in diploid human cell

Gene

stretch of DNA that codes for a protein

• resides on locus (specific location on chromosome)

• ~20,000 genes on human genome

• genes are only small fraction of total genome

Genetic Code

DNA instructions that specifies for amino acid sequence of a protein (polypeptide)

Central Dogma

pathway of information from DNA → protein

1. Transcription (in nucleus): DNA → mRNA

2. Translation (in cytoplasm): mRNA → protein via amino acids

Types of RNA

mRNA: messenger RNA

• coding RNA

tRNA: transfer RNA

• non-coding RNA (20 tRNA for 20 amino acids)

• carry amino acids to ribosomes to add to polypeptide chain during translation

rRNA: ribosomal RNA

• forms small subunit of ribosomes

• joins with proteins (large subunit) to make ribosome

Control of Gene expression

gene is expressed when protein is synthesized from it

all somatic cells contain the same genetic information → potential to express all genes

• pattern of gene regulation distinguishes cell types

• tightly regulated process

  • when DNA is more loosely bound with histones, the gene is more likely to be expressed

  • methylation adding methyl group to DNA, regulating how tightly bound DNA is to histones

  • more methyl groups binds the DNA tighter to histones, lowering the likelihood of gene expression

Transcription (in nucleus)

DNA → synthesis of mRNA

1. RNA polymerase  = enzyme that synthesizes mRNA from DNA

• attaches to promoter of DNA, reads template strand

• assisted by transcription factors = protein that guides enzyme (RNA polymerase) to correct gene 

• Helicase = enzyme that unwinds DNA coding strand + template strand

2. pairs DNA with complimentary RNA base 

• DNA G → RNA C

• DNA A → RNA U

• DNA C → RNA G

• DNA T → RNA A

NOTE: resulting mRNA should look similar to the CODING strand of DNA

3. Transcription stops when RNA polymerase reaches terminator sequence = sequence of nucleotides that end transcription 

5’ → 3’

helicase unzips DNA → transcription factors guide RNA polymerase to promoter of template DNA strand → RNA polymerase pairs DNA w/ complimentary RNA base → transcription stops at terminator sequence 

mRNA Processing

transcription produces pre-mRNA (immature)

pre-mRNA → mRNA

3 major edits happens

1. add 7-methylguanosine cap to 5’ end of mRNA

• function: allows mRNA to pass through selective nuclear pores and be identified by ribosomes as mRNA in cytoplasm 

2. add (lots of) poly-A tails to 3’ end of mRNA

• buffer to prevent degradation of mRNA in cytoplasm by mRNA degradative enzymes  

Processing of pre mRNA → mRNA (nucleus)

transcription produces pre-mRNA (immature)

3 major edits happens to mRNA before it leaves the nucleus

1. At 5’ end of mRNA: 7-methylguanosine cap added

• function: allows mRNA to pass through nuclear pores and be identified by ribosomes as mRNA in cytoplasm

2. at 3’ end of mRNA: poly adenine (poly-A) tail added

• function: acts as buffer to prevent degradation of mRNA in cytoplasm by RNA degrading enzymes

3. Splicing

• removal of INTRONS (noncoding segment to be deleted) and join EXONS (coding segment for protein)

→ mature mRNA: 5’ cap, exons, poly-A tail 

Alternative Splicing

Generating diverse protein products from single gene

• removal of introns and rejoining of exons

• different introns and exons spliced for different cells

• “splice variants” expressed in different cells/tissues

  • response to different signals at different steps of development

• (in nucleus)

Translation

Translation of mRNA sequence → polypeptide

• Codon: triplet of nucleotides within mRNA which codes for an amino acid

• translation of mRNA → polypeptide requires effort of mRNA, tRNA, and rRNA

• AUG = methionine (START CODON)

  • almost every protein starts with methionine

  • ribosome recognizes start codon and begins to produce protein

don’t need to memorize codons

Transfer RNA (tRNA)

function: match amino acid to codon sequence of mRNA

• clover leaf shaped non-coding RNA

• Parts:

  • acceptor stem: end that binds to amino acid (contains 1 of 20 amino acids)

  • anticodon loop: has triplet nucleotide sequence that is complementary to codon of mRNA

• tRNA has 20 amino acids and works with ribosomes

Ribosomal RNA (rRNA)

function: forms complex with ribosomal proteins to form ribosomal subunits

synthesis of ribosomal subunits 

• ribosomal proteins made in cytoplasm through translation and sent into nucleolus

• rRNA made in nucleolus + ribosomal proteins (made in cytoplasm) = ribosomal subunits (made of both rRNA and proteins)

• ribosomal subunits (large subunit + small subunit) assembled in nucleolus

• small + large subunits leave through nuclear pores separately into cytoplasm and only come together during translation 

• in cytoplasm, during translation, small + large subunits combine to create ribosome

3 major binding sites of ribosome:

1. mRNA binding site

2. tRNA binding sites

• P site: peptidyl tRNA → 1st tRNA binding site

• A site: aminoacyl → site where tRNA molecule brings new AA

Ribosomal Anatomy

1 mRNA binding site, 2 tRNA binding sites

• P site: peptidyl tRNA

  • first site where tRNA binds

• A site: aminocyl tRNA

  • site where tRNA molecule brings in new amino acids

• binding of tRNA to A site weakens bond between amino acid and tRNA in p-site

Steps of translation

1. the 5’ cap of mRNA is recognized by small ribosomal subunit 

• start codon AUG is aligned with the future P site location 

• tRNA binds anticodon to codon of mRNA and brings methionine amino acid via acceptor stem 

2. Once anticodon of tRNA and codon of mRNA are bound together, large ribosomal subunit binds to small ribosomal subunit, completing ribosome → complete P and A site

3. new tRNA binds to the next codon in the A site

• weakens bond between amino acid and tRNA in P site

4. the first amino acid is detached from tRNA and joined to second amino acid via peptide bond 

• the ribosome moves down a codon and the first tRNA is detached, moving the second tRNA into the P site, freeing the A site for another tRNA 

5. process repeats, elongating chain until the stop codon is reached 

• polypeptide chain exits through E site (exit site) and ribosomal subunits separate 

detached tRNA bind to new amino acids to be recycled. 

