Block 2 Flashcards
1
Q
location of actin fibrils in cells
A
filopodia (villi projections); stress fibers bundles (across cells); lamellipodia; amorphous gel; contractile ring
2
Q
microfilament polimerization
A
ATP + G-actin form trimer (rate limiting) –> filament; + end grows faster. ATP and Mg2+ required for polymerization
3
Q
profilin
A
promotes G-actin polymerization by binding monomers
4
Q
thymosin
A
inhibits G-actin assembly into Filamentous Actin—binds G-actin and inhibits polymerization
5
Q
Arp2/3
A
bind (-) actin; serve as nucleating factors (bypass of rate LS)and allow for formation of branched (70 degrees), dendritic array of tree of actin (think lamellipodium)
6
Q
formins
A
bind (+) actin filament; cause straight filaments
7
Q
regulation of MF
A
CDC42 -> Rac -> Rho GTPase (Ras like).
Rac critical for control of lamellipodia (via WASp and Arp2/3)
Rho-GTPase control stress fibers (via WASp and Arp2/3). CDC42 is critical for filopodia ie interact with formins.
8
Q
myosin 6 and Va
A
6 = moves to (-) end of actin (exception; all other myosins move towards +) Va = moves vesicles in cytoplasm
9
Q
movement of cell via actin
A
(1) Rac -> WASp -> arp2/3 -> polymerization of dendritic arbors of actin
(2) placement of integrins to interact w matrix
(3) depolymerization at back of the cell; myosin contration to move cell and nucleus
10
Q
MT polymerization
A
originates from centrisome (2 centrioles + clould of gamma tubulin ring-like complexes)
aggreagates of beta+alpha- form 13 protofilaments that then create MT (+ end is fast growing)
11
Q
stabilization of MT
A
mt-GTP “recruits” EB1. EB1 interacts w plasma membrane via mDia and APC (activated by Rho-GTP)
12
Q
Tau, MAP2
A
Tau - space MT closer together; MAP2 - space MT further apart
13
Q
drugs that destabilize MT (5)
A
podophyllotoxin, vinblastine, vincristine, cholchicine, garlic called S-allymercaptocysteine
14
Q
drugs that stabilize MT (3)
A
Taxol, Epothilone, Cryptophysins
15
Q
IF in epithelia, neurons, nuclei
A
epi - keratin
neurons - neurofilaments
nuclei - lamins
16
Q
epidermolysis bullosa
A
a blistering disorder due to autoimmune attack or inherited abnormalities on the desmosome or its components that cause disorganization of dermis-epidermis interface.
17
Q
plakins
A
allow for cross-bridge of IF to MT and MF
18
Q
link cytoskeleton into nucleus via lamins
A
nesprins-sun complex
19
Q
types of junctions that contain cadherins
A
adhesion, desmosomes, hemidesmosomes
20
Q
general characteristics of cadherins
A
EC domain activated by Ca; homotypic binding; domain swapping
21
Q
adhesion junctions as signaling molecules
A
intracellular domain of cadherin interacts with beta catenin - alpha catenin - vinculin - actin.
beta catenin is also a transcription factor (cotranscription factor LEF-TCF)
beta catenin degraded by APC (inhibited by Wnt signaling)
22
Q
desmosomal cadherin
A
desmoglein, desmocollin
23
Q
pemphigus vulgaris
A
auto-antibodies attack desmoglein 3 (desmosomal cadherin). blistering within keratinocyte layer, skin shedding
24
Q
tight junction proteins
A
claudins (also impart selectivity)
occludins. both are tetraspanins
25
gap junctions (proteins and regulation)
6 connexins make a connexon -groups of them form gap junction
open in low Ca2+ or high pH
close in high Ca2+ or low pH
synchronize the activity of groups of cells
26
nectins/syncam
heterophilic adhesion junctions; present in eye and ear Nectin1-3 interaction for ex. +/- charges and different chain lengths allow for heteropholic interactions
27
examples of GAGs
hyaluronic acid; chondroitin; dermatan sulfate; keratan sulfate; heparan sulfate; heparin
28
GAGs - characteristics
(think repeating sugars)
| sulfated; have carboxyl groups (ie glucouronic acid) - hold water, Na+; firm but not hard - resist compression
29
hyaluronan
type of GAG but: polymerized at cell surface (not made in Golgi); not sulfated
30
proteoglycan
core protein + GAGs
| linked via serine (O-linked) -> xylose-galactose-galactose-glucuronic acid (tetrasaccharide primer)
31
aggrecan
type of glycoprotein. long protein core+ thousands of GAG chains.
can link to hyaluronic acid via link proteins --> principal component of cartilage
32
Laminin
```
matrix protein (trimer w subunits alpha, beta, gamma) shape of cross; Short arms of laminin “self assemble.” Long arms (1) bind to integrin receptors in focal adhesion spots and in hemi-desmosomes and (2) interact with other components of the matrix.
rich in the basal lamina
```
33
Fibronectin
matrix protein (dimer) interacts with laminin and with integrins via the RGD sequence recognized by integrins. Self-dimerize when interact with integrins. rich in the basal lamina
34
collagen IV
reticular matrix under laminin matrix (basal lamina)
35
collagen II
cartilage
36
collagen III
spleen; lymphocytes
37
nicogen and perlecan
link laminin matrix to collagen IV
| perlecan is a heparin sulface proteoglycan
38
integrins
transmembrane proteins (alpha-beta dimers) that interact w matrix and cytoskeleton of IF or actin. bind to RDG sequence present in most matrix proteins; present in focal adhesions (Cell-Cell and Actin-Linked Cell-Matrix-Adhesion) and Hemidesmosomes (Cell-Matrix) and Desmosomes (Cell-Cell).
