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1
Q

In the plasma membrane, what are the different type of phospholipids?

A

1) Phosphatidylinositol : inner membrane leaflet serving as electrostatic scaffold for IC prots
2) Phosphatidylserine : inner surface confers negative charge -> when flips to EC face (apoptosis) = EAT ME signal
3) Glycolipids and sphingomyelin : EC face cell/cell/matrix interactions

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2
Q

What are nuclear organizing regions (NOR)?

A

Non-membrane bound strcuture that forms around chromosomal loci of ribosomal ARN (ARNr) genes

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3
Q

What does the REr do for protein synthesis?

A

1- Translation of ARNm begins on ribosomes that are free in cytosol
2- Developing peptide detected by signal recognition particle -> translation pauses until ribosomal peptide-ARNm complex attached to outer surface of REr
3- Protein formation continues unti signal peptidase remove signal
4- Proteins inserted into RE fold can form polypeptide complex (oligomerize) = disulfide bonds are formed and N-linked oligosaccharides are added
–> if prot not oligomerize = degraded in RE = stress response if too many = apoptosis

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4
Q

What is the function of REs (smooth)?

A

Synthesis of lipids, steroids and carbohydrates, metabolism of exogenous substance (ex : drug, toxin)

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5
Q

What are the sites of protein synthesis?

A

1- Proteins destined to plasma membrane or beyond = synthese in RER and assemble in Golgi
2- Proteins destined to cytosol = synthese on free ribosomes

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6
Q

What is the role of glycosylation in Golgi apparatus?

A

As protein traverse carbohydrates halfs are added by glycosylation and proteins are packaged into secretory vesicles to be released on the trans surface

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7
Q

Mitochondria half-life

A

Constant turn over, half-life 1-10J

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8
Q

Role of thermogenin

A

Its an inner membrane protein that can make the energy be used to generate heat
+++ in brown fat = generate heat by non-shivering thermogenesis

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9
Q

Function of peroxisomes

A

B-oxidation of fatty acids (to use for energy) and degradation by catalasee of the hydrogen peroxid produced (generates hydrogen peroxide)

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10
Q

Components of cytoskeleton

A
  • Actin microfilaments (G-actin, F-actin) = cell motility (microvilli, tight junctions, adherens junction)
  • Intermediate filaments = physical strenght and shape of cells (desmosomes) :
  • Microtubules = motor proteins (motile cilia, flagella), non-covalent dimers of alpha/beta tubulin (shrink/hollow define polarity)
    kinesin = anterograde transport - -> +
    dyneins = retrograde + -> -
    + = elongates or recedes in response to simutli by add/substract of tubulin dimers
  • = embedded in microtubule organizing center (MTOC or centrosome) near nucleus where its paired with centrioles
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11
Q

What are the cell/cell interactions?

A

1) Occluding jct (tight jct) (actin)
2) Achoring jcts (desmosome)
Between cells = desmosome (cadherin)
Cell-ECM = hemidesomosme (integrins)
a) Belt-desmosome (broad band between cells) = E-cadherin
b) Adherens jct = actin + vinculin + cadherin
3) Communicating jct (gap) = connexins

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12
Q

GROWTH FACTORS *****
Epidermal growth factors (EGF) :
a) produced by
b) function
c) Receptor family

A

a) produced by macrophages and epithelial cells
b) function = mitogenic for hepatocytes, firboblasts, multiple epithelial cell types
c) Receptor family = EGFR1 (aka ERB) with tyrosine kinase activity

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13
Q

Hepatocytes growth factors (HGF ; scatter factor)
a) produced by
b) function
c) Receptor family

A

a) produced by fibrolasts, most mesenchymal cells, endothelial, non-hepatocytes liver cells
-> sythese as inactive precursor (pro-HGF), activated by serine protease released at injury sites
b) function = mitogenic on hepatocytes and most epitheliu, morphogen in embryonic dev (influence patterns of differenciation), promotes cell migration, enhance hepato survival
c) Receptor family = MET with tyrosine kinase activity

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14
Q

Platelet derived growth factor (PDGF)
a) produced by
b) function
c) Receptor family

