Week 1 Flashcards
(238 cards)
1
Q
Endosymbiont Hypothesis and evidence
A
Mitochondria arose early in evolution of eukaryotic cells by endocytosis of bacteria capable of oxidative phosphorylation
Mitochondria has unique structure similarities to bacteria
- Inner membrane derived from bacteria
- Outer membrane derived from eukaryotic cell
2
Q
Mitochondria Import across the outer membrane is ________ and occurs when _________ interacts with ____________
A
passive, facilitated diffusion
N-terminus of protein (containing highly positive sequence) interacts with very negatively charged domain in GIP channel
3
Q
Mitochondria import across the inner membrane is _____ through ______.
Process?
A
ATP dependent
through TIM23/22 gated channel
- N-terminus (+) sequence bids channel, opens it
- Protein unwound by ATPase chaperone and fed through channel unfolded
- Channel closes immediately after protein comes through in order to maintain proton gradient
4
Q
Oxidation of NADH –> NAD results in ________, creating a ___________ and ________
A
release of one e- that goes through electron transfer through 4 protein complexes embedded in inner mitochondrial membrane
- proton concentration (1 e- –> 5 H+ pumped across)
- Electrical potential (- matrix, + outside)
5
Q
ATP is produced from the ________ and _________
A
proton gradient and electrical potential
6
Q
ATP synthase spans _______ and is made up of 2 complexes ______ and ______.
ATP synthase flips through 3 conformations key for function:
A
inner membrane
F1 protein complex
Fo protein complex
1 - bind ADP and P
2 - forms an ATP
3- loses affinity for ATP
7
Q
F1 protein complex (ATP synthase)
A
actual enzyme that makes ATP
-Bound to Fo
8
Q
Fo protein complex (ATP synthase)
A
uses energy of proton movement through the channel to generate ATP
-3 H+ needed for 1 ATP
9
Q
ATP is transported out of mitochondria via __________
A
ATP-ADP antiporter
10
Q
Mitochondria role in regulating cell death due to cell damage
A
Cell damage → Bak/Bak-dependent permeabilization of outer-mitochondrial membrane → cytochrome C release
Cytochroms C → formation of apoptosome protein complex
11
Q
Mitochondria role in regulating cell death due to ischemic injury
A
Ischemic injury → MPTP-dependent permeabilization of inner and outer mitochondrial membranes
→ cytochrome release
No ATP present due to lack of O2
Results in necrosis (instead of apoptosis)
12
Q
Mitochondrial fusion occurs to __________. _____ and ______ proteins do this
A
repair damaged mitochondria
OPA1 and Mfn 1/2 GTPases
13
Q
Mitochondrial fission occurs for _________ and is carried out by ______ and ______ proteins
A
for mitophagy
GRP1/BAX or Fis1/Drp (depending on if you look at ppt or handout…)
14
Q
Mitochonrial Quality control occurs via these three processes
A
- Fusion and fission (occurs regularly, vital for maintaining mitochonria)
- Proteolytic degradation
- Mitophagy
If these all fail, mitochondria will trigger apoptosis
15
Q
Proteolytic degradation in mitochondria….
done by which two proteases?
A
Detects defect in enzyme → extract and replace with a new one
Done by sIII, and mAAA proteases that recognize and degrade protein
16
Q
Mitophagy
A
• Mitochondria badly damaged enough, gets eaten up
17
Q
AD optic atrophy and Charcot-Marie-Tooth neuropathy
A
caused by mutations in OPA and Mfn2 (respectively) mitochondiral fusion proteins
18
Q
Mutation in mAAA protease results in _________
A
hereditary spastic paraplegia
19
Q
Release of ROS by mitochondria results in _______ and _________
A
senescence and increased sensitivity to neuronal degeneration
20
Q
Arsenic poison works by…
A
inhibiting oxidative phosphorylation and ATP production
21
Q
Features of epithelia (5)
A
- Adherent to one another
- Cells arranged in one to several layers
- Polarized (asymmetric)
- Undergo turn-over/renewal (Driven by epithelial stem cells)
- Avascular (nutrients must diffuse through CT and basal lamina)
22
Q
Apical surface =
Basal surface =
A
Apical surface = outer surface, directly exposed to fluids or environment
Basal surface = inner surface, connected to underlying connective tissue via basal lamina
23
Q
Epithelial cell functions (7
A
o 1) Barrier – protects internal tissues
o 2) Selective absorption and transport of molecules from the environment
o 3) Selective secretion of molecules and fluids
o 4) Movement of particles and mucous through passage ways
o 5) Biochemical modification of molecules
o 6) Communication to and from other tissues and organs
o 7) Reception of sensory stimuli (e.g. smell, taste, touch)
24
Q
Endothelium = ? Mesothelium = ?