Human Genetic Makeup

• humans are 99.9% genetically identical to each other

• ~1 in every 300 base pairs is a variable region

• singular nucleotide polymorphism (eg 25% have A at the site, 75% have a G)

  • substitution

  • deletion

  • insertion

• this particular pattern at these variable sites makes us genetically unique

• mutations = when variability interferes with resulting protein function

  • inherited mutation: passed down from parents

  • spontaneous mutations: errors in DNA replication

  • induced mutations: exposure to mutagen (eg UV light, radiation, tobacco)

Cellular Metabolism

• all chemical reactions that occurs in an organism

• usually energy

Metabolism

all chemical reactions that occur in organism

2 types: 

Catabolism

• breaking of molecules to release energy

• ex. hydrolysis

Anabolism

• building of organicc molecules by using energy

• ex. dehydration synthesis

Coenzymes

• organic type of cofactors

• remove H+ ions from organic substances

• binds to active sites of enzymes to catalyze reactions

• NAD+ and FAD

  • energy carriers → transport 2e- 

  • Act as intermediaries

    • accept e- from one molecule → transfer to another molecule

  • remove H+

oxidation reacton: reaction resulting in losing electron

reduction reaction: reaction resulting in gaining electron

OiL: Oxidation lose

RiG: Reduction gain

Coenzymes Redox Reactions (KNOW)

both NADH and FADH₂ are 2 e- carriers 

NADH:

NAD⁺ + H⁺ +  2e- < == > NADH

FADH₂

FAD + 2H⁺ + 2e- < == > FADH

Carbohydrate Metabolism

Glucose catabolism (breakdown) → primary ATP production process

• generates ATP and other high energy compounds

  • glucose + oxygen → carbon dioxide + water + ATP

• anaerobic reaction: glycolysis

  • occurs in cytosol

  • no O2 required

  • small amounts of ATP produces

• aerobic reaction: cellular respiration

  • occurs in mitochondria

  • uses O2

  • produces bulk ATP

Glycolysis

• breakdown of 6 carbon glucose → two 3-carbon pyruvic acids

• pyruvate = ionized pyruvic acid

• occurs in cytoplasm

• factors required:

  • glucose molecules

  • cytoplasmic enzymes

  • ATP and ADP

  • inorganic phosphates

  • NAD+ (coenzyme)

• invest 2 ATP

• produce 4 ATP (net gain 2 ATP)

cccccc

1. in cytoplasm, phosphate is added to glucose (taken from ATP→ADP) “glucose 6 phosphate”

pcccccc (-ATP)

2. 2nd phosphate group is added to other end (ATP → ADP)

pccccccp (-ATP)

3. molecule is split into two 3-carbon molecules 

pccc pccc

4. inorganic phosphate group from cytosol is added to other end of each molecule. 2NAD+  → 2NADH (NAD+ from mitochondria removes 2e- and H+ and is sent back to the mitochondria for Electron Transport Chain)

pcccp pcccp (+2NADH)

5. phosphate removed from each 3-carbons molecule producing 2 ATP (2ADP→2ATP)

pccc pccc (+2ATP)

6. both molecules’ phosphates are rearranged releasing 2 H2O molecules 

p         p          (+2 H2O)

ccc     ccc

7. last phosphates are removed from both molecules producing 2ATP (2ADP → 2ATP). 2 pyruvate remain (used in either citric acid cycle or fermentation)

ccc ccc (+2 ATP +2 pyruvate)

glycolysis products + location

location: cytoplasm

• 2 H2O

• 4 ATP (net 2 ATP)

• 2 NADH (used later in electron transport chain)

• 2 Pyruvate (used in either fermentation or citric acid cycle)

Aerobic Respiration

ATP production in mitochondria

• mitochondrial absorb and break down pyruvate requiring oxygen

2 phases:

• Citric Acid Cycle (in mitochondrial matrix)

  • coenzymes transfer e- → ETC

• Electron Transport Chain (inner mitochondrial membrane)

  • e- passed down protein cascade producing H+ (proton) gradient (ADP→ ATP)

Mitochondria

Mitochondrial Membranes

• Outer membrane 

  • large diameter pores open to ions and small organic molecules (pyruvate can pass into inter membrane space )

• Inner Membrane

  • contains carrier proteins for ETC

  • move pyruvate → mitochondrial matrix 

• Intermembrane Space 

  • separate outer and inner membrane 

Aerobic/Cellular Respiration (DRAW OUT!)

