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M2M Unit 4 > Week 1 > Flashcards

Week 1 Flashcards

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
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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

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3
Q

Mitochondria import across the inner membrane is _____ through ______.

Process?

A

ATP dependent

through TIM23/22 gated channel

  1. N-terminus (+) sequence bids channel, opens it
  2. Protein unwound by ATPase chaperone and fed through channel unfolded
  3. Channel closes immediately after protein comes through in order to maintain proton gradient
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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)
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5
Q

ATP is produced from the ________ and _________

A

proton gradient and electrical potential

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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

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7
Q

F1 protein complex (ATP synthase)

A

actual enzyme that makes ATP

-Bound to Fo

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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

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9
Q

ATP is transported out of mitochondria via __________

A

ATP-ADP antiporter

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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

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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)

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12
Q

Mitochondrial fusion occurs to __________. _____ and ______ proteins do this

A

repair damaged mitochondria

OPA1 and Mfn 1/2 GTPases

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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…)

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14
Q

Mitochonrial Quality control occurs via these three processes

A
  1. Fusion and fission (occurs regularly, vital for maintaining mitochonria)
  2. Proteolytic degradation
  3. Mitophagy

If these all fail, mitochondria will trigger apoptosis

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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

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16
Q

Mitophagy

A

• Mitochondria badly damaged enough, gets eaten up

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17
Q

AD optic atrophy and Charcot-Marie-Tooth neuropathy

A

caused by mutations in OPA and Mfn2 (respectively) mitochondiral fusion proteins

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18
Q

Mutation in mAAA protease results in _________

A

hereditary spastic paraplegia

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19
Q

Release of ROS by mitochondria results in _______ and _________

A

senescence and increased sensitivity to neuronal degeneration

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20
Q

Arsenic poison works by…

A

inhibiting oxidative phosphorylation and ATP production

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21
Q

Features of epithelia (5)

A
  1. Adherent to one another
  2. Cells arranged in one to several layers
  3. Polarized (asymmetric)
  4. Undergo turn-over/renewal (Driven by epithelial stem cells)
  5. Avascular (nutrients must diffuse through CT and basal lamina)
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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

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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)

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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
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25
Q

Epithelial classifications:

simple
stratified
Pseudostratified

A

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

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26
Q

Epithelial classifications:

Squamous
Cuboidal
Columnar
Transitional

A
  • 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
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27
Q

Spatial Relationship between layers of epithelia

A

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)

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28
Q

Epithelial to Mesenchymal Transition

A

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

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29
Q

Cellular basis for apical-basal polarity of epithelial cells

A

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

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30
Q

Functions of polarity (4)

A

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

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31
Q

Trans-epithelial transport

A

transport of ions and molecules from apical to basal or vice versa

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32
Q

Transcytosis

A

endocytosis of substances from one membrane region, trans-cellular transport of vesicles, and exocytosis from another membrane region

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33
Q

Tight Junction

2 key proteins?

A

-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

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34
Q

Adherence Junctions

Key protein?

A

Promote attachment, polarity, morphological organization, and stem cell behavior within epithelial sheet

Key proteins: cadherins

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35
Q

Cadherins are ______ with _______ and ________ domains that act to…

A

Transmembrane proteins

Extracellular domains - interact with each other

Cytoplasmic tails – bind adapters/signaling proteins and ACTIN filaments

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36
Q

Cadherin associated proteins

A

(e.g. B-catenin, protein kinases)

control aspects of epithelial polarity, development and function

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37
Q

Desmosomes

Key proteins?

A

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

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38
Q

Gap junctions

A

Promote rapid communication between epithelial cells, through diffusion and small molecules

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39
Q

Microvili

A
  • actin-containing protrusions, connected to cytoskeleton in cell interior
  • Increase surface area → increases transport and secretion across membrane
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40
Q

Stereocilia

A

type of microvili

  • Found in sensory cells in ear
  • Very long, actin-filled microvilli
  • NOT related to cilia
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41
Q

Cilia

3 types

A

microtubule-containing protrusions

Primary, Motile, and Sensory Cilia

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42
Q

Primary Cilia

A

single non-motile extension

-Promote signal transduction systems that control epithelial cell division, fate, and function

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43
Q

Motile Cilia

A

motile, found on specific epithelia cells

  • Move mucous and other materials along passageways
  • In respiratory tract, oviduct
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44
Q

Sensory Cilia

A

non-motile, function in sensory reception

-Connect sensory systems with CNS

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45
Q

Basal Lamina

A

-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
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46
Q

Specific attachments of basal lamina?