39
focal adhesion
Cell-Cell and Actin-Linked Cell-Matrix-Adhesion - all connect to actin fibers in cells. composed of integrins linked to actin cytoskeleton via talin (**regulated by mechanical forces that pull on it and reveal vinculin binding site**), vinculin, paxillin. β-Catenin and Focal Adhesion Kinases are associated with these junctions
40
integrin "activation"
folded up when inactive.
(1) inside - outside signaling: extracellular signal=>receptor=> second messenger=> Binding of Talin on the inner face of the integrin=> integrin unfolds and interacts with extracellular matrix.
(2)Outside->Inside Signaling: integrins bind to ligands -> send signals for cell survival “anchorage dependent survival.” cells that are not bound die (“anoikis” = “a state of homelessness)
41
LFA1
type of integrin present in white blood cells. binds to Ig superfamily counterreceptors (ICAM); alpha mutation results in impaired recruitment of leucocytes; beta mutation = leucocyte adhesion deficiency; impaired inflammatory response
42
alpha(iib)beta3
integrin present in platelets that ligate to fibrinogen. mutation in alpha = bleeding, no platelet aggregation (Glanzmann's disease). mutation in beta = Glanzmann's disease and mild osteopetrosis
43
A6B4
integrin present in hemidesmosomes in epithelia that ligate to laminin. mutation in A or B = severe skin blistering
44
focal adhesion kindase (FAK)
activated by integrin binding of matrix and by growth factor signaling. In turn, they regulate the binding of integrins to the matrix and hence organize the shape of the cell as well as its potential motility
45
selectin
receptors on WBC’s that bind sugars by a lectin domain (recognize carbohydrates); mediate transitory binding; allow for WBC to roll along endothelium. when it has to leave the blood vessel it expresses leukocyte integrin (ex: LFA1) that bind to endothelial ICAM and VCAM
46
Nernst Equilibrium (basic concept)
for charged molecules moving across a semipermeable membrane -> equilibrium between concentration and charge gradients
47
starling forces
hydrostatic pressure and osmotic/oncotic pressures are opposing. in blood vessels - water w nutrients will come out of the capillary in the arterial side (higher pressure) and come into venous side w waste
48
cyclic changes that allow myosin to "walk" along actin
| cross bridge cycle
(1) rigor = myosin attached,no ATP
(2) +ATP = myosin released, sliding possible
(3) myosin head is cocked, ATP hydrolized but ADP and Pi still bound
(4) Pi falls off, reattaches weekly at first (force generating/power stroke)
(5) ADP falls, myosin head again locked to actin
49
anchoring actin in sarcomeres
* Cap Z, alpha actinin -> + end at Z disc
* tropomodulin -> - end
* nebulin regulates length of actin filaments
50
titin
anchors thick filaments (myosin II) in Z discs - determines sarcomere length and gives it elasticity
51
Transverse tubules
(t tubules) invaginations of plasma membrane (sarcolemma) in muscle cells that allow for electrical signal to spread quickly (Ca2+ release).
has a voltage sensitive protein L-type, Ca2+ channel (dihydropyridine receptor) that when depolarized forces conformational changes in the ryanodine receptors in the neighboring sarcoplasmic reticulum
52
ryanodine receptor
Ca2+ release channel; releases Ca2+ from sarcoplasmic reticulum after being activate by both mechanical and Ca mediated changes (mechanical>chemical)
53
SERCA
reverses stimulus when skeletal muscle contraction is done by taking up Ca2+. pumps Ca/H+ back into sarcoplasmic reticulum where Ca is stored bound to CALSEQUESTRIN and CALRETICULIN
54
sarcomere
unit of myofilaments (Z-Z; A band and two halfs of I bands).
thin filaments inserted into the Z discs
H band = "center"- myosin but no actin
M zone= center of the H band where thick filaments are suspended and stabilized in register
A band = "all thick" - spans all of myosin (dark band)
I band = actin but no myosin (light band)
Contraction: A band is Always the same length, Z lines get closer, I and H bands shorten and disappear.
55
*muscle contraction - SA vs nerves
SA node cells pace; nerves modulate rate and force of contraction
56
3 types of glia cells
astrocytes (support)
oligodendroglia (myelin)
microglia (defense; macrophage analogue)
57
pentobarbital
drug that prolongs opening of GABA channels, inducing sleep; used to stop seizures
58
Flux "equation"
J(i) = Pi x A x delta(mu)
| flux of "i" = pathway x area x driving force
59
lamins
10nm diameter filaments (IF) that form network inside the inner nuclear membrane. can be assembled and disassembled (phosphorylation causes disassembly) during mitosis. Lamin A and B are the two major lamins
60
Emerin
specialized proteins in the internal nuclear membrane near pores that interact w lamin network
61
nuclear pore
ring of 8 subunits, central plug, basket, fibrils directed towards cytoplasm, transmembrane proteins gp120, POM121
62
NLS
nuclear localization signal - PKKKRKV (could also be bipartite KRP.......KKKK). sufficient. can be anywhere in protein
63
nuclear export sequence
leucine rich (L-NES)
64
nuclear import
alpha importin (= alpha karyopherin) recognized NLS. +beta karyopherin. complex binds to Ran-GDP and pore proteins; enter nucleus; important releases cargo when Ran-GTP replaces Ran-GDP. RanGTP-important exit nucleus
65
nuclear export
RanGTP binds exportin+cargo>> exit nucleus >> RanGDP rebinds
66
MAN1
protein in the inner nuclear membrane that can regulate signaling by classical second messengers (MAN1 turns off SMAD inside nucleus)
67
steroid signaling (enter cell, bind to receptors which are transcript. factors) is there amplification? what are some examples?