• in presence of oxygen, mitochondrial absorbs and break down pyruvic acid molecules

• Mitochondria

  • outer membrane: large diameter pores open to ions and small organic molecules

  • inner membrane: has carrier proteins, moves pyruvic acid into mitochondrial matrix

Part 1: Citric Acid (Krebs) Cycle

1. 1 pyruvate (3 carbon) →1 carbon lost as CO2

2. Acetyl CoA (2C) → combines with oxaloocetic acid (4c)

4. ketoglutaric acid (5C) → 1 lost as

5. Succinctyl CoA (4C)

6. Oxaloacetic acid (4C)

Part 2: Electron Transport Chain

• FADH2 and NADH deliver H+ and e- to enzymes in inner mitochondrial membrane

• NADH donates e- to FMN (protein complex) then sent to coenzyme Q

• FADH directly to CoQ

• CoQ releases protons into intermembrane space, passes e- to series of cytochromes → protein surrounding pigment like copper or iron

• e- passes through system losing energy

• Oxygen accepts e- and combines with H+ to form H2O

• electrons of ETC lose energy as they pass from coenzyme → cytochrome

Citric Acid (Krebs) Cycle (part 1 of cellular respiration)

for 1 pyruvate (glucose → 2 pyruvate → double products)

• within mitochondrial matrix

Intermediate step: pyruvate oxidation

• Pyruvate (3 C) is oxidized (NAD+ → NADH), loses 1 C as CO2

• produces Acetyl CoA (2C)

Citric Acid Cycle

1. Acetyl CoA (2C)

• → combines with Oxaloacetic acid (4C) by coenzyme A

2. Citric Acid (6C)

• → loses 1 C as CO2

• → oxidized (NAD+ → NADH)

3. Ketoglutaric Acid (5C)

• → lose 1 C as CO2

• → oxidized (NAD+ → NADH)

4. Succinyl CoA (4C)

• reconfigured many times into

• → 1 NADH

• → 1 FADH2

• → 1 GTP from GDP (donates P to ADP → ATP)

Products

• 3 CO2 (discarded into plasma as waste)

• 4 NADH (go to ETC)

• 1 FADH2 (go to ETC)

• 1 GTP (→ 1 ATP)

Citric Acid cycle Products + location (for 1 glucose/ 2pyruvate)

mitochondrial matrix

• 6 CO2 (including production of acetyl CoA)

• H+ ions and e- transferred to 8 NADH and 2 FADH2 (go to Electron Transport Chain)

• 2GDP→2GTP (donates phosphate to 2ADP→ 2ATP)

Electron Transport Chain

NADH and FADH2 deliver H+ and e- to inner mitochondrial membrane

1. NADH transports H+ and e- → FMN → Coenzyme Q (CoQ) 

2. FADH transports H+ and e- directly → CoQ

3. CoQ releases H+ into intermembrane space and pass e- to cytochromes (protein surrounding pigment which binds with e-) 

4. cytochrome chain transports e- and uses e- to pump H+ into intermembrane space via H+ ion pumps (loses energy) → steep proton gradient in intermembrane space 

5. Oxygen acts as last e- acceptor, combining with H+ to form H2O 

6. chemiosmosis: H+ diffuses back into mitochondrial matrix via H+ Ion channel, and KE powers ATP synthase to make ADP→ 32ATP

Summary of Products

Glycolysis (in cytoplasm):

• 2 NADH

• 2H₂O

• 2ATP (net) 4 total

• 2 pyruvate

Citric Acid Cycle (in mitochondrial matrix) (for 1 glucose)

• 8 NADH

• 2 FADH₂

• 6 CO₂

• 2 ATP (from GTP)

Electron Transport Chain (in inner mitochondrial membrane) (for 1 glucose)

• 4 H2O

• 32 ATP 

Integumentary System

Components

Most Superficial

• Epidermis:

  • 4-5 layers of stratified squamous epithelium

• Dermis: 2 layers

  • papillary layer → papillae, areolar tissue

  • reticular layer → dense connective tissue

• Hypodermis (not apart of integumentary system) 

  • underlying subcutaneous layer of adipose + areolar connective tissue

Integumentary system function

1. Protection

• physical barrier

• immune functions: keep pathogens out

• protects from UV damage: melanocytes

2. Body Temperature Regulation

• regulation of conductive/convective heat loss

  • conductive: transfer of heat from one solid to another

  • convective: transfer of heat from liquid to gas (air)

  • blood vessels to skin constrict/dilate to regulate blood flow to skin

  • skin blood flow regulated primarily by neural mechanisms

• more blood to skin = more heat transfer

• less blood to skin = heat conservation

• regulation of evaporative heat loss 

  • neural regulation of activity of sweat glands 

3. Vitamin D₃ Synthesis

• sunlight converts cholesterol in epidermis/diet → cholecalciferol (inactive D3)

• sent to liver for modification 

• sent to kidney to form → calcitriol (active D3)

• calcitriol stimulates Ca ²⁺ and PO₄^3- absorption from digestive tract (increase # transport proteins) 

4. Sensation

• mechanoreceptors, thermoreceptors, nociceptors

5. excretion

• glands

Neural regulation

• negative feedback loops

• hypothalamus = control center

Function of Intergumentary system Vitamin D-3 Synthesis

1. sunlight converts cholesterol in epidermis to cholecalciferol (inactive) (or absorbed from diet)

2. sent to liver for modification

3. sent to kidney to form calcitriol (active)

4. calcitriol stimulates Ca2+ and PO4³- absorption from digestive tract (increased # of transport proteins

Functions Sensation and excretion

sensation → mechanreceptors, thermo receptor

Epidermis: outermost layers

• stratified squamous epithelium

• ranges in thickness:

  • thin skin → 0.1-0.15 mm

  • thick skin (globular)→ 0.5-4.5 mm

    • eg soles of feet, palms of hands

• separate from dermis by underlying basement membrane

• avascular → no blood vessels = less metabolic demand

• epidermal ridges project into dermis → increase surface area for attachment + fluid movement

Epidermis: Cell Types

• Keratinocyte (Stratum Corneum)

  • most abundant cell type

  • synthesize and accumulate the protein keratin

  • produce lamellar granules ( lipid secretions) → waterproofing

  • put fat into skin to waterproof

• Langerhans cells (dendritic cells) (stratum spinosum)

  • immune response against microbes and cancers via phagocytosis

  • found in stratum spinosum

• Stem Cells (basal cells in stratum basale)