A

connect basal surface to basal lamina

Integrins
Focal Adhesions

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47
Q

Integrins

A

strengthens epithelial-CT attachment

  • connect intermediate filaments to epithelial cell
  • Protein-protein interactions
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48
Q

Focal adhesions

A

connect actin filaments inside cell to basal lamina

-Regulate cell polarity, function in signaling

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49
Q

Exocrine glands

A
  • 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
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50
Q

Secretory units

A

clumps of secretory epithelial cells

-Organized into bowl-shaped lobules called alveoli (acini) or into tubes (tubular glands)

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51
Q

Ducts

A

tubular structures, emanate from secretory units

-Passageways for secretion

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52
Q

Endocrine glands

A
  • 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
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53
Q

Endocrine hormone pathway:

A

cross basal surface of gland cell and basal lamina then basal lamina and endothelial layer of capillary to reach blood stream

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54
Q

Epithelial stem cell properties (5)

A

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

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55
Q

2 key principles of epithelial stem cell signaling pathways

A

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

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56
Q

Stem cell regulation

A
  • 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

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57
Q

Carinoma

A

cancer of epithelial origin

-Result from defects in regulatory pathways that control epithelial stem cells and their progeny during tissue development and maintenance

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58
Q

Adenocarcinoma

A

cancer derived from glandular epithelium

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59
Q

Cystic Fibrosis gene

A

AR inheritance (carriers asymptomatic)

CF gene: large ATP-binding transporter gene

  • Chr7
  • Encodes for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein
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60
Q

CF protein

A

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
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61
Q 
Classes of CF mutations:
class 1
class 2
class 3
class 4
class 5
A

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

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62
Q

Pathophysiology of CF lung disease

A

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

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63
Q

Ivacaftor

A

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
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64
Q

Lumacaftor

A

CFTR modulator protein rescue drug

  • targets class 2 mutation (del/del genotype)
  • Corrector plus potentiator
  • Helps 50% of CF population
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65
Q

Components of cilia (4)

A

1) Basal body anchor
2) Axoneme
3) Transition Zone
4) ciliary membrane

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66
Q

Basal Body

A
  • Core anchors from which cilia are formed
  • Organizes ciliary axiome
  • Microtubule rich
  • Central hub with 9 fold radial symmetry
  • 3 microtubules per subunit
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67
Q

Axoneme

A
  • Structural skeleton of cilium, provides tracks for movement within cilia
  • made of doublet MTs
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68
Q

Intraflagellar Transport (IFT) uses _______ to go in the + direction and ________ to go in the - direction

A
  • kinesin + IFT-B protein complex → +

* dynein + IFT-A protein complex → -

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69
Q

Transition Zone

A
  • 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

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70
Q

Ciliary membrane

A

Continuous with plasma membrane but compositionally distinct

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71
Q

Cilia Assembly (2 Steps)

A

1) centroles/basal bodies assembled

2) Formation of cilium

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72
Q

Centrole/Basal Body formation

A

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

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73
Q

Formation of cilium

A
  • 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)
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74
Q

Structural distinctions between motile and sensory cilia

A

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
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75
Q

Why are cilia good for signaling?

A
  • 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
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76
Q

Hedgehog (Hh) signaling

A

importance of cilia in development

→ limb formation, bone formation, neurogenesis

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77
Q

Ciliary Nodes

A

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
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78
Q

Bardet-Biedl Syndrome (BBS)

A

Ciliopathy

-BBS proteins participate in protein complex required for vesicle transport within cilium

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79
Q

Polycystic Kidney Disease (PKD)

A

-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
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80
Q

Adult stem cells are _________, NOT ______________.