A

a) produced by activated macrophages, endothelium, smooth cells, tumors, platelets, keratinocytes and released by activated platelets
b) function = induce fibroblasts, endothelial, smooth muscle cells prolif + chemotactic for these and inflamm cells
c) Receptor family = PDGFR alpha and beta with tyrosine kinase activity

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15
Q

Vascular Endothelial growth factor (VEGF)
b) function
c) Receptor family
d) inducer

A

Induces all the activities necessary for angiogenesis
b) function
VEGF-A = major angiogenic factor in injury and tumors (endo cells migration/prolif, formation intima)
VEGF-B and PIGF = embyronic vessel dev
C-D = angio and lymphangiogenesis
maintenance of endothelium
c) Receptor family = VEGFR-1, 2 et 3, tyrosine kinase
d) most important inducer = hypoxia through HIF-1

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16
Q

Fibroblasts Growth factor (FGF)
a) produced by
b) function
c) Receptor family

A

a) source = macrophages, mast cells, endo cells
b) function = wound healing, hematopoiese, development, angiogenesis (FGFb only)
c) Receptor family = FGFR1 à 4, tyrosine kinase activity

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17
Q

Transforming frowth factor B (TGF-B)
a) produced by
b) function
c) Receptor family

A

a) produced by platelets, endothelium, epithelial cells, inflammation -> secreted as precursor
b) function multiple opposing effects (pleiotropic)
Scar formation, prod of collagen, fibronectin, proteoglycans
inhibits collagen degrad (by decrease MMP and increase TIMP)
AI cytokine = inhibe lympho prolif and leucocyte activity
Inhibits prolif of epi/endo cells
c) Receptor family - B1 et B2 = serine/threonine kinase activity = induce phosphorylation of Smads = form heterodimers = nuclear translocation

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18
Q

Steps of fibrillar collagens biosynthetic pathway

A

Collagens = heterodimers (I, V, XI), homotrimers (type II et III)
1. alpha-chain that make up fibrillar collagens synthese as precursor pro-a-chains with large globular peptides regions flanking the central triple-helical domain
2. After proline and lysine hydroxylatin and lysine glycosylation within RE, 3 procollagen chain align to form triple helix
3. Carboxyl end of propeptide completely removed by endroproteinase activity afrer secretion and resulting triple helical rod-like domain polymerize in staggered fashion to form fibrils
4. N-terminus propeptide variably processed depending on the collagen chain :
a) type I et II = N-propeptide processing complete
b) V, XI = large portion of N-propeptide remain attached = regulate fibril size
5. After secretion, collagen achieves lateral stability through cross-linking involving lysyl oxidase and previously hydroxylated residues

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19
Q

Composition of elastin

A

Central core of elastin with a meshlike network of fibrillin glycoprotein = control availability of TGF-B
Marfan syndrome = fibrillin defect

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20
Q

Role of fibronectin

A

Role in opsonizing material for phagocytosis (plasma form)
-> Sp domain that bind distinct ECM component (collagen, fibrin,heparin, proteoglycans) and attach cell integrin

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21
Q

How do integrin attach to ECM component?

A

Via tripeptide arginine-glycine-aspartic acid motif (RGD)

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22
Q

CDK inhibitors and CDK involve in cell cycle:
A) G1
B) G1-S
C) S
D) S-G2
E) G2-M

A

A) G1
CDK inhibitors = p16, p15, p18, p19
CyclinD/CDK4
B) G1-S
CDK inhib = p21 (CDKN1A), p27 (CDKN1B), p57 (CDKN1C) -> inhibits CyclinE/CDK2, CyclinD/CDK6
C) S
CDK inhib = same que B)
CyclinA/CDK2
D) S-G2
Same = p21, p27, p57
CyclinA/CDK1
E) G2-M
Same = 21-27-57
CyclinB/CDK1

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23
Q

Result of cellular energy metabolism alteration (less O2)

A

Less oxygen -> decrease ATP and increase adenosine monophosphate -> stimulate phosphorylase and phosphofructokinase activities -> increase glycogenolysis and glycolysis -> glycogen stores depleted rapidly -> accumulation of lactic acid and inorganic phosphates -> reduce IC pH -> decrease activity of cytosolic enzymes