no amplification.
| ex: cortisol, testosterone, estradiol, thyroid hormone
68
contact dependent cell surface signaling
cell 1 - delta; cell 2 - notch receptor.
delta tries to endocytose notch receptor, pulls on it, reveals notch proteolysis site. notch is proteolyzed, cytoplasmic domain (notch intracellular domain = NICD) goes to nucleus, kicks out CSL receptor, activates tons of genes.
asymmetric. ex: capillaries
69
Frizzles/Wnt
wnt ligand binds frizzles, blocks degradation of beta-catienin, which goes to nucleus and binds TCF/LEF transcript. factor bound to DNA
70
G-protein linked receptor
7trasnmembrane receptor. when ligand binds
(1) GDP is exchanged for GTP in G protein Alpha (A). A and Gamma (G) +Beta (B) dissociate (GB).
(2a) G-A signals by
(i) adenyl cyclase >> ATP->cAMP >> PKA, which phosphorylates transcription factors
(ii) activating phospholipase C, which cleaves inositol into diacyl glycerol (>> PKC) and IP3 (>> Ca2+ channel)
(2b) G-GB >> K channel
71
tyrosine kinase receptor
ligands are dimers >> dimerize receptors, cross phosphorylate, recruit adaptors, activate Ras activating proteins.
Ras GTP >> Map-k-k-k >> Map k-k >> Map-k >> many genes; proliferation.
Ras = onco gene
72
Avastin
drug that targets VEGF (vascular endothelial growth factor, a tyrosine kinase pathway). VEGF stimulates vascular developmetn
73
JAK-STAT
ligand binds to receptor >> receptor recruits JAK >> Jak (tyrosine kinase) phospho receptor, STATs bind to phospho sites, get phosphorylated as well, dimerize, move into nucleus, activate gene expression
74
SMADS
type of STATs - after heterodimerization, move into nucleus, regulate genome
75
adherens junction
connects actin filament bundle in one cell with that in the next (vs. desmosome - connects IF)
76
PCP
glutamate-activated channel - creates hallucinogen/behavior changes
77
BTx
keeps Cl channel open
78
GABA
opens channel
79
pentobartital
keeps GABA channel open; sleep; prevents seizure
80
how to "address a protein" to apical side of epithelium
GpI linkage to lipid raft (cholesterol and glycosphingolypids). GpI linkage added by recognition of 30terminal aa (dominant)
81
transcytosis
directing proteins from basolateral membrane to apical membrane (epithelia)
82
how to "address a protein" to basolateral side of epithelium
protein must have beta turn (hydrophobic-XX-tyrosine). from golgi AP proteins place them in clathrin (mu subunit binds to .XXY., beta subunit binds to clathrin). vessicle interacts with EXOCYST (~10 proteins that lead it to v-snare, t-snare interaction and fusion)
83
cytoplasmic proteins that aggregate at tight junctions
Zo-1, Zonab (carrier protein), cyclins (cell cycle regulator), cytoskeleton. When cell-cell bound >> cyclin prevented from going to nucleus. Wound >> tight junction broken >> cyclin can go into nucleus and promote cell proliferation
84
example of selective destruction as a way of maintaining cell polarity in epithelium
IgG receptor PIGR. it binds antibodies in the basal side, transcytoses them to apical lumen, where it is cleaved
85
regulation of apical/basal membrane ratio
Know: LKB1, PAR1, and PAR3 all stimulate apical identity.
FYI: apical identity defined by PAR1 in basolateral and Par3 in apical surface. LKB1 transmits
extracellular signal à PAR1-mediated phosphorylation events prevent basal invasion by the apical
polarity determinants. Phosphorylated PAR3 binds PAR5 during relocation to apex.
86
3 components of connective tissue (broad). 3 types
(1) matrix - GAG-sulfated and non-sulfated, proteoglycans. H2O
(2) fibers - collagen, elastin
(3) cells - fibroblast/fibrocytes/chondroblast/chondrocytes/osteoblast/osteocytes
types: loose, dense (refers to fibers), embryonic
87
collagen (typical aa, formation)
triple alpha helices, common feature of glycine-x-y.
• formed in ER w N and C-terminal telopeptide to prevent crosslinks >> exocytosis >> procollagen peptidase takes off telopeptide >> fibrils form >> lysyl oxidase crosslinks extracellularly to prevent degradation >> fibrils combine to form fibers
• post translational hydroxylation of proline and lysine allow for interchain H bonds **hydroxylation requires Vit C >> SCURVY**
88
collage types I-IV. how many types of alpha chain
Type I – skin, bones, tendon.
Type II – cartilage.
Type III – reticular (+skin - think Ehlers Danslos).