A

PLURIPOTENT not todipotent

Pluripotent → give rise only to the cells of that tissue

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81
Q

Mesehchymal Cells

A

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

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82
Q

Fibroblasts

A
  • 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
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83
Q

Myofibroblasts

A
  • derivatives of fibroblasts
  • Do contractile function for CT
  • Generated at wound sites for scar tissue
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84
Q

Adipocytes

A
  • derivatives of fibroblast

- Stores fat as energy for other cells

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85
Q

White fat vs. brown fat

A

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)

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86
Q

Lymphocytes are involved in…

A

acquired immunity to foreign organisms, viruses, and materials

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87
Q

Macrophages

A

large “engulfing” cells

-Differentiate from monocytes

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88
Q

Function of macrophages (5)

A

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

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89
Q

Neutrophils and Eosinophils are involved in defense against…

A

defense against microorganisms

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90
Q

Mast cells

A
  • secretory cells activated by immune response
  • Differentiate from basophils
  • Promote vasodilation and swelling in CT
  • Important in edema and allergic hypersensitivities
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91
Q

Types of connective tissue family cells (5)

A

1) Mesenchymal cells
2) Fibroblasts
3) Myofibroblasts
4) Adipocytes
5) Osteoblasts/ Osteocytes/ Osteoprogenitors

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92
Q

Types of connective tissue immigrant cells (5)

A 
Lymphocytes
Macrophages
Neutrophils/Eosinophils
Mast Cells
Osteoclasts
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93
Q

ECM is made up of ______ and _______ as well as many other ___________ embedded within or diffusing through the ECM

A

structural fibers and ground substance

extracellular macromolecules

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94
Q

Collagen is the _________ fiber of the ECM.

A

most abundant structural fiber

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95
Q

One collagen molecule = ?

A

3 intertwined a-chain polypeptides –> form multimeric cross-linked collagens

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96
Q

Types of collagen (3)

A

1) Fibrillar collagen
2) Fibril-associated collagen
3) Network forming collagen

97
Q

Fibrillar collagen

A

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
Q

Fibril-associated collagen

A

Link collagen fibrils to each other and other tissue components (basal lamina)

99
Q

Network-forming collagen

A
  • thin fibers
  • interlaced networks of porous sheets
  • In basal lamina, attach basal lamina to ECM
  • Filtration barriers

-EX) Collagen type 4

100
Q

Collagen is made by ________

A

fibroblasts

101
Q

Production and processing of collagen (3 steps)

A
  • 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
Q

Loose connective tissue is made up of…

A

thin collagen fibrils, sparse, arranged in irregular latices

103
Q

Dense connective tissue is made up of…

A
  • 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
Q

Elastic fibers contain ________ and _________ proteins and assemble into ______ and _______ sheets

A

elastin and fibrillin

stretchable and resilient

105
Q

Ground Substance is made up of…(4)

A

1) Proteoglycans
2) Secreted proteins and glycoproteins
3) Inorganic and small organic solutes
4) Water

106
Q

Proteoglycans

A

protein core + acidic polysaccharides (GAGs)

107
Q

3 features of proteoglycans

A

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
Q

Response to tissue injury (3 steps)

A

1) Inflammation and blood clotting
2) Proliferation phase (new tissue formation)
3) Tissue remodeling

109
Q

Inflammation and blood clotting in tissue injury response

A

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
Q

Proliferation phase in tissue injury response

A

1) Fibroblasts stimulated to divide and secrete ECM components
2) Macrophages signal angiogenesis, repair and remodeling

111
Q

Tissue remodeling in tissue injury response

A
  • 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
Q

2 Functions of cartilage

A
  1. Provide resilient but pliable support structure

2. Direct formation and growth of bone

113
Q

Chondrocytes

A
  • make cartilage matrix and tissue, embedded in CT

- From mesynchemal stem cells

114
Q

Lacuna

A

-isolated compartment created by chodndrocytes as they secrete and surround themselves with matrix

115
Q

Chondrocytes grows via __________ and _________

A

appositional growth

interstitial growth

116
Q

Appositional growth

A
  • growth at the surface
  • Driven by division of precursor cells
  • Growth driven in upward direction
  • Done by both chondrocytes and osteoblasts
117
Q