  • deepest layer of epidermis (stratum basale)

  • differentiate into keratinocytes

• Melanocytes

  • produce melanin (pigment)

  • star shape wrap around keratinocytes

  • located in stratum basale

• Merkel Cells (tactile) (stratum basale)

  • tactile

  • mechanoreceptors that make contact with sensory neurons to elicit sensation of light touch

    • tactile cell + nerve ending = merkel’s disc

  • found in stratum basale

Epidermis of skin has 4-5 layers ( DRAW OUT, know each cell and what layer its found in)

deep

1. Stratum Basale: single layer of cuboidal/ columnar cells

• source of cell renewal (stem cells)

• location of melanocytes and Merkel cells

• further from stratum basale = less active because its farther from blood supply

2. Stratum spinosum: many layers (8-10) of keratinocytes. Cells flattening

• Langerhans cells located here

3. Stratum granulosum: 3-5 cell layers of keratinocytes

• transition between metabolically active cells and superficial dead keratinized cells

4. stratum lucidum: single layer of densely packed dead keratinocytes present in thick skin

• layer of attachment

• thick skin experiences more friction than thin skin, needing extra structural support from protein structures holding the skin in place

5. stratum corneum: 15-30 layers of fully keratinized dead keratinocytes (lacking nuclei)

Superficial

Layers of Epidermis 

Superficial:

Stratum Corneum

• 15-30 layers of fully dead keratinized keratinocytes (lose nuclei

• keratinocytes

Stratum Lucidum 

• single layer of densly packed keratinocytes for support (only in thick skin) 

Stratum Granulosum 

• 3-5 layers of keratinocytes transitioning from metabolically active → dead 

• flatten as cells move up

Stratum Spinosum 

• 8-10 layers of keratinocytes, cells flatten 

• langerhans cells here

Stratum Basale 

• single layer of cuboidal/columnal cells 

  • source of cell renewal (stem cells), melanocytes, merkel cells

most metabolically active = closer to basment membrane

REMEMBER ORDER OF LAYERS

Come Let’s Get Sun Burned (superficial to deep)

Melanocytes

• located in stratum basale

• contain melanosomes

  • synthesis of the pigment melanin from amino acid tyrosine

• delivered intact to neighboring keratinocytes

  • granules help to protect epidermal cells from DNA damage via UV light

  • eventually degraded by lysosomes in keratinocytes

• exposure to UV light → production of melanin → tanning

Factors affecting skin color

• epidermal pigmentation

  • melanin:

    • yellow-red = pheomelanin (pigment

    • brown-black pigment = eumelanin (pigment

    • differing rates/amounts/type/distribution of melanin = differences in skin color

    • Note: within individual, areas darker pigmentation due to differing densities of melanocytes

• Blood Flow to skin: pigment in blood → hemoglobin

  • oxygenated = bright red

  • deoxygenated = dark red/purple

  • redness/flushing = increased blood glow to skin

    • Erythema: localized area of redness due to excess blood in dilated vessels

    • Cyanosis = bluish coloring

Dermis (2 layers)

between epidermis and hypodermis

• Papillary layer

  • dermal papillae

  • vascular areolar tissue

  • capillary beds for blood e xchange

• Reticular layer (NOT reticular tissue)

  • deeper layer of dense connective tissue with abundant collagen and elastin fibers

• Location of accessory structures:

  • blood vessels

  • lymphatic vessels

  • nerves and sensory receptors

  • hair follicles

  • glands

Accessory Structures: sensory receptors

• Mechanoreceptors (5 types) :

  • Merkels discs: sensitive to fine tough and pressure, stratum basale

  • Meissner’s corpuscle: (concentrated in glabrous skin, nonhair skin) sensitive to fine touch and pressure; dermal papillae

  • Ruffini’s ending: sensitive to skin distortion and pressure; deep dermis

  • Pacinan (lamellated) corpuscle: sensitive to deep pressure and vibration; deep dermis/hypodermis

  • nerve endings surrounding hair root: sensitive to hair movement

• all sensitive to touch but diff location

• Nociceptors: sensitive to painful stimuli, free nerve endings

• Thermoreceptors: sensitive to temperature, free nerve endings

glamorous skin (non hairy skin) = touch sensitive, palms, feet, lips, genitalia,

higher layer = lighter touch

Accessory Structures: nails

• nails =dense layers of dead, heavily keratinized, keratinocytes

  • function: protection, limit distortion, tools

• Nail root: deep epithelial fold; contains stratum basale that gives rise to the nail

• Nail body: visible portion of nail

• Nail bed: epidermal layer just below body 

• Lunula: base of nail with no blood vessels (white)

• Eponychium: cuticle, extension of stratum corneum from root over base of nail

Accessory Structures: hair

• hair: dead keratinized cells, which project above surface of skin

• produced in organs within the dermis called hair follicles

• hairy skin has either:

  • vellus hair: small, short, delicate

  • terminal hair: large, course, and usually pigmented (distribution of melanin into hair as its produced)

• follicle: specialized imagination of epidermis within surrounding connective tissue

  • base of follicle:

    • hair papilla: indentation in connective tissue (blood vessels) most active because they are closest to blood vessels

    • hair bulb: surrounds papilla and is site of production

  • hair root: anchors hair, extends from base

Follicle: specialized invagination of epidermis in surrounding connective tissue sheath

base of follicle

• hair papilla: indentation in connective tissue (blood vessels)

• hair bulb: surrounds papilla and is site of production

Hair root: anchors hair, extends from base to halfway to skin surface (hair cells active)

Hair shaft: extends from halfway point to surface (hair cells dead) 

arrector pili → muscle that stands hair up, attached to sensory nerve endings. 