A
Endothelium: tissue that faces blood and lymph
-Made of endothelial cells
Mesothelium: sheets of cells that line the enclosed internal spaces of the body cavities
- Made of tightly adherent cells
- Free surface faces blood/lymph, and rests on basal lamina
25
Epithelial classifications:
simple
stratified
Pseudostratified
Simple: cells arranged in a single layer
Stratified: more than one layer, outer layers do not directly contact basal lamina
-Named according to outermost layer
Psuedostratified: some cells reach the free surface, but all directly rest on the apical to basal axis
26
Epithelial classifications:
Squamous
Cuboidal
Columnar
Transitional
- Squamous: flattened cells
- Cuboidal: cube-like
- Columnar: taller than they are wide
- Transitional: e.g. bladder - stratified, but when stretched, change shape from cuboidal to squamous and appear to decrease in layering
27
Spatial Relationship between layers of epithelia
space (lumen) → Epithelia-epithelia basal lamina → CT → CT embedded tissues (blood vessels, muscle, nerves – all with their own basal laminae that connects them with the CT)
28
Epithelial to Mesenchymal Transition
o Occurs during embryogenesis
o Embryonic epithelia often disassemble and move into the mesenchymal (connective) tissues and migrate to other locations to form new epithelia
• Mesenchyme = developmental precursors for many other tissues
o Cells can also transform into distinct non-epithelial cell lineages that give rise to other tissues
29
Cellular basis for apical-basal polarity of epithelial cells
1) Plasma membrane composition locally segregated into domains
- Membrane in apical domain contains distinct membrane proteins and phospholipid content compared to the basal domain
2) Cytoplasm is polarized
- Cytoskeleton is asymmetric – organelles distributed in precise, polarized pattern
- Secretory vesicles in apical different from basal
30
Functions of polarity (4)
1) Allows unidirectional secretion/absorption of molecules to or from one side of the epithelium
2) Trans-epithelial transport
3) Transcytosis
4) Important for localizing intercellular signaling among epithelial cells, or between epithelial cells and other cell types
31
Trans-epithelial transport
transport of ions and molecules from apical to basal or vice versa
32
Transcytosis
endocytosis of substances from one membrane region, trans-cellular transport of vesicles, and exocytosis from another membrane region
33
Tight Junction
2 key proteins?
-Highly selective barrier, limits/prevents diffusion of substances between epithelial cells
Key proteins: occludins and claudins
“Tightness” of this barrier can be regulated
-Tight → ensures substances absorbed/secreted must pass through the epithelial cell by specific transport pathways
34
Adherence Junctions
Key protein?
Promote attachment, polarity, morphological organization, and stem cell behavior within epithelial sheet
Key proteins: cadherins
35
Cadherins are ______ with _______ and ________ domains that act to...
Transmembrane proteins
Extracellular domains - interact with each other
Cytoplasmic tails – bind adapters/signaling proteins and ACTIN filaments
36
Cadherin associated proteins
(e.g. B-catenin, protein kinases)
control aspects of epithelial polarity, development and function
37
Desmosomes
Key proteins?
Promote mechanical strength, resist shearing forces, promote structural organization of epithelial sheet
Key proteins: different class of cadherins
Link to INTERMEDIATE FILAMENTS and other adapter proteins
38
Gap junctions
Promote rapid communication between epithelial cells, through diffusion and small molecules
39
Microvili
- actin-containing protrusions, connected to cytoskeleton in cell interior
- Increase surface area → increases transport and secretion across membrane
40
Stereocilia
type of microvili
- Found in sensory cells in ear
- Very long, actin-filled microvilli
- NOT related to cilia
41
Cilia
| 3 types
microtubule-containing protrusions
Primary, Motile, and Sensory Cilia
42
Primary Cilia
single non-motile extension
-Promote signal transduction systems that control epithelial cell division, fate, and function
43
Motile Cilia
motile, found on specific epithelia cells
- Move mucous and other materials along passageways
- In respiratory tract, oviduct
44
Sensory Cilia
non-motile, function in sensory reception
-Connect sensory systems with CNS
45
Basal Lamina
-Thin sheet of EXTRACELLULAR material
- Underlies basal surface of each epithelial tissue (including muscles, nerves, and blood vessels)
- Separates epithelial cells from connective tissue
- Attaches epithelial cells to extracellular matrix on CTs
- Formed by collagen networks
- Synthesized and secreted by epithelial cells
46
Specific attachments of basal lamina?
connect basal surface to basal lamina
Integrins
Focal Adhesions
47
Integrins
strengthens epithelial-CT attachment
- connect intermediate filaments to epithelial cell
- Protein-protein interactions
48
Focal adhesions
connect actin filaments inside cell to basal lamina
-Regulate cell polarity, function in signaling
49
Exocrine glands
- secrete materials onto epithelial lined surfaces or the outside world
- glands are CT, but remain connected to epithelia apical surface from which they formed
- Secrete contents onto surface of epithelia – ALWAYS on APICAL surface
- contain ducts and secretory units
50
Secretory units
clumps of secretory epithelial cells
-Organized into bowl-shaped lobules called alveoli (acini) or into tubes (tubular glands)
51
Ducts
tubular structures, emanate from secretory units
-Passageways for secretion
52
Endocrine glands
- secretes substances into the blood stream (no ducts)
- Endocrine glands detach from parental epithelia
- Organized into clumps or cords of cells embedded in CT (isolated from lumen from which they formed), surrounded by basal lamina, with extensive capillary network
- ALWAYS secrete hormones into blood from BASOLATERAL membrane that act over long distances
53
Endocrine hormone pathway:
cross basal surface of gland cell and basal lamina then basal lamina and endothelial layer of capillary to reach blood stream
54
Epithelial stem cell properties (5)
1) Capable of dividing – re-enter cell cycle to produce new cells
2) Self renewal – when they divide, always reproduce themselves (the mother cell) to maintain stem cell populations in the body
3) Produce differentiated progeny
4) Tightly regulated
5) Structural organization – tied to distinct type of tissue
55
2 key principles of epithelial stem cell signaling pathways
1) Each pathway used by multiple, distinct stem cell systems in different organs/tissues
2) A single signaling pathway often triggers different developmental outcomes in different stem cell lineages
- Due to different developmental histories, different environments, and different levels of signals/receptors
56
Stem cell regulation
- Stem cell division and differentiation VERY tightly regulated → stem cells divide slowly and infrequently
- Stem cells thus much less abundant than differentiated offspring
Transit Amplifying cells – divide rapidly and differentiate
Loss of regulation → disease
57
Carinoma
cancer of epithelial origin
-Result from defects in regulatory pathways that control epithelial stem cells and their progeny during tissue development and maintenance
58
Adenocarcinoma
cancer derived from glandular epithelium
59
Cystic Fibrosis gene
AR inheritance (carriers asymptomatic)
CF gene: large ATP-binding transporter gene
- Chr7
- Encodes for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein
60
CF protein
CFTR
- Expressed in epithelial cells (lungs, pancreas, etc.)