Perichondrium

A
  • external layer of CT that surrounds cartilage, contains fibroblasts and mesenchymal stem cells
  • produced via appositional growth
118
Q

Interstitial growth

A
  • growth within matrix
  • internal growth
  • done by chondrocytes, but NOT osteoblasts
119
Q

3 types of cartilage

A

1) Hyaline cartilage
2) Elastic cartilage
3) Fibrocartilage

120
Q

Hyaline Cartilage

A
  • contains thin collagen, thin fibrils

- Ground substance rich in proteoglycans and free GAG (hyaluronic acid), promoting hydration and flexibility

121
Q

Functions of hyaline cartilage

A

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
Q

Elastic Cartilage

A

-contains collagen fibrils and proteoglycans

-Abundant elastic fibers and interconnecting sheets
(External ear, epiglottis, larynx)

-Elastic, flexible, does not calcify (under normal circumstances)

123
Q

Fibrocartilage

A

-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
Q

How does cartilage get nutrients?

A

Cartilage is AVASCULAR – all nutrients and metabolites must diffuse within the matrix to and from the perichondrium

125
Q

Cartilage growth in childhood vs. adulthood

A

-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
Q

Bone cell types (4)

A

1) Osteoprogenitors
2) Osteoblasts
3) Osteocytes
4) Osteoclasts

127
Q

Osteoprogenitors

A

-stem cells capable of cell division → osteoblasts and osteocytes

128
Q

Osteoblasts are found on ___________ to facilitate __________ growth

A

endosteal surfaces (surface of bone matrix)

Appositional growth

129
Q

Osteoblasts

A
  • 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
Q

Osteocytes

A
  • 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
Q

Osteoclasts

A
  • 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
Q

Bone ECM is composed of _________, ________, ________, and _________

A
  • Dense parallel collagen fibers
  • hydroxyapatite (crystalized Ca2+ and PO4)
  • Canaliculi
  • Proteoglycans and glycoproteins
133
Q

Haversian canals

A

channels that traverse the long axis through compact bone

134
Q

Volkman’s canals

A

link Haversian canals to each other and to the periosteum at the bone surface

135
Q

Bone is highly ______ and _______ in order to allow for ______________

A

vascularized and innervated

ideal mobilization of Ca2+ from matrix to bloodstream

136
Q

Bone formation can occur via ____________ or __________ ossification

A

Intramembranous

Endochondral

137
Q

Intramembranous Ossification forms _______ bones with no _________.

A

flat bones

no pre-made cartilage

138
Q

Intramembranous Ossification (4)

A

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
Q

Endochondral Ossification forms _______ bones with ___________

A

long bones

pre-made cartilage present

140
Q 
diaphysis = ?
Epiphysis = ?
A 
diaphysis = internal shaft
Epiphysis = bulbous enda
141
Q

Steps for endochonral ossification

A

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
Q

Epiphyseal growth plate

A

-cartilage growth plate where endochondral ossification continues

  • Between epiphysis and diaphysis
  • Contributes to interstitial growth, lengthens bone
  • Present in children
143
Q

Bone remodeling:

-Bone resoprtion by ________ at ________ surface. Coupled to ________ resulting in ____________

A

osteoclasts at endosteal surace

coupled to bone formation and calcification resulting in no net gain or loss of bone

144
Q

Bone remodeling:

-Bone formation by ________ . These cells secrete ________ containing ________ that then ____________

A

Osteoblasts

secrete vesicles containing high levels of Ca2+ and PO4 –> hydroxyapatite precipitate –> vesicles rupture –> mineralization cascade outside matrix

145
Q

Regulation of bone formation and remodeling via…(4)

A

1) short-range signals
2) long-range signals
3) mechanical stress
4) neuronal stimulation

146
Q

Short-range signals in bone remodeling are __________, which can stimulate ________ or ________ in the local bone environment

A

Bone Morphogenetic Proteins (BMPs)

chondrogenesis or osteogenesis

147
Q

Osteoperosis

A

decrease in bone mass due to defects in resorption/formation coupling

148
Q

Osteopetrosis

A

defective resorption and increased bone mass

149
Q

Osteomalacia Rickets

A

interferes with mineralization → abnormal increase in uncalcified osteoid

150
Q

Parathyroid hormone –> ?