Hair growth

• hair grows continually: 0.33 mm/day (scalp)

• hair matrix

  • within hair bulb

  • site of epidermal stem cells (divide, pushed up, keratinized)

• medulla (inner), cortex (middle), and cuticle (outer)

  • inner → outer layers = less → more keratin

• keratinization complete at border of root and shaft

epithelial cells that line follicle are arranged in layers (not part of hair, surround and support hair)

• inner to outer

  • internal root sheath (not part of hair, support hair in epithelial cells)

  • external root sheath

  • glassy membrane

Accessory structures: secretion modes

• merocrine secretion: uses exocytosis to discharge secretory vesicles at apical surface of gland cell

• apocrine secretion:

  • apical (top) end breaks off, shedding cytoplasm and secretion

  • cell survives and regrow

• holocrine secretion:

  • superficial gland cell bursts and leaks stuff

  • cell dies

  • replaced via stem cells

Accessory Structures: Glands

Sebaceous glands/follicles 

• holocrine secretion (cell explodes) called sebum: complex lipid mixture 

• function: waterproofing, moisturizing, antimicrobial action 

Sweat glands (both MEROCRINE):

Apocrine Glands: 

• armpits, groin, nipples 

• MEROCRINE SECRETION 

• secrete onto hair follicles

• scent 

• emotional + sexual stimuli

•  bromhidrosis: stinky BO → bacteria break down secretions from apocrine glands

Eccrine Glands (found throughout body)

• merocrine 

• watery secretion: small amount of electrolytes and waste products

• regulated by nervous system (thermoregulation, excretion) 

Function of Bone

• Support, movement, and protection

  • basic body shape

  • supports body weight

  • protects vital organs (eg lungs, heart)

  • movement (skeletal muscle pull bone → movement)

• Metabolic function

  • Hematopoiesis: forms blood cells in red bone marrow

  • Storage of minerals and lipids

    • calcium salts, phosphates

    • lipids in yellow bone marrow

    • vitamin D3 production → increase uptake of phosphates and calcium ions to bones

Structure of Bone (98% extracellular matrix connective tissue)

Compact vs. Spongy

• Compact: outside, dense 

• Spongy: inside, “cobweb”

Long vs. Flat

Long: all limbs, hallowed chamber, no spongy 

• Epiphysis

  • ends of bone 

  • spongy bone

• Diaphysis

  • long shaft

  • no spongy bone

  • medullary cavity: hollow insides 

Flat: skull and ribs

• interior is spongy bone

Bone (Osseous Tissue)

Specialized cells dispersed in hardened extra cellular matrix 

ECM:

• 1/3 collagen → strength and flexibility 

  • triple helix of tropocollagen link → fibrils → fibers, form framework

• 2/3 calcium → hardness, brittle, resist compression,  interact to form hydroxyapatite crystals (calcium and phosphorus)

  • crystals deposit between gaps in collagen

• ground substance (interstitial fluid) → proteoglycans (type of glycoprotein—sugary proteins) and glycoproteins

  • sugar groups are polar→ hydrophilic → keep water in place

Types of bone cells

bone cells make up <2% of bone

• Osteoprogenitors

  • stem cells → divide to form osteoblasts

• Osteoblasts

  • immature bone cell that produces collagen (ECM)

• Osteocytes

  • mature bone cells, regulate matrix → release chemicals

  • connected by canaliculi → channels allowing for exchange of nutrients, waste, and oxygen

• Osteoclast (from immune cells, DIFFERENT LINEAGE)

  • multinucleated

  • breaks down and recycle bone matrix via acid and enzymes

  • balance osteoblasts

Compact (Dense) Bone

Function: protection, support, resist stress

• dense matrix 

  • arranged around blood vessels 

• Osteon (haversian system): cylindrical unit of circular layers of lamellae + osteocytes trapped between layers and in lacunae

  • canaliculi connect haversian canal and lacunae for nutrient and waste exchange

• Haversian Canal: center of osteon, canal for blood vessels

• Perforating Canal: transverse blood vessel canals connecting haversian canals

Spongy (Cancellous) Bone

Function: support, store bone marrow

• less dense matrix 

• open network 

• trabeculae → interconnecting bundles of spongey bone 

  • thin with lamellae and osteocytes between layers (no central blood vessel)

  • canaliculi → pores for osteocyte nutrient exchange 

• endosteum interior layer covering bone 

• contains bone marrow in gaps of trabeculae → hematopoiesis

Bone Marrow

Surround trabeculae of spongy bone

Red Bone Marrow 

• site of hematopoiesis → produces blood cell

• found in interior of flat bones, epiphysis of long bones (and in medullary cavity in children)

Yellow bone marrow 

• site of storage of adipocytes 

• found in medullary cavity 

  • red bone marrow as child → yellow bone marrow as adult 

Covering of Bone

Periosteum

• membrane that covers outer layer of bone except articular surfaces 

• attachment points (tendons, ligaments) 

• 2 layers 

  • inner cellular layer of osteoblasts and osteoprogenitor cells (for bone replenishment) 

  • outer fibrous membrane (fibroblasts in fibrous matrix)

• isolates and protects bone

Endosteum 

• incomplete cellular covering on interior surface of bones

• covers trabeculae and lines Haversian canals 

• endothelial (epithelial) cells mixed with osteoprogenitor cells and largest concentration of osteoclasts 

• important for growth and remodeling 

Bone Development (Ossification)

2 types of bone formation

1. Intramembranous ossification

2. Endochondral ossification

• both types 

  • bone matrix initially laid as osteoid (organic proteins + collagen) by osteoblasts → subsequently mineralized

  • bone produced first in disorganized fashion → woven bone

  • woven bone is remodeled around blood vessels to form organized bone 

Intramembranous Ossification

bones forming from membrane

• intramembranous bones:

  • bones of skull and clavicle 

• formed directly from mesenchyme: sheet like embryonic tissue giving rise connective tissue 

• begins 8 weeks gestation, complete after 2 years (for brain growth) 

• fontanels = soft spots between bones of skull (fibrous membrane connecting cranial bones)

Steps of intramembranous ossification 

starts 8th weeks of embryonic development 

1. mesenchymal cells cluster, differentiate osteoblasts → osteoblasts produce collagen to form osteoid (collagen + organic proteins) → mineralized with calcium salts forming bone matrix

2. as ossification proceeds some osteoblasts are trapped in boney pockets where they differentiate into osteocytes. developing bone grow outwards from ossification center in struts called spicules

3. Blood vessels begin to branch within region and grow between spicules → spicules connect and trap blood vessels in bone 

4. deposition of bone by osteoblasts near blood vessels → plate of spongy bone and woven blood vessels WOVEN BONE

5. remodeling of blood vessels → osteons, osteoblasts on bone surface + connective tissue around bone → periosteum

Endochondral Ossification (cartilage)

bones formed from cartilage

begins 8-12 weeks into gestation → early adulthood 

every bone other than intramembranous bone 

• hyaline cartilage model → convert into bone 

• formation of bone INDIRECTLY FROM MESENCHYME

  • mesenchymal cells deposit cartilage to model growing bone → replaced with both tissue

Endochondral Ossification steps

1. formation of hyaline cartilage models

• mesenchymal cells cluster → develop into chondroblasts

• chondroblasts (immature cartilage cells) produce hyaline cartilage matrix

• chondrocytes enlarge and stimulate formation of calcified cartilage

2. formation of bony collar (solid bone)

• blood vessels grow around cartilage model

• outer ring of cells differentiate into → osteoblasts →

• osteoblasts produce bone collar

3. Vascular Invasion (hollow out bone for medullary cavity)

• blood vessels, osteoblasts, osteoclasts → invade center

• primary ossification center forms

• osteoblasts replace calcified cartilage → bone (solid bone)

• osteoclasts eat center of bone → medullary cavity

4. Elongation (overlap with step 3)

• blood vessels invade epiphysis → form secondary ossification centers

• hyaline cartilage plate at metaphysis (growth/epiphyseal plates) persists after birth 

  • allow for further bone elongation after birth 

5. Epiphyseal Plate ossification 

• post puberty, epiphyseal plate ossifies and lengthening stops → becomes epiphyseal line 

Bone Growth at Growth plate

begins at epiphysis 

• first layer: reserve zone 

  • non-proliferative (non-dividing) chondroblasts (operate as stem cells) 

• second later: zone of proliferation 

  • growth factors stimulate rapid proliferation/ mitosis of chondroblasts 

  • cartilage matrix begins forming 

  • when chondroblasts are completely surrounded by cartilage matrix in lacunae → diff into chondrocytes

• third layer: zone of hypertrophy

  • chondrocytes mature and enlarge

  • matrix expands 

• fourth layer: Zone of Calcification 

  • chondrocyte death → emptying of lacunae

  • calcification of matrix

osteoblasts invade and deposit bone matrix on calcified cartilage: convert cartilage → bone

end near diaphysis 

cartilage growth rate = osteoblast bone production rate → at puberty, osteoblast conversion rate overtakes cartilage growth rate, and replaces all cartilage→ growth stops

Bone Remodeling

• continual process of bone matrix turnover throughout life

  • partially replaces matrix, but leaves whole bone intact 

  • regeneration of damaged bone → adaptive response 

• metabolic function: calcium + phosphate regulation, releases old minerals and deposits new minerals

• site specific: areas with great friction eg femur head 

• osteoblasts: form new matrix proteins (balance osteoclasts)

• osteoclasts: destroy old matrix (balance osteoblasts)

• osteocytes: stimulate breakdown of old calcium crystals + formation of new ones

Factors Affecting Bone Growth

Vitamins

• Vitamin C → required for normal collagen synthesis in osteoblasts

• Vitamin D → promotes calcium + phosphate absorption from diet

• deficiencies → fragile bones

Hormones

• calcium regulating hormones 

  • Parathyroid hormone: stimulates osteoclasts when not enough Ca in blood → break down bone for Ca

  • Calcitonin: inhibits osteoclasts when there is too much Ca2+ in blood 

• Growth hormone: stimulates cell growth and division

• Thyroid hormone: stimulates cell metabolism and osteoblast activity

• sex hormones

  • Androgens and estrogens at puberty → increase osteoblast activity → increase bone formation over rate of epiphyseal plate expansion (estrogen is faster) → stop growing faster

  • lack of estrogen at menopause → accelerates loss of bone

Fractures

Any crack or 

Division of Nervous System

Central Nervous System (CNS): brain and spinal cord

Peripheral Nervous System (PNS): Neural tissue outside of CNS

• nerves: carry information between CNS and body, connective tissue + axons

Prototypical Neuron Structure

Cells specialized for intercellular communication

dendrite: receives information

soma/cell body: site of nucleus, organelles, protein production, etc

axon hillock: generates action potential

axon: long, myelinated section in which action potential passes down → sends signals 

Axon terminals/synapse: site of communication with next neuron 

Anatomical Neuron Classification 

Anaxonic neuron

• more than 2 processes (axons and dendrites)