- ATP-binding
- Functions as an epithelial ion channel that controls the movement of salt and water into and out of cells
61
```
Classes of CF mutations:
class 1
class 2
class 3
class 4
class 5
```
Class 1: non-sense or frame-shift mutation → no synthesis of CFTR protein
Class 2: block in processing and maturation in ER
Class 3: block in regulation (gating mutation)
-Protein on cell surface, but it is closed
Class 4: altered conductance
-CFTR at cell surface, but not working
Class 5: reduced synthesis, lower amounts of receptor on the membrane
62
Pathophysiology of CF lung disease
Normal: Peri-cilliary fluid layer lines tubes and cilia of out epithelial cells
Without CFTR → no Cl- moves out of cell → hyper-absorption of Na+ into cell, and water follows → thick dehydrated, sticky mucous layer lining epithelial cells
63
Ivacaftor
CFTR modulator protein rescue drug
- Targets class 3 gating mutation
- Binds → conformational change in CFTR protein that allows improved chloride transport
- Reduces chloride sweat values
64
Lumacaftor
CFTR modulator protein rescue drug
- targets class 2 mutation (del/del genotype)
- Corrector plus potentiator
- Helps 50% of CF population
65
Components of cilia (4)
1) Basal body anchor
2) Axoneme
3) Transition Zone
4) ciliary membrane
66
Basal Body
- Core anchors from which cilia are formed
- Organizes ciliary axiome
- Microtubule rich
- Central hub with 9 fold radial symmetry
- 3 microtubules per subunit
67
Axoneme
- Structural skeleton of cilium, provides tracks for movement within cilia
- made of doublet MTs
68
Intraflagellar Transport (IFT) uses _______ to go in the + direction and ________ to go in the - direction
* kinesin + IFT-B protein complex → +
| * dynein + IFT-A protein complex → -
69
Transition Zone
- Links basal body to axoneme and ciliary membrane
- “Gatekeeper”
- Limits diffusion of membrane and soluble proteins into/out of cilium
- Ensures ciliary membrane is a distinct compartment for cellular signaling
-Defects highly associated with ciliopathies
70
Ciliary membrane
Continuous with plasma membrane but compositionally distinct
71
Cilia Assembly (2 Steps)
1) centroles/basal bodies assembled
| 2) Formation of cilium
72
Centrole/Basal Body formation
Basal bodies derived from centrioles
Mother centriole functions as basal body/anchor
Centriole duplication during G1 to S phase with DNA duplication
-Once-and-only-once, tightly regulated
73
Formation of cilium
- Ciliary vesicle caps basal body → microtubule doublets assemble into ciliary vesicle → fuses with plasma membrane of the cell
- Cells with many cilia per cell use many basal bodies (uncoupled from cell cycle and replication)
74
Structural distinctions between motile and sensory cilia
MOTILE:
- 9+2 microtubule arrangements
- 9 doublet MTs around central pair of singlet MTs
- Some motile cilia have 9+0 arrangement
- KEY: Contain axonemal dynein arms between the doublet microtubules
SENSORY:
- 9+0 MT arrangement
- No axonemal dynein arms
75
Why are cilia good for signaling?
- High receptor surface-volume ratio
- Signal localized and polarized with discrete cell domains
- Receptors positioned away from interfering cellular domains
- Cilium can function as a mechanical detector of flow
- Sense physical stimuli, light, and chemical stimuli
76
Hedgehog (Hh) signaling
importance of cilia in development
→ limb formation, bone formation, neurogenesis
77
Ciliary Nodes
importance of cilia in development
-establish left-right body asymmetry
- Invagination of ciliated cells (9+0 organization)
- Beat in a rotary fashion to produce leftward flow of signaling molecules
- Signals detected by non-motile sensory cila at periphery of ciliary node → organogenesis
78
Bardet-Biedl Syndrome (BBS)
Ciliopathy
-BBS proteins participate in protein complex required for vesicle transport within cilium
79
Polycystic Kidney Disease (PKD)
-AD and AR forms (AD more common)
- AD = mutation in polycycstin 1/2
- AR = mutation in fibrocystin
- Mutation in channel proteins responsible for Ca2+ signaling
- Sense mechanical flow of urine in kidney lumen
Symptoms:
- Renal cysts
- Liver and pancreas cysts
- Intracranial aneurysms
80
Adult stem cells are _________, NOT ______________.