Calcitonin –> ?

A

Parathyroid hormone –> calcium liberation (bone resorption)

Calcitonin –> calcium uptake into bone

151
Q

Tumor heterogeneity

A
  • 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
Q

Prognostic vs. predictive biomarkers

A
  • 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
Q

Nivolumab and Pembrolizumab

A
  • 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
Q

Tunica Intima

A
  • inner layer of vessels
  • Contains layer of endothelial cells
  • ALWAYS squamous – allows for effective diffusion of O2 and CO2
155
Q

Tunica Media

A
  • middle layer of vessel

- Comprised of multiple layers of elastic laminae, smooth muscle cells, or collagen

156
Q

Tunica Adventitia

A
  • outer supporting layer
  • Comprised of collagenous tissue
  • Can contain blood vessels (vaso vasorum) in larger vessels that supply oxygen and nutrients to adventitia
157
Q

Large muscular/elastic arteries

Intima
Media
Adventitia

A
  • 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
Q

Role of smooth muscle and elastic layers in media of large muscular/elastic arteris

A
  • 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
Q

Smaller muscular arteries lose…

A

their outer elastic lamina (retain inner elastic lamina)

160
Q

Arterioles

Intima
Media
Adventitia

A

-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
Q

Capillaries

A
  • Smallest vessels, exchange by diffusion
  • 1-2 endothelial cells surrounding the lumen
  • Surrounded by pericytes
  • No muscular layer
162
Q

Post-Capillary Venules are special because…

A

1) Slowest flow (where capillaries empty)
2) Diapedesis (leukocytes crossing vessel walls)
3) Endothelium responsive to vasoregulation and permeability between cells (histamines)

163
Q

Veins have no _______, and only a few layers of _______. Also contain ________ to prevent back flow, and aided by ________

A
  • inner elastic lamina
  • smooth muscle
  • one-way flap valves
  • skeletal and smooth muscle contraction
164
Q

Pulmonary vasculature

A

-Low pressure arteries, less thick walled

165
Q

Lymphatic vessels

A
  • 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
Q

Types of Capillaries (3)

A

Continuous
Fenestrated
Discontinuous

167
Q

Continuous capillaries

A

endothelial cells form uninterrupted lining

transfer materials across via pinocytosis

168
Q

Fenestrated capillaries

A

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
Q

Discontinuous capillaries

A

allow RBC/leukocytes to pass through holes

EX) allow RBC passage in spleen

170
Q

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.

A

arterio-venous shunts and metarterioles

connect larger arterioles and venules

171
Q

Anastamoses

A

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
Q

End arteries

A

supply a section of a tissue that cannot have an alternate arterial supply

→ occlusion of a vessel prevents blood flow in that area

173
Q

Portal Systems

A

begin in a capillary bed and end in a capillary bed.

EX) Hypothalamic-anterior pituitary portal system and the hepatic portal system.

174
Q

Pampiniform Plexus

A

-countercurrent arrangement between an artery and venous network.

EX) Found in spermatic cord for optimal heat exchange

175
Q

Actin are ______ filaments and bound by ________ and _______ regulatory proteins

A 
thin filaments (F-actin)
Tropomyosin and troponin
176
Q

Tropomyosin binds to _______ and blocks _______ when Ca2+ is not present (relaxed)

A

actin

blocks myosin binding site on actin

177
Q

Troponin is bound to _________. When Ca2+ binds troponin…

A

tropomyosin

conformational change in troponin –> tropomyosin exposes binding site for myosin and actin to bind

178
Q

Myosin are ________ filaments made up of __________ and ____________

A

thick filaments

  • pair of heavy chains
  • 2 pairs light chains
179
Q

Myosin head

A
  • 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
Q

Myofiber (muscle fiber)

A

1 muscle cell

  • long cylindrical cell
  • contains collections of myofibrils
181
Q

Myofibril

A
  • bundles of myofilaments (actin and myosin) that make up a myofiber
  • each myofibril contains its own SR network
182
Q

Myofilament

A

actin and myosin

a bunch come together to form myofibrils

183
Q

Endomysium

A

separates individual muscle cells

  • lamin, collagen, proteoglycans
  • support and contains signaling molecules
184
Q

Perimysium

A

around collection of muscle fibers

-contains arterioles and nerve bundles

185
Q

Epimysium

A

thick connective tissue that protects the whole muscle

186
Q

Each muscle is innervated by _________ from the spinal cord.