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24
Q

Reversible changes

A

ATP depletion
Cell swelling
Baisse oxidative phosphorylation

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25
Irreversible changes
Loss of membrane permeability Severe mitochondrial damage Lysosomal swelling/disruption Calcium entry in cell Plasma membrane damage Mitochrondrial swelling with large amorphous densities
26
Enzyme responsable for conversion of O2- to H2O2 (removal of ROS) + location
Superoxidase dismutase (SOD) : - Manganese-SOD in mitochondria - Copper-zinc-SOD in cytoplasm
27
Oxidative modifications of proteins by free radicals
Oxydation of amino acids side chains -> formation of covalent-protein-protein cross-links and oxidation of protein backbone GSH -> (glutathion peroxydase) -> GSSG -> (glutathion reductase) -> GSH Can damage active sites of enzymes, disrupt conformation of structural proteins, enhance proteasomal degradation of unfolded/misfolded proteins
28
Lesions in DNA by free radicals
Free radicals can cause single and double-strand breaks in DNA, cross-linking DNA strands and forming adducts
29
Response of increase of unfolded proteins in ER
Increase production of chaperones Enhance proteasomal degradation of abnormal proteins Slow protein translation (to reduce misfold) If not enough = apoptosis
30
Role of glycolysis, steps, end product
= Anaerobic generation of ATP (short term survival of cell) PFK1 catalyze phosphorylation of fructose 6-phosphate to fructose 1,6-biphosphate (**step) End product = ATP, pyruvate, heat Pyruvate can also enter tricarboxylic acid (TCA) cycle Neurons can’t generate ATP anaerobic
31
Ultrastructure of acute swelling secondary to hypoxic injury
- clumped chromatin - cytosol electron lucent - ribosome detach from REr - RE vesiculated - myelin figures = damaged membranes coil into whorls - cytoskeletal damage = loss of microvilli etc - blebbing
32
Role of CD59
Glycoprotein-R on leucocytes, epi/endo cells, some cancer cells Blocks penetration of C5b-8 precursor in membrane and incorporation of C9 into the MAC (protect host cell) = bloque l’action du MAC
33
Example of DAMPs (damage-associated molecular patterns)
ATP, uric acid (breakdown product of DNA) and others
34
Mechanism of cell swelling in oncotic necrosis
O2 deficit -> anaerobic glycolysis -> lactic acid, baisse pH -> Na+/H+ exchanger export excess H+ in exchange for Na+
35
Calcium channel in ischemia
Ischemia opens plasma membrane calcium channel = increase Ca in cytosol = activation of protein kinase C, endonuclease, phospholipase, various protease
36
What explains the glassy homogenous appearance of necrotic cells
Loss of glycogen particle
37
Susceptibility of organs to ischemia-reperfusion injury
Brain > heart > kidney > intestine > skeletal muscle
38
Physiologic and pathological example of necroptosis (programmed necrosis)
Physio = formation of bone growth plate Patho = steatohepatitis, acute pancreatitis, ischemia-reperfusion injury, virus that encode caspase inhibitors
39
Triggers of necroptosis
TNF FasL DNA damage CD3 via LT-R Liposaccharide via TLR Interferon-y
40
Mechanism of necroptosis
- Ligation of TNF on TNFR1 = recruits RIPK1 et 3 into a complex that phosphorylate MLKL -> MLKL monomers translocate from cytosol to plasma membrane = disruption (pore) - Status of RIPK1 direct cell to survival, apoptosis or necroptosis - Inhibition of caspase 8 important to assembly of necrosome
41
Effect of unpaired electron on free radicals
= prone to extract a H+ from the polyunsaturated fatty acids in cell membrane = become itself a free radical that will extract H+ from neighboring fatty acids
42
Impact of fescue in cattle
Mycotoxines ingérées = vasoC
43
Initiator caspases that start process of apoptosis
Caspase 8 (activated by death-inducing signaling complex DISC of the extrinsic pathway) Caspase 9 (activated by apoptosome in intrisinc pathway) Caspase 2 (activated by p53 following DNA damage)
44