PLURIPOTENT not todipotent
Pluripotent → give rise only to the cells of that tissue
81
Mesehchymal Cells
precursors to all connective tissue family members
-Primarily function in embryogenesis, but some persist through adulthood as stem cells for generation of new connective tissues
82
Fibroblasts
- Secretory machines – produce fibrous proteins, proteoglycans, and ECM components
- Capable of cell division to make new fibroblasts or differentiate into other CT cell family types (myofibroblasts, adipocytes, chondrocytes, osteprogenitors)
- Highly regulated
- Proliferation stimulated by tissue injury
83
Myofibroblasts
- derivatives of fibroblasts
- Do contractile function for CT
- Generated at wound sites for scar tissue
84
Adipocytes
- derivatives of fibroblast
| - Stores fat as energy for other cells
85
White fat vs. brown fat
in Adipocytes
In adults it is “white fat”, in newborns and children it is called “brown fat” (high in mitochondria, convert fatty acid into heat)
86
Lymphocytes are involved in...
acquired immunity to foreign organisms, viruses, and materials
87
Macrophages
large “engulfing” cells
| -Differentiate from monocytes
88
Function of macrophages (5)
1) Phagocytosis of cells, ECM, and invaders
2) Promote/control angiogenesis
3) Send other signals to other cells
4) Remove damaged tissue, remodeling of repaired tissue
5) Remodel normal developing tissue/organs during morphogenesis
89
Neutrophils and Eosinophils are involved in defense against...
defense against microorganisms
90
Mast cells
- secretory cells activated by immune response
- Differentiate from basophils
- Promote vasodilation and swelling in CT
- Important in edema and allergic hypersensitivities
91
Types of connective tissue family cells (5)
1) Mesenchymal cells
2) Fibroblasts
3) Myofibroblasts
4) Adipocytes
5) Osteoblasts/ Osteocytes/ Osteoprogenitors
92
Types of connective tissue immigrant cells (5)
```
Lymphocytes
Macrophages
Neutrophils/Eosinophils
Mast Cells
Osteoclasts
```
93
ECM is made up of ______ and _______ as well as many other ___________ embedded within or diffusing through the ECM
structural fibers and ground substance
extracellular macromolecules
94
Collagen is the _________ fiber of the ECM.
most abundant structural fiber
95
One collagen molecule = ?
3 intertwined a-chain polypeptides --> form multimeric cross-linked collagens
96
Types of collagen (3)
1) Fibrillar collagen
2) Fibril-associated collagen
3) Network forming collagen
97
Fibrillar collagen
bundles of collagen molecules aligned head to tail for length, and stacked for thickness
- tensile stress
- most abundant type in body (type 1)
- very thick and long
98
Fibril-associated collagen
Link collagen fibrils to each other and other tissue components (basal lamina)
99
Network-forming collagen
- thin fibers
- interlaced networks of porous sheets
- In basal lamina, attach basal lamina to ECM
- Filtration barriers
-EX) Collagen type 4
100
Collagen is made by ________
fibroblasts
101
Production and processing of collagen (3 steps)
- Synthesized intracellularly, modified intracellularly secreted, and further modified extracellularly
1) Activated fibroblasts increase secretory machinery that exocytose material from rough ER
2) → golgi - modifies AA of collagen intracellularly
3) → into ECM
- Collagen must be secreted to form bundles
- Cleaved by enzymes at N-telo peptides → large scale bundling, and end-to-end linkages (extracellularly)
102
Loose connective tissue is made up of...
thin collagen fibrils, sparse, arranged in irregular latices
103
Dense connective tissue is made up of...
- contain thick collagen fibrils (more collagen relative to ground substance)
- Can have irregular orientations or in parallel-organized sheets
- In tissues of great strength, resist strong shearing forces (tendons and ligaments)
104
Elastic fibers contain ________ and _________ proteins and assemble into ______ and _______ sheets
elastin and fibrillin
stretchable and resilient
105
Ground Substance is made up of...(4)
1) Proteoglycans
2) Secreted proteins and glycoproteins
3) Inorganic and small organic solutes
4) Water
106
Proteoglycans
protein core + acidic polysaccharides (GAGs)
107
3 features of proteoglycans
1) highly negatively charged
2) rigid extended structure causes them to readily form gels (hydrated)
- Allows molecule diffusion and resistance too compression forces
3) proteoglycans can also bind to and inactivate/activate other proteins
108
Response to tissue injury (3 steps)
1) Inflammation and blood clotting
2) Proliferation phase (new tissue formation)
3) Tissue remodeling
109
Inflammation and blood clotting in tissue injury response
1) platelets released and produce blood clots to temporarily seal wound
2) Fibroblasts, mast cells, macrophages release signals that promote:
- swelling
- chemotaxis (histamines/ cytokines)
- fibroblast proliferation
- monocyte/lymphocyte migration
110
Proliferation phase in tissue injury response
1) Fibroblasts stimulated to divide and secrete ECM components
2) Macrophages signal angiogenesis, repair and remodeling
111
Tissue remodeling in tissue injury response
- ECM, cellular composition, overall structure of CT, epithelium and tissues altered
- Macrophages break down damaged tissue and release signals to recruit proliferation of new cells