Each motor neuron innervates ________________ within one muscle.

A

a group of motor neurons

a subset of muscle fibers

187
Q

Motor unit

A
  • 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
Q

Dystrophin

A

protein that spans the plasma membrane and links the cytoskelton with the extracellular matrix

189
Q

Titin

A

very big protein, links myosin thick filaments to the Z-line

-Keeps myosin filaments centered in a sarcomere

190
Q

a-Actinin

A

cross links actin filaments

191
Q

Paralbumin

A

Ca2+ binding protein in muscle

-Binds and releases Ca2+, diffuses faster than Ca2+

192
Q

Myoglobin

A

present in muscle cells, stores and releases O2

193
Q

Creatine and phosphocreatine

A

replenishes ATP during high metabolic demand in muscle cells

194
Q

Tropomodulin

A

cap ends of actin filaments

195
Q

Nebulin

A

keep actin filaments organized

-Important for passive tension in a muscle

196
Q

Steps of Muscle Contraction (10)

A

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
Q

Myosin-Actin cycle continues as long as _____ and _____ are present

A

Ca2+ and ATP

198
Q

Relaxation of muscle occurs by…

A

Ca2+ ATPase pumps Ca2+ back into SR, tropomyosin again blocks myosin-acting binding site

199
Q

Energy usage in muscle contraction

A

Cock myosin head

Pump Ca2+ back into SR and out of the cytoplasm

200
Q

Why do we need the T-System

A

-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
Q

T-tubule

Present in…
Not present in….

A
  • 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
Q

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 __________.

A

Terminal Cisterna

DHP receptor (dihydropyridine)

RyR (Ryanodine receptor)

Calsequestrin

203
Q

Calsequestrin

A

binds 50 Ca2+ molecules at terminal cisterna

204
Q

DHP receptor

A
  • in t-tubule membrane

- Depolarization –> DHP receptor changes conformation and causes opening of RyR receptor

205
Q

RyR

A

receptor in SR membrane that releases Ca2+

206
Q

Excitation - Contraction Coupling allows _________ and __________ synchronization

A

electrical signal and Ca2+ signal

207
Q

E-C in skeletal muscle cells involves ________, while E-C in cardiac muscle cells involves __________

A

physical contact between RyR and DHPR (not reliant on extracellular Ca2+)

Ca2+ causing RyR receptor opening (DHPR is extracellular Ca2+ dependent)

208
Q

Tension regulation in skeletal muscles via __________ and ____________

A

1) AP frequency

2) Motor unit recruitment

209
Q

Muscle stretched so much that there is no actin-myosin overlap → ?

Tension increases ________ and as amount of ________ increases

Tension plateaus when…?

A

no tension can be generated

linearly, overlap

actin moves into the central region of myosin where no myosin head groups are present

210
Q

What is the length of a sarcomere?

A

Constantly changing

-Z lines move depending on whether the muscle is contracted or relaxed
Relaxed = 2.5 micrometers, contracted = shorter

211
Q

Slow muscle fibers

A
  • Postural or relatively maintained contractions

- Reddish (dark) due to high myoglobin content

212
Q

Fast muscle fibers

A
  • Rapid bursts of activity
  • Pale
  • High glycolytic content
213
Q

Cardiac muscle (5 characteristics)

A
  • 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
Q

Intercalated discs contain __________ on their transverse portion and _________ and their lateral regions

A
  • adhesive junctions that prevents shearing between cardiac muscle cells (transverse portion)
  • gap junctions for synchronous depolarization and contraction (lateral regions)
215
Q