Effector caspases in apoptosis
Caspases 3, 6, 7 and 12
45
Role of extrinsic (death -R) parthway and caspases involved
Eliminates self-reactive lymphocytes Cell-killing by CTL Caspase 8 and 10
46
Mechanisms of extrinsic pathway
FasL (expressed on LT) bind to Fas (3 ou +) -> cytoplasmic death domain form binding site for FADD that binds inactive caspase 8 ou 10 (after same sequence than mitochondrial pathway)
47
What can inhibit extrinsic pathway
Inhibited by protein FLIP = binds to pro-caspase-8 = block FADD binding
48
What forms cytoplasmic DISC
TNF-R-associated death domain (TRADD), Fas-associated death domain (FADD) and caspase 8
49
Different ubiquitination status of RIPK1
Can associate with trimerized DR = direct cell to regulated necrosis (if caspase are inhibited) OR toward survival via activation of NFkB Has an N-terminal death-domain (DD) that links it to the apoptotic pathway through proteins (TRADD, FADD = activates procaspase 8)
50
What do apoptotic cells express?
Phosphatidyl serine Annexin 1 Calceticulin
51
Intrinsic mitochrondrial pathway A) Anti-apopto B) Pro-apopto C) regulated apoptosis initiators
A) Anti-apopto BCL2, BCL-X, MCL1, B) Pro-apopto BAX, BAK = activation = enhance mitochondrial permeability (activators = BID, BIM, puma, p53) Sensitisers = BAD, NOX, BIK, MULE, BN1P3, Hrk C) regulated apoptosis initiators BAD, BIM, BID, PUMA, NOXA BH3 = activator/sensitizer Activator = act on BAX/BAK Sensitizers inhibits anti-apoptosis BCL2
52
Mechanisms of mitochondrial pathway
1. Survival signal (GF) = prod anti-apopto 2. Deprivation of signal = upregulation of BH3 = activates BAX/BAK = form membrane pores of mitochondria = prots leaks in cytoplasm (ex cytochrome C) = activation of caspase cascade
53
What caspase is activated by ER stress?
Caspase 12 (ER-resident caspase)
54
Role of Granzyme B from CTL and NK cells
Can trigger apoptosis by activating caspase 3 and 7 and 10
55
Signals for autophagy
Secretion of lysophosphatidylcholine = chemotactic factor for phagocytes Expression of phosphatidylserine (marks cell for heterophagy)
56
What does the autophagosome requires?
The action of 2 ubiquitin-like conjugation systems that result in covalent linkage of the lipid phosphatidylethanolamine (PE) to microtubule-associated protein light chain 3 (LC3) PE-lipidated LC3 = autophagy marker
57
Autophagy signaling pathway
- formation of ULK1 complex, FIP 200, autophagy-related gene (ATG) 13 and 101 - ULK1 = formation of isolation membrane - Beclin 1-VPS 34 = drives nucleation of the isolation membrane - ATG9 and VMP1 = recruits lipids to the isolation membrane - 2 UBL prot conjugation system ATG12-UBL system and prot-light-chain (LC) 3-UBL = cleaves LC3 and catalyze conjugation of ATG prots - Soluble NSF attachment prot-R (SNARE) = fusion of lysosome to autophagosome
58
Mechanisms of hypertrophy
1. Sensors detect increased load -> activate PI3K/AKT and G-prot coupled-R pathways 2. Pathways stimulate increase prod of TGF-B, insulin-like growth-factor, fibroblast-GF and vasoactive agents (a-adrenergic agonist, endothelin, angiotensin II) 3. Activation of transcription factors (GATA4, NFAT, MEF2) = increase expression of genes
59
What is Niemann-Pick disease type C?
A lysosomal storage dz = mutation in enzyme involved in cholesterol trafficking
60
How does Periodic-Acid-Schiff work?
Breaks 1,2-glycol linkages to form aldehydes which are revealed by the regeant Glygol linkages occur in substance other than glycogen = use PAS with and w/o diastase Diastase digests glycogen (with diastase = glycogen negative)
61
Inclusions virales : - nucléaires - cytoplasmiques - les deux
- Nucléaire : virus ADN = parvo, herpès, adénovirus - Cyto : virus ADN = pox et virus ARN = rhabdo - 2 : Distemper (dans le noyau = heat shock protein)
62
Where could we see lead inclusions? Colo?
Intra-nuclear inclusions in renal tubular epithelial cells Easily observed with Acid-fast stain (ZN)
63
What does it mean to say that amyloid is anisotropic?