- Extensive tissue damage → remodeled tissue is imperfect = scar tissues
112
2 Functions of cartilage
1. Provide resilient but pliable support structure
| 2. Direct formation and growth of bone
113
Chondrocytes
- make cartilage matrix and tissue, embedded in CT
| - From mesynchemal stem cells
114
Lacuna
-isolated compartment created by chodndrocytes as they secrete and surround themselves with matrix
115
Chondrocytes grows via __________ and _________
appositional growth
| interstitial growth
116
Appositional growth
- growth at the surface
- Driven by division of precursor cells
- Growth driven in upward direction
- Done by both chondrocytes and osteoblasts
117
Perichondrium
- external layer of CT that surrounds cartilage, contains fibroblasts and mesenchymal stem cells
- produced via appositional growth
118
Interstitial growth
- growth within matrix
- internal growth
- done by chondrocytes, but NOT osteoblasts
119
3 types of cartilage
1) Hyaline cartilage
2) Elastic cartilage
3) Fibrocartilage
120
Hyaline Cartilage
- contains thin collagen, thin fibrils
| - Ground substance rich in proteoglycans and free GAG (hyaluronic acid), promoting hydration and flexibility
121
Functions of hyaline cartilage
1) Allows metabolites to readily diffuse through tissue
2) Promotes resiliency to compression forces during joint movement
3) Allows growth of chondrocytes and matrix from within the matrix (interstitial growth)
4) During growth can calcify and attract cells that initiate bone formation
122
Elastic Cartilage
-contains collagen fibrils and proteoglycans
-Abundant elastic fibers and interconnecting sheets
(External ear, epiglottis, larynx)
-Elastic, flexible, does not calcify (under normal circumstances)
123
Fibrocartilage
-contain large bundles of regularly arranged collagen
-Similar to dense connective tissue
(Intervertebral discs, where tendons attach to bone)
-Resists compression and sheer forces
124
How does cartilage get nutrients?
Cartilage is AVASCULAR – all nutrients and metabolites must diffuse within the matrix to and from the perichondrium
125
Cartilage growth in childhood vs. adulthood
-In fetus, large segments of skeleton composed of cartilage (later replaced by bone)
- Growth of cartilage stops after childhood --> Limited capacity for cartilage repair in adults
- Only cartilage that remains is on articular surfaces (hyaline cartilage)
126
Bone cell types (4)
1) Osteoprogenitors
2) Osteoblasts
3) Osteocytes
4) Osteoclasts
127
Osteoprogenitors
-stem cells capable of cell division → osteoblasts and osteocytes
128
Osteoblasts are found on ___________ to facilitate __________ growth
endosteal surfaces (surface of bone matrix)
Appositional growth
129
Osteoblasts
- High engine secretory machines capable of cell division
- Makes ECM for bone
- Actively secretes osteoid (uncalcified)
- Pinch off matrix vesicles containing enzymes that initiate bone calcification, and loaded with calcium and phosphate → hydroxyapetite
- Connected to each other via gap junctions
130
Osteocytes
- derived from osteoblasts
- Do not divide (arrest in Go)
- Do very little secretion
- Modify matrix and sense what’s going on in matrix
- Extend canaliculi (tiny channels) through cell matrix
- Found throughout bone matrix
131
Osteoclasts
- Derived from monocytes from hematopoietic stem cells in bone marrow
- Phagocytic cells – degrade cartilage, bone matrix
-Reabsorb already made bone for bone matrix remodeling
→ mobilizing Ca2+ into bloodstream
-Promote inward growth of blood vessels, recruit osteoprogenitor cells, recruit nerves
132
Bone ECM is composed of _________, ________, ________, and _________
- Dense parallel collagen fibers
- hydroxyapatite (crystalized Ca2+ and PO4)
- Canaliculi
- Proteoglycans and glycoproteins
133
Haversian canals
channels that traverse the long axis through compact bone
134
Volkman's canals
link Haversian canals to each other and to the periosteum at the bone surface
135
Bone is highly ______ and _______ in order to allow for ______________
vascularized and innervated
ideal mobilization of Ca2+ from matrix to bloodstream
136
Bone formation can occur via ____________ or __________ ossification
Intramembranous
| Endochondral
137
Intramembranous Ossification forms _______ bones with no _________.
flat bones
| no pre-made cartilage
138
Intramembranous Ossification (4)
1) Sheet of mesenchymal cells come together (condensation), form organized matrix
2) Differentiate into osteoprogenitors → osteoblasts → secrete osteoid, begin to make bone matrix via appositional growth
3) Calcification of matrix occurs
4) Remodeling by osteoclasts → creates shape of bone
- Promote blood vessel growth within trabecular network of bone
139
Endochondral Ossification forms _______ bones with ___________
long bones
| pre-made cartilage present
140
```
diaphysis = ?
Epiphysis = ?
```
```
diaphysis = internal shaft
Epiphysis = bulbous enda
```
141
Steps for endochonral ossification
1) Hyaline cartilage forms primitive early long-bone structure
2) cartilage begins to be transformed into bone
3) bone continues to grow via appositional growth at surface and interstitial growth internally (via division of chondrocytes)
4) Perichondrium --> periosteum
5) Osteoblasts secrete osteoid and causes local cartilage calcification
6) Osteoclasts recruited to degrade cartilage (angiogenesis, etc.)