Type IV – basement membrane (forms sheet, not fibrils)
>> 42 types of alpha chains. 40 types of combinations documented. Types II, III, VII, XVII, XVIII have only one alpha type. Types I, IV, IX, XI have 2 or 3 types of alpha chains
89
Ehlers Danlos
problems with procollagen pepsidase (ADAMTS2) - no mature collagen. Could also result from defect in lysyl oxidase. (**TYPE III collagen**)
90
elastin
random coiled. FIBRILLIN 1 limits elasticity. (aorta, ear, giraffe's neck)
91
Marfan's syndrom
due to defect in fibrillin. Arachnodactyly (very long fingers). Lens dislocate, aorta is floppy, low diastolic BP. will die of aortic rupture
92
loose connective tissue
* areolar (under epithelium of skin, glut, breast ducts, etc) - has immune cells, allows for nutrients through, resistant to compression
* adipose (white, brown in chest, sternum, vertebral column, babies)
* reticular (lymphoid organs - nodes, spleen) collagen II. silver stain
93
gynecomastia
breast tissue growth in males. can be side effect of medications such as spirolactone
94
white adipose; regulation
signet ring cells (one large fat droplet)
* NE/Epi: TG breakdown upregulated via G-alpha>> cAMP>>PKA>>perilin and hormone stimulated lipase
* Insulin: TG breakdown downregulated via PDE-3B, which destroys cAMP
95
leptin
signals to brain, “satiety hormone”. dysfunction in leptin (ob/ob) or receptor (db/db) can lead to obesity.
- ob/ob mice sutured to WT >> ob/ob lose weight, saved.
- db/db mice sutured to WT >> stays obese, WT dies
(db=dead battery=no reception)
96
brown fat
generates heat and consumes O2. brown fat removed >> (-) O2 consumption. Low O2 >> (-) heat
97
mesenchyme; Wharton's jelly
mesenchyme = embryonic connective tissue
| Wharton's jelly = mucus jelly surrounding umbilical cord
98
cartilage (ratio of fibrous/ground substance and general characteristics)
50%fibrous matrix(collage II, a little of IX, XI) 50% ground sub. resists compression; chondrycytes live within their lacunae; communication via ECM (slow)
99
bone (ratio of fibrous/ground substance and general characteristics)
99.6% fibrous matrix. resists tension. osteocytes communicate w each other via CANALICULI using gap junction; also interact w matrix
hydroxyappitite
100
development of bone and cartilage
1) Initial Mesenchyme Condensations: Wnt >> Sox9/Runx1 >> mesenchymal condensation
2) high pO2 and some tensile stresses>> bone tissue. BMP 2, 4, 7, then runx2 and osterix >> osteocalcin >> bone formation
3) low pO2 and intermittent compression, Indian hedgehog growth factor (Ihh) and FGF >> Sox9, Sox5, Sox6 drives the progenitor cell to chondrocytes. (Sox9 creates cartilage but maintains it in a mature, quiescent state)
101
types of cartilage and where they are found
Hyaline (trachea, articular surfaces)
Fibrocartilage (intervertebral disks)
Elastic (ear, epiglottis)
102
ways cartilage grows
* Appositional - chondroblasts add to perichondrium
| * Interstitial - chondrocytes expand from w/in isogenous nests (lacunae)
103
2 types of ossification
* endochondrial - most bones
| * intermembranous - skull and clavicle only
104
endochondrial ossification
1) Diaphysis (bone collar): Hyaline cartilage precursor > stress> hypertrophic chondrocytes> VEGF and collagen X> periosteal bone collar > primary ossification center > vascularization/osteoprogenitors > fully ossified diaphysis
2) epiphysis (growth plates - interstitial growth): hyaline cartilage at bone plate > IHH> chondrycytes stimulated to (+) proliferate to proliferative zone from stem cell zone and mature into BONE (-)make PTHrP, which slows down proliferation and bone maturation
105
intermembranous ossification
no cartilage precursor; between membranes. growth occurs at suture lines. osteocytes on surface and matrix
106
bone types
Woven: disorganized, fetal Lamellar: adult bone - Organized into osteons: lamellae (highly organized collagen) around central canal = Haversian canal (vessel, nerve), osteocytes btwn lamellae. canalliculi oriented in the same direction
- Grossly categorized as:
1) Cancellous, aka spongy = trabecular - Bone heads
2) Compact aka dense = cortical - Bone shafts
107
factors that increase bone resorption
parathyroid hormone
glucosteroids
thyroid hormone
high doses of vit D metabolites
108
factors that decrease bone resorption
calcitonin
| gonadal steroids
109
factors that increase bone formation
growth factor
vit D
gonadal steroids
110
factors that decrease bone formation
glucocorticoids
111
bone remodeling. (osteocyte regulation)
* baseline: +sclerostin > Wnt OFF> no bone formed
| * stress: -sclerostin > Wnt ON >bone formed
112
bone remodeling (osteoclast regulation)
osteoclasts are under regulation of MCSF (macrophage colony stimulating factor) > osteoclasts develop, mature, "live in" Howship's lacunae, use H+pump, express RANK-R.
(+) RankL (from osteoblast) >> ++ bone resorption
(+)OPG (osteoprotegerin from osteoblast)>>-- bone resorption by binding RankL
under inflammation - RANKL increases, reabsorption increases
113
astrycyte
type of glia cell - support to neurons. (instead of collagen)
has much IF made of glial fibrillary acidic protein, desmosomal junctions, processes that wrap around blood vessels/neurons
114
microglia
macrophages from bone marrow invading the brain.