It means its birefringent = can refract polarized light into 2 rays that vibrate in perpendicular waves Apple-green birefringence = EC bundles of non-branching filaments 7-10nm in diameter
64
Classification of amyloid by precursor peptide : 1. AL amyloid : where, horse, Congo 2. Serum amyloid A (AA) : étio, where, race, Congo
1. AL amyloid = deposited almost anywhere, nasal AL in horses (nose, conjunctiva, skin), retains congophilia and apple-green refringence after pre-tx with potassium permanganate 2. AA = chronic inflamm (secondary), produced by hepatocytes, +++ kidneys (glomeruli), liver (space of Disse), splenic white pulp, sensitive to potassium permanganate = congo/apple-green loss after tx Hereditary of familial forms = Shar-Pei, Abyssinian cats = +++ medullary interstitium instead of glomeruli
65
What type of collagen compose fibrosis, source?
Excess in fibrous collagen type I Liver - stellate cells are the source of the collagen
66
Cause of gout in bird/reptiles?
VitA deficiency, high-prot diet, renal injury Uric acids and urate = end products of purine metabolism
67
What is pseudogout?
Deposits of calcium pyrophosphate crystals Differentiated from gout with chemical analysis
68
Where/when can we see deposit of cholesterol?
Form at sites of hemorrhage or necrosis Found in atheromas (atherosclerosis) = rare except in hypothyroidism Cholesterol granulomas (cholesteatomas) = plexus choroid of horses
69
Causes of pathological metastatic calcification?
1. Increase secretion of PTH with bone resorption (hyperpara) 2. Resorption of bone (tumors of bone marrow, metastasis to bone, accelerated bone turnover (paget dz), immobilisation) 3. VitD dz (intox, sarcoidosis
70
How can chronic knidney dz cause calcification + where?
By phosphate retention Uremic gastropathy = damage to gastric arteries and arterioles results in ischemic injury and calcification of mucosa
71
Cause of vitD toxicosis
Cestrum diurnum (plante) Rodenticides (cholecalciferol) Primary hyperparathyro (neoplasia) Humoral hyperCa of malignancy (pseudohyperpara)
72
How can ischemia cause dystrophic calcification?
Ischemia opens membrane Ca channels = increase IC Ca = activates calpains that cleave Na+/Ca2+ exchangers in mitochondria and other cell membranes = decrease efflux of Ca and decrease reuptake of Ca by RE = Ca overload Heterotopic bone may form in the focus of calcification (small bony spicules in pulmonary interstitium of old dogs) Formation of psammoma bodies and asbestos bodies
73
Mechanism of skin pigmentation
Melanin formed in melanosomes (organelle) -> transferred through DC processes to adjacent keratinocytes
74
What is the first step of melanin synthesis?
Conversion (oxidation) of tyrosine to dihydroxyphenylalanine (DOPA) catalyzed by tyrosinase (copper-containing enzyme)
75
Cause of partial albinism (Chediak-Higashi syndrome CHS)
Mutation of LYST gene (encodes for a lysosomal trafficking regulator protein) = melanocytes have enlarged melanosomes but melanin not transferred to skin
76
Cause of hyperpigmentation
Endocrine skin dz (hyperadrenocorticism**) Epidermal response to chronic injury
77
Lipofuscin colo + cause
Sign of free radical injury and lipid peroxydation Autofluorescent, react with fat stains = Sudan black B, Oil red O, PAS
78
What is the predominant component in neuronal ceroid-lipofuscinosis (hereditary lysosomal storage dz)
Subunit C of mitochondrial ATP synthase
79
Ultrastructure of lipofuscine and ceroid
Lipo = granular Ceroid = myelin figures = whorls Lectin IHC to distinguish neuronal
80
Mechanism of cyanid (CN-) tox
Block oxidative phosphorylation in mitochondria by binding cytochrome oxidase = cell can’t use O2 in hemoglobin = venous blood is as red as arterial blood
81
Carbon monoxide poisoning
Hg higher affinity for CO than O = small amount of CO reduces oxygen transport Carboxyhemoglobin = blood bright cherry red, tissues bright pink
82
Nitrite poisoning