7) Bone deposition by osteoblasts (at primary and secondary ossification centers)
142
Epiphyseal growth plate
-cartilage growth plate where endochondral ossification continues
- Between epiphysis and diaphysis
- Contributes to interstitial growth, lengthens bone
- Present in children
143
Bone remodeling:
-Bone resoprtion by ________ at ________ surface. Coupled to ________ resulting in ____________
osteoclasts at endosteal surace
coupled to bone formation and calcification resulting in no net gain or loss of bone
144
Bone remodeling:
-Bone formation by ________ . These cells secrete ________ containing ________ that then ____________
Osteoblasts
secrete vesicles containing high levels of Ca2+ and PO4 --> hydroxyapatite precipitate --> vesicles rupture --> mineralization cascade outside matrix
145
Regulation of bone formation and remodeling via...(4)
1) short-range signals
2) long-range signals
3) mechanical stress
4) neuronal stimulation
146
Short-range signals in bone remodeling are __________, which can stimulate ________ or ________ in the local bone environment
Bone Morphogenetic Proteins (BMPs)
chondrogenesis or osteogenesis
147
Osteoperosis
decrease in bone mass due to defects in resorption/formation coupling
148
Osteopetrosis
defective resorption and increased bone mass
149
Osteomalacia Rickets
interferes with mineralization → abnormal increase in uncalcified osteoid
150
Parathyroid hormone --> ?
| Calcitonin --> ?
Parathyroid hormone --> calcium liberation (bone resorption)
Calcitonin --> calcium uptake into bone
151
Tumor heterogeneity
- Can have part of tumor that is PDL1 antibody + (for example) and part that is -
- “Clonal” heterogeneity in the tumor may lead to outgrowth of resistant cell components, which leads to tumor progression despite previous response
152
Prognostic vs. predictive biomarkers
- Prognostic: reflect natural history of disease independent of therapy- based on the tumor and the patient themselves
- Predictive: reflects the impact of a therapeutic intervention (predicts response to treatment).
153
Nivolumab and Pembrolizumab
- PDL1 antiobody drugs
- PDL1 and PD1 receptor bind --> T cell inactivation
- Patients with previously failed chemotherapy (advanced disease) had successful treatment
- More PDL1 expression in tumor --> better success rate and survival
154
Tunica Intima
- inner layer of vessels
- Contains layer of endothelial cells
- ALWAYS squamous – allows for effective diffusion of O2 and CO2
155
Tunica Media
- middle layer of vessel
| - Comprised of multiple layers of elastic laminae, smooth muscle cells, or collagen
156
Tunica Adventitia
- outer supporting layer
- Comprised of collagenous tissue
- Can contain blood vessels (vaso vasorum) in larger vessels that supply oxygen and nutrients to adventitia
157
Large muscular/elastic arteries
Intima
Media
Adventitia
- Initma – thin endothelial cell layer + layer of loose connective tissue
- Media – Inner elastic lamina + multiple layers of smooth muscle combined with layers of fenestrated elastic laminae + outer elastic lamina
- Adventitia - contains vasa vasorum, comparatively thick (collagen/elastin)
158
Role of smooth muscle and elastic layers in media of large muscular/elastic arteris
- Smooth muscle → contraction controls blood flow to capillary beds
- Elastic layers help modulate/buffer BP
- Aneurysms occur when endothelial layer gets damaged (typically protected by cushy smooth muscle and elastic layers)
159
Smaller muscular arteries lose...
their outer elastic lamina (retain inner elastic lamina)
160
Arterioles
Intima
Media
Adventitia
-Intima: endothelial cells + basal lamina
(Basal lamina – controls what molecules can enter and exit (different in different tissues))
- Media: several layers of smooth muscle (control blood flow into capillaries)
- Adventitia: small, blends into nearby CT (no vaso vasorum)
161
Capillaries
- Smallest vessels, exchange by diffusion
- 1-2 endothelial cells surrounding the lumen
- Surrounded by pericytes
- No muscular layer
162
Post-Capillary Venules are special because...
1) Slowest flow (where capillaries empty)
2) Diapedesis (leukocytes crossing vessel walls)
3) Endothelium responsive to vasoregulation and permeability between cells (histamines)
163
Veins have no _______, and only a few layers of _______. Also contain ________ to prevent back flow, and aided by ________
- inner elastic lamina
- smooth muscle
- one-way flap valves
- skeletal and smooth muscle contraction
164
Pulmonary vasculature
-Low pressure arteries, less thick walled
165
Lymphatic vessels
- One way flow from tissues → blood
- Small spaces in CTs connecting larger spaces lined with thin squamous endothelium
- Abundant flap-like valves and filters (lymph nodes with leukocytes)
166
Types of Capillaries (3)
Continuous
Fenestrated
Discontinuous
167
Continuous capillaries
endothelial cells form uninterrupted lining
transfer materials across via pinocytosis
168
Fenestrated capillaries
pores in endothelial cells
- Permit bulk flow of plasma across endothelial boundary through holes in endothelium
- Basal lamina allows things to pass through here
EX) Kidney glomerulus
169
Discontinuous capillaries
allow RBC/leukocytes to pass through holes
EX) allow RBC passage in spleen
170
Blood flow is regulated into capillary beds via _______ and ________ that connect ________ and _________. Their vasoconstriction /dilation can direct blood flow through or permit bypass of capillary beds.
arterio-venous shunts and metarterioles
connect larger arterioles and venules
171
Anastamoses
connections between arteries and veins that permit collateral circulation to occur within tissues.