115
oligodendroglia and schwann cells
| myelination
* make myelin or its equivalent. nodes of ranvier/ saltatory action potential.
* 1 Schwann cell myelinates 1 axon; oligodendroglia myelinate more >1 neuron
* Myelin = plasma membrane with a few glycoproteins (myelin basic protein in CNS/protein P0 in the periphery)
* proteolipid protein (plp) holds together the stacks of membrane wrappings (very hydrophobic; located in the “extracellular clefts”)
116
electrical synapse
FAST; passive diffusion through GAP; rare - ex: brainstem neurons that control breathing
117
chemical synapse
slow and more important
action potentia> Ca2+ channels open> Ca2+ enters> NT vesicles fuse> NT release> NT crosses cleft, bind to receptors
small stimulus - release of small NT from docked vesicles that were packaged regionally (vesicle recycling maintains volume)
large stimulus = release of peptide NT that were packaged in Golgi
118
ionotropic receptors
ligand-gated (direct) ON or OFF
| nicotinic AchR - fast (present on skeletal m.)
119
metabotropic receptor
```
GPCR-coupled
muscarinic AchR (present on smooth m.) >MapKinase... slow
```
120
synapsin
tethers vesicles to actin near the active zone in neurons
121
Ca-calmodulin activation
causes docking of reserve vesicles of NT at plasma membrane - activates v-snares called synaptobrevin to interact w t snares syntaxin
synaptotagmin calcium - catalize fusion of t and v snares
122
botulinum
cleaves and inactivates SNAREs --> paralysis ACh (excitatory NT and NMJ)
123
alpha-conotoxin
blocks Ach gated channels
124
Ach synthesis/degradation
synthesized in terminal bouton by choline acetyl-transferase
taken up by H+/Ach exchange
degraded by achetylcholineesterase in baseal lamina in synapse
125
NT amino acids
GABA (from glutamate)
Glycine (from serine?)
Glutamine
Aspartate
126
NT amines
```
DOPA
Dopamine
Norepinephrine
Epinephrine
(all 4 - catecholamines. excitatory. from tyrosine. Sympathetics , motion control, mental health (Parkinsons Dz, BP, Schizophrenia)
```
serotonin (mood, sex, appetite)
histamine (allergy)
127
action potential
1. Resting MP = Leak K channels
2. Receptor/Synapse stimulus sums to threshold
3. Voltage gated Na channels open
4. Voltage gated K channels open and Na channels inactivate
5. Voltage gated K channels stay open leading to “undershoot”
6. Voltage gated K channels close and leak K channels open
128
accounts for no retrograde flow in neuronal action potential transmission
Na channel inactivation (latency)
129
accounts for no retrograde flow in neuronal action potential transmission
Na channel inactivation (latency)
130
WASp mechanism
hormones or other signals=>CDC42=>unfolding of Wasp=>ARP2/3 activation=>actin polymerization=>force for migration of the leading edge of the cell. ex: WBC making podosomes to migrate across endothelial cells through capillaries . magakaryocytes migration to sinusoids within bonoe cavity to deposit platelets there
131
WASp mechanism
hormones or other signals=>CDC42=>unfolding of Wasp=>ARP2/3 activation=>actin polymerization=>force for migration of the leading edge of the cell. ex: WBC making podosomes to migrate across endothelial cells through capillaries . magakaryocytes migration to sinusoids within bonoe cavity to deposit platelets there
132
type of connective tissue in dura and arachnoid mater
dura - dense fibrous irregularly arranged
| arachnoid - loose areolar
133
types of nerons
monopolar - sensory
bipolar - special sensory
multipolar - everything else
pseudounipolar - fused processes
134
comparing axons/dendrites
axons:
- tau
Dendrites: have Nissl bodies (RNA), ER, ribosome, mRNA; map2
135
vesicular transport in neurons
+ end (towards synapse) = kinesin
(fast transport for synpatic vesicles, slow for tubulin, actin and other housekeeping proteins)
- end (towards cell body) = dynein = retrograde transport used to recycle organelles; **tenanus toxin and viruses** uses this mechanism
136
vesicular transport in neurons
+ end (towards synapse) = kinesin
(fast transport for synpatic vesicles, slow for tubulin, actin and other housekeeping proteins)
- end (towards cell body) = dynein = retrograde transport used to recycle organelles; **tenanus toxin and viruses** uses this mechanism
137
cardiac muscle
branched; striated; nuclei in the middle
Intercalated discs: desmosones (IF),adhesion (MF), gap junctions (located laterally)
1 T tubule per sarcomere, thicker than skeletal m.
Excitation-contraction-coupling is dependent on L-type Ca channels’ triggering Ca influx (vs. skeletal muscle -> L-channel mechanical change to ryanodine receptors more important than Ca influx).