Smooth muscle (5 characteristics)

A
  • small, thin
  • not striated
  • single nucleus
  • no troponin/tropomyosin, t-tubules, or SR (most)
  • has actin and myosin
216
Q

Contraction in smooth muscle cells by…

A

1) Ca2+ binds calmodulin → activates kinase →

2) Phosphorylation (and dephosphorylation for relaxation) of myosin light chain controls actin-myosin interaction
- NO troponin/tropomyosin

217
Q

Repair in smooth muscle cells

A
  • Can repair itself

- Cells de-differentiate, enter mitosis and regenerate new muscle cells

218
Q

Skeletal muscle (4 characteristics)

A
  • 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
Q

Skeletal muscle develops when _________ fuse to form ___________

A

myoblasts fuse to form myotubes (primitive muscle cells)

220
Q

Satellite Cells

A
  • stem cells
  • source of new myoblasts to repair injured muscle
  • Regulated by fibroblasts
  • Growth stimulated by exercise
221
Q

Exercise increases muscle size by increasing _________. It does NOT increase _______ or __________

A

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
Q

Exercise stimulated satellite cells to divide and fuse in order to…

A

provide nuclei and protein synthesis machinery to support extra muscle cell volume

223
Q

Are sprinters born or made?

A

“Sprinters are born not made”

224
Q

Muscles can fatigue because _______, __________ and ________ are produced which decreases ____________ and __________.

A

Creatine, phosphate, and H+ (lower pH)

effects:

1) Decreases Ca2+ effect on troponin
2) Decreases force generated by myofilaments

225
Q

Gap junctions are used in cardiac muscle for…

A

for transmission of electrical current from one cell to the next in order for the heart to contract synchronously

226
Q

Grading tension in cardiac and smooth muscle accomplished via… (2)

A

1) NT and hormone responses

2) Length-tension relationship (NOT a factor for skeletal muscle)

227
Q

Young health athlete with murmur and person/family history of sudden cardiac death…

A

Hypertrophic Cardiomyopathy

228
Q

Clinical features of HCM (4)

A
  • Can be asymptomatic throughout life
  • Cardiac murmur
  • Cardiac “pump” Failure (dyspnea, angina)
  • Arrhythmia (syncope, sudden death)
229
Q

Patient in surgery with masseter spasm and/or hyperthermia…?

A

Malignant hyperthermia

230
Q

Clinical features of malignant hyperthermia (4)

A
  • Muscle rigidity (masseter spasm)
  • Increased CO2 production
  • Rhabodomyolysis
  • Hyperthermia
231
Q

In classic DMD _______ is in most/all cases by adulthood

A

cardiomyopathy

232
Q

DMD clinical features

A
  • Abnormal gait (toe walking)
  • Gowers sign
  • Calf pseudohypertrophy
  • High creatinine kinase (1000s)
  • Cardiomyopathy 100% by 18 years
233
Q

Hypertrophic Cardiomyopathy is caused by a ________ mutation in ______________

A

missense structural genes (cardiac myosin heacy chain head region)

234
Q

HCM can result in…(4)

A
  • Cardiomyocyte and cardiac hypertrophy
  • Myocyte disarray (Sarcomere’s disarrayed)
  • Interstitial and replacement fibrosis
  • Dysplastic intramyocardial arterioles
235
Q

Malignant hyperthermia is caused my a mutation in ________. When the patient is exposed to __________ or ___________ (volatile anesthetics) the patient _______________

A

RyR

halothane, succinylcholine

overheats because Ca2+ pouring out and ATP Ca2+ pump releases a ton of heat

236
Q

Malignant Hyperthermia can be treated with ___________

A

dantrolene 2.5 mg/kg

blocks Ca2+ release from SR

237
Q

DMD is a __________ disease due to a mutation in __________ and can be treated with _________

A

X-linked (males only)

Dystrophin

Coritcosteroids

238
Q

Myostatin

A
  • inhibits muscle growth, negative feedback for muscle growth
  • Mystatin knock out → increased muscle mass and strength

M2M Unit 4 (1 decks)

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