Source = plants or contaminated water from fertilized fields Nitrate -> nitrite in rumen = can oxidize iron in the heme to the Fe3+ (ferric) state converting hemoglobin to methemoglobin = low affinity for O Blood = chocolate brown
83
How can we remove hematin from slides?
By soaking the dewaxed tissues before H&E stain in a saturated alcoholic solution of picric acid
84
Iron storage and transport, ferritin concentration
Transport = transferrine Iron associated with apoferritin in cells to form aggregates of ferritin micelles Ferritin concentration serum correlates with iron stores
85
Characteristics of hematoidin
Bright yellow crystalline pigment derived from hemosiderin In macrophages Free of iron Similar to bilirubin biochemically Deposit in tissues at sites of hemorrhage
86
Formation of bilirubin
After removal of iron, rest of the heme converted by heme oxygenase to biliverdin then biliverdin reductase to bilirubin
87
What is porphyria, cause, lesions
Heme synthesis disorders = deposition of porphyrin pigments in tissues Porphyrin ring in Hg molecule composed of 4 pyrrole moieties linked together around the central iron ion Congenital in calves, cats, pigs = genetic defects caused by deficiency of uroporphyrinogen III synthase Pink tooth, bone and urine red-brown and fluo red under UV
88
Cell cycle regulation to pass through restriction point G1
Cyclin D activation of CDK4/6 results in phosphorylation of retinoblastoma protein (RB) = release transcription factor E2F = enables cell to pass through G1 restriction point After, cell independant of EC growth signals
89
Cellular aging theory that combines DNA damage and metabolic abnormalities
Endo/exo factors -> telomeres dysfct -> impaired DDR or increase ROS = activate p53 -> compromise mitochondrial fct through repression of coactivators of peroxisome proliferator-activated receptor gamma (PPARy) Repression of PPARy coactivators by p53 = exacerbate oxidative injury and decreases energy production
90
What is a telomere and how is it protected?
Telomere = repetitive nucleotide (TTA-GGG) sequences that cap the ends of linear chromosomes = template for complete replication of chromosomal DNA + prevent misinterpret as double-stranded DNA breaks Telomeric DNA protected from inappropriate repair by associated proteins that form the shelterin complex Telomeres are shortened after each division because DNA polymerase needs a leading primer
91
Action of telomerase in immortal cells (germ cells, certain stem cells, certain leucocytes = LT activé, cancer cells)
Telomerase = RNA subunit template component (TERC) and catalytic component (TERT, reverse transcriptase) -> active telomerase replenishes telomeres Germ cells have sufficient telomerase to stabilize telomere completely Stem cells = partially
92
What is senescence and its regulation?
Irreversible arrest of cell cycle regulates by 2 tumor suppressor pathways (p53-p21 and P16INK4a-RB) If DDR persistant, p53 cause growth arrest through cell cycle inhibitor p21 Persistent DDR through p38 MAPK, prot kinase C and ROS = activate p16INK4a -> activate RB protein = stop cell cycle
93
How does telomere attrition (small section of telomere not replicated at each division) cause senescence?
Loss of telomere until DNA is broken = signal cell arrest Telomere uses its own RNA as template for adding nucleotide to the end of chromosomes
94
How can caloric restriction increase life span?
Insulin and insulin-like growth factor 1 signaling -> AKT and mTOR (downstream target) Sirtuins = family of NAD-dependent protein deacetylases = promote expression of genes that increase longevity (inhibits metabolic activity, reduce apoptosis, stimulate protein folding, counteract ROS) CALORIC RESTRICTION = reduce IGF-1 pathway and increase sirtuin
95
Modification of histones (more than 70 different histone modifications generically denoted as marks)