Ca2+ entering from the L-type channel promotes Ca2+-induced Ca2+ release (CICR) from the SR via Ca2+ release channels (ryanodine receptors)
138
smooth muscle
no striation; nucleus in the middle of cells; caveolae instead of T-tubules
139
myoepithelial cells
branced cells made from epithelia under hormonal regulation for contraction (ex: oxytocin for secretion of milk)
140
myoepithelial cells
branced cells made from epithelia under hormonal regulation for contraction (ex: oxytocin for secretion of milk)
141
organization of skeletal muscle
Muscle fiber = muscle cell. Muscles are bundles of fibers, which are bundles of fibrils, which are bundles of filaments. (Hint: the shorter the name, the larger the structure!)
endomysium around myofiber
perimysium around bunches of myofibers
epimysium around entire muscle
142
effect of Ca2+ release from sarcoplasmic reticulum into skeletal muscle cytoplasm
Ca2+ binds TroponinC/I/T
(TnI binds to actin and inhibits biding to myosin; TnT binds to tropomyosin)
Ca binds to TnC >> complex swivels, tropomysin moves and opens myosin binding site>> allows cross-bridge cycle to occur
143
effect of Ca2+ release from sarcoplasmic reticulum into skeletal muscle cytoplasm
Ca2+ binds TroponinC/I/T
(TnI binds to actin and inhibits biding to myosin; TnT binds to tropomyosin)
Ca binds to TnC >> complex swivels, tropomysin moves and opens myosin binding site>> allows cross-bridge cycle to occur
144
innervation "types" for smooth muscle
```
Multi-unit: each cell innervated 1:1, precise, fast (vas deferens, some blood vessels)
Unitary: one nerve innervates many cells, slow.
in general (not just smooth m): motor unit = nerve and all of its innervated muscle fibers.
muscle pool = many motor neurons innervating many muscle fibers.
```
145
bungarotoxin
from snake; binds to acetylcholine receptor in muscle (cholinergic nerve junction)
146
excitation-contractrion coupling in smooth m.
1. Extracellular Ca2+ enters though channels in caveolae.
2. [Ca2+]i increased by CICR and IP3- induced Ca2+ release from SR.
3. Ca2+ binds calmodulin. 4. Ca2+-calmodulin complex activates myosin light chain kinase (MLCK).
5. MLCK phosphorylates and activates myosin (II) so that it can interact with actin.
6. Force is delivered to dense bodies (analogous to Z discs), causing flattening and contraction but no directional force.
7. SR Ca2+ is repleted by store-operated Ca2+ channels in plasma membrane.
* K channel involved but not Na dependent action potential!
147
dynein
molecular motor that causes retrograde (- end) transport of vesicles along MT tracks. cocking mechanism. only a a couple of variants. dynactin, Lis1=nudE/L modify dynein
148
kinesin
motor protein that moves towards +end (NH3 end of proteins)
149
orientation of +/- ends of MT in epithelia
+end basolateral
| - end apical side
150
lissencephaly
"smooth brain" disease caused by mutation in dynein regulator Lis1 (usually cell progenitors in brain migrate from ventricle to cortex; cannot do so w/out lis1)
151
Lis1
regulator of dynein; determines force generation to move large structures such as nuclei along MT towards centrosome
152
layers and types of skin
epidermis, dermis, hypodermis
glaborous/volar/non hairy (thick)
hairy = thin
153
layers and compositon of epidermis
Basale=>Spinosum=>Granulosum=>Corneum
Cells = Keratinocytes, Melanocytes, Langherans cells, Merkel cells
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keratinocytes
divide in the basale layer (stem cells=>transit amplifying cells=>committed to differentiate=>upward migration). In the spinosum- have desmosomes that make the cells look spiny. In the granulosum- filled with granules of lipids and cellular metabolites that cause cell adherence. in the corneum- flattened lipid-waxes made in the granulosum layer. No nuclei in the corneum, cell death and finally shedding within 2 weeks.
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melanocytes
from the Neural Crest; migrate to the skin. make granules and transfer them to different layers of more basal keratinocytes via phagocytosis. The melanin reduces UV-B damage to skin. Melanoma is a cancer of the melanocytes that form clumps in the epidermis and they migrate and form metastasis.
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langerhan cells
in the spinosum layer. They are antigen presenting cells (CD11+, dendritic marker)
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merkel
in stratum basale; derived from keratinocytes. contain granules of neurotransmitters that signal to nerves; innervated by sensory neurons. Useful to detect fine spatial details in touch
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epidermal appendages
* hair - associated w dermal papilla (cells from dermis); aerector pili muscle; stem cells
* sebaceous glands - attach to hair follicle
* eccrine sweat glands - water for thermalregulation
* apocrine sweat glands - pheromones. urogenital-axillary zones
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nociceptive nerves
detect noxious stimuli
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pacinian corpuscles
nerves; sense high freq vibration encoding fine texture
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meissner corpuscles
sense low freq vibrations -coarse stimuli
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squamous cell carcinoma (scc)
confined to the epidermis or invasive into the dermis. They come from keratinocytes and the image is one of large proliferative cells in the epidermis
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eczema (atrophic dermatitis)
a disorder of the barrier function due to filaggrin mutations
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mild epidermal bullosa (simplex)
caused by mutations in keratin that attach to hemidesmosomes integrines in basal keratinocytes. blisters within epidermis
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intermediate epidermal bullosa (junctional)
antibodies target integrin of hemidesmosome in keratinocytes. blisters form at interaction of epidermis and dermis
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severe "dystrophic" epidermal bullosa
antibodies or mutations affecting collagen VII below dermo-epidermal junction
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bullos pemphigoid
antibodies to BP180 (adhesion protein that holds epidermis to dermis)
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poly = neutrophil = PMN = segmented
50% of wbc in circulation) multilobar nuclei, poor stainers with red and blue dyes ie neutral staining. They do not divide or proliferate. “Bands” are younger version of neutrophils.
for phagocytosis and the release of substances from granules. make “Pus”. respond to Gram+and Gram- bact, also to some parasites and dead tissue
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monocytes
(5-9% of circulating wbc in circulation)
non segmented nuclei, horseshoe shaped or oval shaped nucleus. Not granulocytes; precursor" macrophage
eat dead cells, foreign proteins, and parasites ie Leishmania. Macrophages in spleen and liver eat degraded RBC and become filled with hemosiderin, a iron based brown degradation product.