-Vessel occluded or if pressure prevents flow of blood to an area → area alternatively supplied by flow from an anastomosing artery.
172
End arteries
supply a section of a tissue that cannot have an alternate arterial supply
→ occlusion of a vessel prevents blood flow in that area
173
Portal Systems
begin in a capillary bed and end in a capillary bed.
EX) Hypothalamic-anterior pituitary portal system and the hepatic portal system.
174
Pampiniform Plexus
-countercurrent arrangement between an artery and venous network.
EX) Found in spermatic cord for optimal heat exchange
175
Actin are ______ filaments and bound by ________ and _______ regulatory proteins
```
thin filaments (F-actin)
Tropomyosin and troponin
```
176
Tropomyosin binds to _______ and blocks _______ when Ca2+ is not present (relaxed)
actin
| blocks myosin binding site on actin
177
Troponin is bound to _________. When Ca2+ binds troponin...
tropomyosin
| conformational change in troponin --> tropomyosin exposes binding site for myosin and actin to bind
178
Myosin are ________ filaments made up of __________ and ____________
thick filaments
- pair of heavy chains
- 2 pairs light chains
179
Myosin head
- region of actin interaction and ATPase binding activity
- located at the ends of myosin filaments, so middle of thick filament is bare of myosin heads (limits contraction)
- pulls Z lines towards the center of the sarcomere
180
Myofiber (muscle fiber)
1 muscle cell
- long cylindrical cell
- contains collections of myofibrils
181
Myofibril
- bundles of myofilaments (actin and myosin) that make up a myofiber
- each myofibril contains its own SR network
182
Myofilament
actin and myosin
| a bunch come together to form myofibrils
183
Endomysium
separates individual muscle cells
- lamin, collagen, proteoglycans
- support and contains signaling molecules
184
Perimysium
around collection of muscle fibers
| -contains arterioles and nerve bundles
185
Epimysium
thick connective tissue that protects the whole muscle
186
Each muscle is innervated by _________ from the spinal cord.
Each motor neuron innervates ________________ within one muscle.
a group of motor neurons
a subset of muscle fibers
187
Motor unit
- muscle fibers innervated by a motor neuron
- Contract in unison
- Small motor units recruited first, progressively larger motor units recruited as contraction strength increases
- small motor units used for fine movements
- larger motor units used for gross movement and power
188
Dystrophin
protein that spans the plasma membrane and links the cytoskelton with the extracellular matrix
189
Titin
very big protein, links myosin thick filaments to the Z-line
-Keeps myosin filaments centered in a sarcomere
190
a-Actinin
cross links actin filaments
191
Paralbumin
Ca2+ binding protein in muscle
-Binds and releases Ca2+, diffuses faster than Ca2+
192
Myoglobin
present in muscle cells, stores and releases O2
193
Creatine and phosphocreatine
replenishes ATP during high metabolic demand in muscle cells
194
Tropomodulin
cap ends of actin filaments
195
Nebulin
keep actin filaments organized
| -Important for passive tension in a muscle
196
Steps of Muscle Contraction (10)
1) AP in motor axon →
2) Release of ACh NT at synaptic cleft →
3) Bind AChR on the muscle cell post-synaptic membrane
• AChR = ion channel, opens and causes depolarization and Na+ channels open
4) AP propagates down muscle fiber and in t-tubules
5) Depolarization of t-tubules→ conformational change at triad in DHP receptor in t-tubule
6) → RyR Ca release channel in SR opens, Ca flows out
7) Ca2+ binds tropinin → conformational change → tropomyosin exposes myosin-actin binding site
8) Charged myosin binds actin
9) ATP binds, and myosin head dissociates from actin
10) ATP hydrolysis to activate myosin head (spring is loaded)
197
Myosin-Actin cycle continues as long as _____ and _____ are present
Ca2+ and ATP
198
Relaxation of muscle occurs by...
Ca2+ ATPase pumps Ca2+ back into SR, tropomyosin again blocks myosin-acting binding site
199
Energy usage in muscle contraction
Cock myosin head
| Pump Ca2+ back into SR and out of the cytoplasm
200
Why do we need the T-System
-Needed by large cells that cannot rely on Ca2+ diffusion into a cell (too slow) for contraction of myofilaments
- Myofilament contraction near plasma membrane would occur before Ca2+ could get to the interior
- Cell would rip apart
201
T-tubule
Present in...
Not present in....
- Membrane structure that allows AP to propagate throughout cell – allows for instantaneous electrical signal over entire length and cross section of the cell
- In skeletal muscle and cardiac muscle but NOT in smooth muscles
202
T-tubule-SR contact point is called the __________ or aka the triad. This point contains _________ receptor in the T-tubules and ________ receptor in the SR as wells as __________.
Terminal Cisterna
DHP receptor (dihydropyridine)
RyR (Ryanodine receptor)
Calsequestrin
203
Calsequestrin
binds 50 Ca2+ molecules at terminal cisterna
204
DHP receptor
- in t-tubule membrane
| - Depolarization --> DHP receptor changes conformation and causes opening of RyR receptor
205
RyR
receptor in SR membrane that releases Ca2+
206
Excitation - Contraction Coupling allows _________ and __________ synchronization
electrical signal and Ca2+ signal
207
E-C in skeletal muscle cells involves ________, while E-C in cardiac muscle cells involves __________
physical contact between RyR and DHPR (not reliant on extracellular Ca2+)
Ca2+ causing RyR receptor opening (DHPR is extracellular Ca2+ dependent)
208
Tension regulation in skeletal muscles via __________ and ____________
1) AP frequency
| 2) Motor unit recruitment
209
Muscle stretched so much that there is no actin-myosin overlap → ?