• axons indistinguishable from dendrites 

Bipolar neurons

• 2 processes separated by cell body 

• 1 long dendrite and 1 long axon

Unipolar Neuron 

• single long axon process 

• cell body to the side 

Multipolar Neuron 

• more than 2 processes 

• single axon, multiple dendrites 

Functional Neuron Classification

• Afferent neurons (sensory) accepting signals

  • carry information TOWARD spinal cord or brain

  • somatic: information about external world and body position 

  • visceral: information about internal systems

• Efferent neurons (motor) effect signals

  • carry information AWAY from spinal cord or brain to PNS

  • somatic: innervate skeletal muscles (voluntary)

  • visceral: innervate smooth muscle, cardiac muscle, glands (involuntary) 

• Interneurons 

  • Communicate between neurons

Neuroglia 

Supporting Cells, ½ of neural tissue

• Ependymal (CNS)

  • make and secret CSF (cerebral spinal fluid)

• Microglia (CNS)

  • phagocytes

  • remove waste + dead cells 

• Astrocytes (CNS)

  • maintain BBB (blood brain barrier)

    • monitor what passes through

    • grab onto neurons and capillary beds of brain 

  • structural support

  • regulate nutrients 

• Satellite Cells (PNS)

  • regulate nutrients in peripheral nervous system

  • monitor and support

• Oligodendrocytes (CNS)

  • myelination

  • structural support

• Schwann (PNS)

  • myelination + repair

Supporting Structures  

• cerebral spinal fluid CFS (from ependymal cells) 

  • clear fluid in brain and spinal cord 

  • function: protection + support, nutrients delivery for brain, remove waste, immune protection 

  • constant circulation (drains into veins)

• Blood Brain Barrier 

  • highly selective permeable membrane

  • specialized capillaries and neuroglia that tightly regulate what moves into CSF from plasma

  • astrocytes bind neurons to capillary beds of brain → selective food exchange between blood and brain

• Myelin (oligodendrites (CNS) and schwann (PNS))

  • insulating membranes surrounding SOME axons (white matter)

  • from specialized neuroglia: oligodendrites in CNS, schwann cells in PNS

  • increase in speed of action potential down axon with some gaps

  • white matter = myelinated axons

  • gray matter = unmyelinated axons + cell bodies

Schwann Cells and Axons (PNS)

White Matter

• axons surrounded by myelin → prevent mixture with outside fluid

• multiple Schwann cells 

• gaps = nodes of Ranviet 

  • allow for exchange only at these points 

Grey Matter

• unmyelinated axons + cell bodies

• covered by only 1 Schwann cell → can hold multiple axons

• little covered, top of axons still exposed

Myelination Process

Schwann cell wraps around axon, forms layers → myelin sheath

Neural Physiology 

• resting potential in cell body

• graded potential: small localized change in potential, along dendrites → soma

• axon hillock: enacts action potential at high enough graded potential

• triggers synaptic activity (communication to target cell)

Membrane Potential

• Voltage (V) = difference between electrical potential between 2 points (comparing inside to outside of cells, eg -50 mV is more negative on inside) 

• Current (I) = movement of charge too eliminate voltage

  • stronger with higher voltage

• Resistance (R) = anything impeding movement of charge 

I = V/R

Resting Membrane Potential (RMP)

-70 mV for typical neuron (cell is more negative because of proteins)

• electrical potential diff across cell membrane during resting condition

• 3 contributing factors

  • passive chemical gradients

  • passive electrical gradients

  • active transport (K+/Na+ pump)

• MOST IMPORTANT IONS in membrane potential =

  • K+ and Na+ 

• K+ is much more permeable than Na+ 

Chemical and Electrical Gradients (Passive Transport)

• K+ 

  • Salty bowl of special K → high K+ in cell →

  • Chemical Gradients: K+ wants to leave cell 

  • Electrical Gradients: cell is more negative → K+ wants to enter negative cell

  • opposing gradients → net movement out of cell 

  • K+ leak out cell through leak channels 

  • free K+ movement → equilibrium = -90mV → K+ is much more permeable than Na+ 

• Na+ 

  • chemical gradient: Na+ wants to enter cell (more concentration outside) 

  • electrical gradient: Na+ is positive → wants to enter into negative cell

  • chemical + electrical gradient same direction → Na+ really wants to enter cell

  • if Na+ allowed to pass freely → equilibrium = +66 mV, → high Na+ resistance → only a little Na+ allowed to pass during RMP

at RMP → movement of ions → leak channels 

• K+ >>>> Na+

Active Transport: Na+/K+ Pump in RMP

• primary active transport: move ions against passive gradient 

• transport 3 Na+ out, 2K+ in 

• restore resting membrane potential → remove Na+ leaking in and retrieve K+ leaked out 

Changes in RMP

occur due to activation of 

• Chemically gated channels → graded potential

  • binding of chemical → open

• Voltage gated channels → action potential

  • change in voltage → open

Changing Membrane Potential Terms

Polarization

• inside of cell is negative to outside (RMP = -70mV)

Depolarization

• process of making inside of cell less negative -70 → 0

Repolarization

• process of returning membrane potential back to RMP + → -70mV

Hyperpolarization 

• process of making inside of cell MORE negative than RMP (< -70mV)

Graded Potential

Localized change in membrane potential (dendrites and soma) 

• Excitatory post synaptic potentials (EPSPs) 

  • depolarizes (increase voltage >RMP)

  • open chemically gated Na+ channels → Na+ leak in → cell more + 

  • increases likelihood of action potential 

• Inhibitory post-synaptic potentials (IPSPs) 

  • hyperpolarizes cell (decrease membrane potential < -70mV)

  • opens chemically gated K+ channels → K+ leave cell → lose + charge → cell more negative 

  • decrease likelihood of action potential

EPSPs and IPSPs balance → can cancel

Action Potentials

Change in membrane potential down axon 

• graded potential from dendrites and soma

  • localized ion currents → travel down interior of soma to axon hillock (trigger zone) 