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lymphocytes
(about 20-30% of circulation)—round big nucleus and little cytoplasm. “adaptive immunity” ie the cells become educated.
T: Acquired immunity ie response to vaccine; Many subtypes
B: Antibody production after antigen presentation.
T cells respond to viral and bacterial infection. For example, viral myocarditis (Coxsackie virus) is infiltrated by lymphocytes not neutrophils. Lymphocytes also infiltrate organs in “autoimmune disease” as in auto-immune thyroiditis
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eosinophils
Segmented nuclei. Terminally differentiated. Granules with “major basic proteins” that form a crystalline array. Recruited to sites of inflammation and defense in parasitic infection (ex “River Blindness” ) or responding to allergic stimuli like asthma and reactions to medications
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basophils
(1% of wbc): Related to mast cells in tissues. Granules contain histamine, heparin. Turned on by IgE receptors that have bound to allergens. Involved in allergies. Think about anti-histamines!
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serum
no coagulation factors; after clotting leaving serum at top.
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plasma
plus coagulation factors and fibrin and fibrinogen that have not clotted yet and is preserved by additives in the blood collection tube. The anticoagulants include heparin and citrate (binds up Ca2+)
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definition of stem cells
1)Self Renewal;
2)Multi-Lineage Differentiation; 3)Proliferate and Reconstitute the hematopoietic system
CD34+ CD38- Kit+ Lin-
Kit = receptor for stem cell factor
Lin-= no binding of monoclonals that recognize early RBC, WBC
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aplastic anemia
killing of stem cells often with antibodies, some medications, chemotherapy.
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RBC precursors (recognize vs WBC precursors but don't memorize)
Human Stem Cell-HSC=>Burst forming unit-erythyroid, BFU’s (c-kit+)=>Colony forming unit-erythroid CFU’s (GATA1 transcription factor, Erythropoeitin Receptor, EpoR)=>
proerythroblast =>basophilic erythroblast =>polychromatophilic=> normoblast=>nucleus removed=> reticulocyte =>mature RBC
(cell gets smaller and filled w hemoglobin. organelles digested by autophagy)
Proerythroblast progenitor stimulated to proliferate by erythropoietin (Epo-R), and transferrin-iron (Transferrin Receptor1).
process occurs at the surface of macrophages in the bone marrow, an island of cells= stem cell “niche”. macrophage destroys the nucleus of RBC and supplies iron-transferrin to RBC. In bone marrow there are erythroblastic islands, clusters of the erythroid lineage surrounding macrophage.
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Vasculogenesis
DE NOVO formation of blood vessels
-embryo hemangioblasts>> become blood or endothelial cells
-tissues that express VEGFR-1, -2 and neuropilin receptors are targets of VEGF-A
-isolated vasculogenic cords form, also include primitive blood cells
-2 signalling pathways give 2 fates:
vascular: VEGF via VEFGR-1, -2 and Angiopoietin via Tie2
or
lymphatic: VEGFC, D via VEFGR-3
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Angiogenesis
- new sprous from existing vessels
- VEGF-A induces proteases that make gaps in vessels
- TIP cells migrate towards VEGF-A
- trailing cells undergo mitosis to form sprout, which forms a lumen
- tip cells secrete PDGF, turning mesenchymal cells into pericytes
- macrophages help prune, form anastamoses
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hypoxia in vascular growth
HIF1-alpha no longer
degraded
-HIF1-alpha binds DNA to upregulate VEGF, Ang2 PDGF
-new sprouts grow, oxygen levels rise
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Notch in angiogenesis
- tip cell responds to VEGF-A in env ++ Jag/D114
- stalk sees D114, ++Notch
- stalk -- VEGFR2
- lower VEGFR2 in stalk prevents sprouting
- high notch makes arteries, not veins
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knockouts in VEGF pathway
```
ko VEGFR2 (flk gene) = no endothelium
ko VEGFR1 (flt gene) = vascular malformation (refiner)
VEGFR3 mutation: inherited lymphedema
```
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AVASTIN (bevaxizumab)
monoclonal anti-VEGF that treats cancer
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retinopathy of prematurity
| analogous to wet macular degeneration
pO2 in atmosphere >> in womb -> hyperoxia supresses VEGF
| - few blood capillaries > hypoxia > VEGF upregulated > too much blood vessels > leak > retina edema
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ascites
intra periotoneal fluid (abdomen)
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edema in cavities
effusions/hydrothorax
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total body edema
anasarca
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hematoma
massive clot
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hematoma in thoracic cavity
hemothorax
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petechiae
minute (1-2mm) hematoma
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purpura
larger (1cm) hematoma
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ecchymoses
hematoma several cm in size
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3 causes of thrombosis
endothelial injury
abnormal blood flow
hypercoagulability
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lines of Zahn
in blood clots (pale, yellowish lines); indicated thrombus was formed in vivo; microscopically - RBC, platelets, fibrin
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arterial thrombi
coronary, cerebral, aorta and brances
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venous thrombi
9-% deep leg; peri-uterine, peri-prostatic