Tension increases ________ and as amount of ________ increases
Tension plateaus when...?
no tension can be generated
linearly, overlap
actin moves into the central region of myosin where no myosin head groups are present
210
What is the length of a sarcomere?
Constantly changing
| -Z lines move depending on whether the muscle is contracted or relaxed
Relaxed = 2.5 micrometers, contracted = shorter
211
Slow muscle fibers
- Postural or relatively maintained contractions
| - Reddish (dark) due to high myoglobin content
212
Fast muscle fibers
- Rapid bursts of activity
- Pale
- High glycolytic content
213
Cardiac muscle (5 characteristics)
- multi-nucleated (less than skeletal)
- Nuclei in center of cell
- has t-tubules, actin and myosin
- NO satellite cells
- contains intercalated discs (gap junctions)
214
Intercalated discs contain __________ on their transverse portion and _________ and their lateral regions
- adhesive junctions that prevents shearing between cardiac muscle cells (transverse portion)
- gap junctions for synchronous depolarization and contraction (lateral regions)
215
Smooth muscle (5 characteristics)
- small, thin
- not striated
- single nucleus
- no troponin/tropomyosin, t-tubules, or SR (most)
- has actin and myosin
216
Contraction in smooth muscle cells by...
1) Ca2+ binds calmodulin → activates kinase →
2) Phosphorylation (and dephosphorylation for relaxation) of myosin light chain controls actin-myosin interaction
- NO troponin/tropomyosin
217
Repair in smooth muscle cells
- Can repair itself
| - Cells de-differentiate, enter mitosis and regenerate new muscle cells
218
Skeletal muscle (4 characteristics)
- multinucleated extensively
- nuclei right next to plasma membrane (unless damaged then repaired --> in middle of cell)
- actin, myosin, tropinin, tropomyosin, t-tubules, SR
- contain satellite cells
219
Skeletal muscle develops when _________ fuse to form ___________
myoblasts fuse to form myotubes (primitive muscle cells)
220
Satellite Cells
- stem cells
- source of new myoblasts to repair injured muscle
- Regulated by fibroblasts
- Growth stimulated by exercise
221
Exercise increases muscle size by increasing _________. It does NOT increase _______ or __________
cross-sectional area of each muscle cell by increasing the number of myofibrils to increase myofilament size.
-DOES NOT increase myofibril size or add new muscle cells
222
Exercise stimulated satellite cells to divide and fuse in order to...
provide nuclei and protein synthesis machinery to support extra muscle cell volume
223
Are sprinters born or made?
“Sprinters are born not made”
224
Muscles can fatigue because _______, __________ and ________ are produced which decreases ____________ and __________.
Creatine, phosphate, and H+ (lower pH)
effects:
1) Decreases Ca2+ effect on troponin
2) Decreases force generated by myofilaments
225
Gap junctions are used in cardiac muscle for...
for transmission of electrical current from one cell to the next in order for the heart to contract synchronously
226
Grading tension in cardiac and smooth muscle accomplished via... (2)
1) NT and hormone responses
| 2) Length-tension relationship (NOT a factor for skeletal muscle)
227
Young health athlete with murmur and person/family history of sudden cardiac death...
Hypertrophic Cardiomyopathy
228
Clinical features of HCM (4)
* Can be asymptomatic throughout life
* Cardiac murmur
* Cardiac “pump” Failure (dyspnea, angina)
* Arrhythmia (syncope, sudden death)
229
Patient in surgery with masseter spasm and/or hyperthermia...?
Malignant hyperthermia
230
Clinical features of malignant hyperthermia (4)
- Muscle rigidity (masseter spasm)
- Increased CO2 production
- Rhabodomyolysis
- Hyperthermia
231
In classic DMD _______ is in most/all cases by adulthood
cardiomyopathy
232
DMD clinical features
* Abnormal gait (toe walking)
* Gowers sign
* Calf pseudohypertrophy
* High creatinine kinase (1000s)
* Cardiomyopathy 100% by 18 years
233
Hypertrophic Cardiomyopathy is caused by a ________ mutation in ______________
missense structural genes (cardiac myosin heacy chain head region)
234
HCM can result in...(4)
- Cardiomyocyte and cardiac hypertrophy
- Myocyte disarray (Sarcomere’s disarrayed)
- Interstitial and replacement fibrosis
- Dysplastic intramyocardial arterioles
235
Malignant hyperthermia is caused my a mutation in ________. When the patient is exposed to __________ or ___________ (volatile anesthetics) the patient _______________
RyR
halothane, succinylcholine
overheats because Ca2+ pouring out and ATP Ca2+ pump releases a ton of heat
236
Malignant Hyperthermia can be treated with ___________
dantrolene 2.5 mg/kg
blocks Ca2+ release from SR
237
DMD is a __________ disease due to a mutation in __________ and can be treated with _________
X-linked (males only)
Dystrophin
Coritcosteroids
238
Myostatin
- inhibits muscle growth, negative feedback for muscle growth
- Mystatin knock out → increased muscle mass and strength