  • summates all electrical signals 

  • axon hillock reaches threshold (-60mV) → action potential is triggered

  • action potential → voltage gated channels (Na+ and K+) on axon

Anatomy of Action Potential 

RMP (-70mV) → graded potential →axon hillock threshold (-60mV) → action potential activated

(Na+ active gate = closed, inactive gate = open, inactivates any stimulus response when closed)

1. Threshold

• threshold = -60mV → inevitable action potential 

2. Depolarization (more positive) 

• open voltage gated Na+ channels → Na+ enter → cell becomes more positive 

• rapid depolarization 

• active gate opens, inactive gate open, → Na+ gate open 

3. Repolarization (more negative) 

• at +30mV voltage gated Na+ channels close (active gate open, inactive gate closed) → stop Na+ flow

• voltage gated K+ channels OPEN → K+ leaves cell → cell becomes more negative towards RMP

4. Hyperpolarization (more negative than RMP)

• excess loss of positive charge

• around RMP voltage gated K+ channels begin to close but don’t fully close until -90mV

• return to RMP

Voltage Gated Ion Channels

RMP

• Na+ channels: activation gate closed, inactivation gate open

• K+ channels: closed

Depolarization

• Na+ channels: activation gate opens, inactivation gate closes

• K+ channels: closed

Repolarization

• Na+ channels: activation gate closes, inactivation gate closed

• K+ channels: open  

Hyperpolarization

• Na+ channels: activation gate closed, inactivation gate opens (around -40mV)

• K+ channels begin closing -70mV, fully closed at -90mV

COC-123*

Refractory Period 

Absolute Refractory Period 

• cell cannot fire another action potential

• during:

• Depolarization: voltage gated Na+ are already open (can’t open more)

• Repolarization: voltage gated Na+ channels are already closed, inactivation gate closed → channel is inactivated and can’t open to stimuli 

Relative Refractory Period:

• cell can only be stimulated to fire action potential if depolarization event → GREATER than usual

• during:

• Hyperpolarization: more negative than RMP → need more EPSP to reach threshold

Continuous Propagation (movement of action potential) 

• unmyelinated axons (slow action potential)

  • membrane is depolarized in one region 

  • passive Na+ current diffuses locally outside and increases adjacent region’s potential to threshold 

  • adjacent region’s voltage gated channels open → action potential

  • depolarizes section by section down axon

• unidirectional propagation of action potential: regions behind action potential are in refractory period and can’t be reactivated

Saltatory Propagation (jumping)

• myelinated axons (very fast action potential)

  • Na+ diffuses, but is contained by myelin, insulator prevents electric potential from being lost 

  • high density of voltage gated channels at Nodes of Ranvier 

  • Na+ current diffuses down interior axon until node of Ranvier → open gated ion channels → action potential simulated → boosts signal → jump from node to node

• why is this faster?

  • Passive Na+ gradient currents are stronger + travel further

  • less time required to open voltage Na+ channels because potential is mostly conserved

The Synapse

Site of neural communication (action pot. → neurotransmitter)

• each synapse contains

  • Presynaptic cell: neuron 

  • synaptic cleft: 

  • Postsynaptic cell: target neuron or another type of cell 

Action potential reaches synaptic terminal:

• vesicles attach to presynaptic membrane → release neurotransmitter (nt) into synaptic cleft

• neurotransmitter binds to receptors on postsynaptic membrane

• may inhibit or excite postsynaptic cell

• synaptic terminal can reabsorb and reuse neurotransmitters from cleft

Synaptic Transmission process

Cholinergic Synapse: uses Acetylcholine (Ach) as active transmitter

1. Action Pot. arrives and depolarizes synaptic terminal

2. action pot activates voltage gated Ca²⁺ channels → triggers exocytosis of Ach

3. Ach binds to receptors and depolarizes postsynaptic membrane

4. Ach degraded by acetylcholinesterase

Common Neurotransmitters (KNOW)

• Glutamate (glutamatergic synapse): Excitatory neurotransmitter → depolarizes post synaptic cell

• Gamma-aminobutyric acid (GABA) (gabanergic synapse: inhibitory effect → hyperpolarization

• Norepinephrine (NE) (adrenergic synapse): excitatory effect  

• Dopamine (dopaminergic synapse): excitatory or inhibitory effect depending on location 

• Serotonin (serotonergic synapse): excitatory effect → involved in attention and emotion 

• Nitric Oxide (NO) → vasodilation, released by neurons innervating smooth muscle associated with blood vessels

Connective Tissue

Muscle has 3 layers of connective tissue 

• Epimysium 

  • dense connective tissue (collagen fibers) surrounding and separating the entire muscle 

• Perimysium

  • divides muscle into fascicles

    • collagen, elastin, site of blood vessels  

• Endomysium 

  • within fascicle, surrounds individual muscle cells, called fibers 

  • elastic tissue, contains nerve fibers and capillary beds

  • site of myosatellite cells (stem cells) 

Development of Myocytes (muscle cells)

large multinucleated cells formed by fusion of many myoblasts 

• myosatellite stem cells → myoblasts

• multiple myoblasts fuse to form myocyte (muscle fiber cell)

Structure of Muscle Fiber

• muscle fibers made of many myofibrils (made of many repeating sarcomeres)cc

• myofibrils made of many myofilaments: thin (actin) and thick (myosin) filaments

• sarcoplasmic reticulum stores calcium 

Sarcolemma 

• plasma membrane of muscle cell 

• surrounds sarcoplasm (cytoplasm of muscle cells) 

• polarized like neurons: have membrane potential 

  • more negative inside cell

  • sudden change in membrane potential → contraction 

• ion movement across membrane (electrical impulse) → action potential 

• all parts of muscle cell must contract at same time