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mural thrombi
from heart
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fate of venous thrombi that embolize
"right-sided" - lungs
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fate of areterial thrombi that embolize
"left-sided" - brain, spleen, kidneys
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paradoxical embolus
thrombus goes through patent foramen ovale to left side
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causes of DIC (disseminated intravascular coagulation)
| aka consumption coagulopathy
obstetrical catastrophe
sepsis
carcinoma
-- all of these release tissue factor (tissue thromboplastin) >> coagulation via extrinsic pathway
dx: measure fibrin split products (D-dimers)
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criteria for SIRS (systemic inflammatory response syndrome)
2 or more of the following:
1. body temp 38
2. HR >90
3. tachypnea: >20 breaths/min
4. WBC 12,000 or >10%immature neutrophils (bands) (bone marrow giving out)
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reverting postmitotic cells
hepatocytes, renal tubular
| vs. postmitotic, intermitotic
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how ischemia hypoxia damages the cell
impairment of aerobic respiration, conv to anaerobic respiration, lactic acid production, inhibition of NaKATPase, increase in cell osmolarity, swelling
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hypertrophy vs hyperplasia vs metaplasia, dysplasia
hypertrophy - cells get bigger
hyperplasia - increase in cell #
metaplasia - change of one adult cell type to another (ex: squamous metaplasia due to smoking = mucin turned into squamous cell)
dysplasia = pre-malignant cell architectural changes
atrophy = decrease in size; ischemic change
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necrosis vs. apoptosis
necrosis leads to secondary inflammation; apoptosis does not
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some proteins involved in apoptosis
TNF (tissue necrosis factor), FAS, caspases. release of cytochrome C from mitochondria
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some proteins involved in response to ER stress
1) Perk -> eIFalpha -> ATF4 -> **CHOP -| eIF by GADD3
(Chop ++ leads to apoptosis in chronic stress)
CHOP -- chaparenos, ERAD, Ca2+ levels, S-S activity
2) ATF6 -> pre-mRNA XBP1 -- chaparenos, ERAD, Ca2+ levels, S-S activity
3) IRE1 -> pre-mRNA XBP1 --chaparenos, ERAD, Ca2+ levels, S-S activity
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oliguria
loss of urine output
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3 stages of shock
Stage 1 acidosis and chemical abnormalities
Stage 2 manifestation of kidney damage that used to be called acute tubular necrosis, now called intrinsic Acute Kidney Injury, brain damage
Stage 3 resolution phase
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transudate
low protein extravasation from blood due to (1) osmotic (reduced) and (2) hydrostatic (increased) imbalance. low specific gravity fluids (
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exudate
high protein concentration in fluid usually w inflammatory cells. high specific gravity >1.020
Ex: Inflammatory diseases: cancer, infection, autoimmunity
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Hashimoto’s Thyroiditis
Chronic Lymphocytic Thyroiditis
????=>CD4->INF gamma=>macrophages and CD8 cytotoxic, and many plasma cells make antibodies against thyroid tissues. No neutrophil infiltrates. chronic damage to the thyroid; hypothyroidism
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what makes up a granuloma
- palisading T Cells (lined up around) >> activate macrophages via IFN gamma
- epitheloid macrophages (activated)
- giant cells (fused activated macrophages) = Langherans cells
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causes of granulomas
- infection (TB *caesating*, syphilis, schistosomiasis)
- foreign body (silica, talc, suture, etc)
- unknown (sarcoidosis *asteroid bodies crystals, can undergo calcification and form Schaumann bodies*, Crohn’s)
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haptoglobin
circulating hemoglobin binding protein (complex is then cleared by liver). low haptoglobin in blood tests = sign of hemolysis
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tumor markers CK7 CK20 (cytokeratins in epithelia)
```
CK7+20- = lung
CK7-20- = liver
CK7-20+ = colon
```
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plasma tumor markers
CEA (carcinoembryogenic antigen --> colon, pancreas, lung, breast)
AFP (alphafetoprotein) = hepatocellular, germ cell, testis ca
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"hormone tumor markers"
calcitonin - medullar thyroid ca
HCG - testis, placenta ca
PTHrP - squamous cell carcinoma; hypercalcenemia
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"glycoprotein tumor markers"
ca125 - ovary
ca19-9 - bile ducts, pancreas
ca-15-3 - breast
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inherited autosomal recessive syndromes of defective DNA repair
Xeroderma pigmentosum - skin ca
ataxia telangiectasia - ATM gene mutation, G1 arrest. immunodef/ lymphoid malign.
bloom syndrome - helicase mutation; osteosarcoma
fanconi anemia - hypoplasia in kidney, spleen, bone
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trousseau phenomenon
multiple thrombi due to cancer production of mucin
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gleevac
chemotherapy drug that binds to mutated kinase in CML (chronic myelogenous leukemia) (BCR-ABL translocation)
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HERCEPTIN
anti-HER2/neu receptor antibody; chemo
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AVASTIN
anti-VEGF
SUNITINIB - also targets VEGFR and other receptors
antiDLL4 - blocks vascularization (chemo)