1. Methylation of histone : lysine and arginine (hausse/baisse transcription depending on which residue 2. Acetylation of histone : lysine acetylated by histone acetyl transferase (HAT) -> open up chromatin and increase transcription Histone deacetylase = chromatin condensation 3. Phosphorylation of histone : serine residue (hausse\baisse transcription 4. DNA methylation : high levels of methylation in gene regulatory elements = transcriptional silencing Histone marks are reversible through activity of chromatin erasers (supercoiled in metaphase)
96
Role of micro-RNA
- modulate translation of target mRNA - posttrasncriptional silencing of gene expression by miRNA = gene regulation in eucaryotes Primary miRNA trimming by DICER -> miRNA single-stranded associated with multiprotein aggregate called RNA-induced silencing complex (RISC) If perfect match RISC induce mRNA cleavage IF NOT = repress translation
97
What are small interfering RNA (siRNA)?
Short RNA sequences that can be introduced experimentally into cells = serve as substrate for DICER and interact with RISK Used to study gene fct (knockdown) by silencing pathogenic genes
98
Phase of mitosis
Interphase = centromere x2 DNA synthesis Prophase = chromosomes condense mitotic spindle form Prometaphase = nuclear envelop fragment, microtubules attach Metaphase = chromosome in the middle Anaphase = chromatin separates (ass = apart)
99
What are the repair mechanisms for single stranded DNA damage?
1. Base excision repair = at any point in cell cycle = remove damaged bases that could cause mutations by mispairing or lead to breaks in DNA replication 2. Nucleotide excision repair = repair DNA damaged by chemicals, UV, radiation or other mutagens that cause formation of DNA adducts (DNA covalently bonded to a chemical) 3. Mismatch repair = mends erroneous insertion, deletion or mismatched base pairs
100
type III (Cori dz) glycogen storage disease deficiency?
Deficient fct of amylo-1,6- glucosidase (rebranching enzyme) -> structurally abnormal glycogen in hepatocytes
101
Defenition of : 1. Codominance 2. Pleiotropisme 3. Genetic heterogeneity
1. Codominance = both alleles of a gene pair contribute to the phenotype 2. Pleiotropisme = a single mutant gene may lead to many end effects 3. Genetic heterogeneity = mutations at several genetic loci may produce the same trait
102
Familial hypercholesterolemia : Mutation, metabolism
Autosomal dominant Mutation in gene for R-LDL = inadequate removal of plasma LDL by liver and increase serum level Possible mutation of ApoB and PCSK9 Cholymicrons are hydrolyzed by an endothelial lipoprotein lipase in the capillaries of muscle and fat
103
Impact of mutations (hypercholest)
- mutation in LDLR gene - mutation in ApoB = reduce binding of LDL with LDL-R - activating mutation in PCSK9 = reduces nbre of LDL-R on the cell surface bc of increased degradation during recycling process
104
Classes of mutations (hypercholest)
I = complete failure of LDLR synthesis II = LDLR accumulate in endoplasmic reticulum (folding defects) III = ApoB binding sites ; LDLR reaches cell surface but can’t bind LDL IV = LDLR fail to localize in coated pits V = No dissociation between LDL and LDLR in endosome VI = failure of initial targeting of LDLR on basolateral membrane
105
Lysosomal storage dz : acid hydrolysases in lysosomes is modified where
Acid hydrolysase is synthesized in RE and transported to Golgi There is posttranslational modifications = attachement of terminal mannose-6-phosphate then transported to Golgi via vesicles that fuse with lysosomes
106
What are the consequences of inherited deficiency of a fct lysosomal enzyme?
1. Primary accumulation 2. Tight linkage between autophagy, mitochondrial fct and lysosomes = if accumulation of macromolecules = lysosomal process of organelles delivered by autophagocytic vacuoles is reduced = persistance of dysfct and leaky mitochondria with poor Ca2+ buffering capacity + altered membrane potentials -> ROS -> triggers intrinsic apoptosis
107
What is Niemann-Pick Disease type A vs B?
= lysosomal accumulation of sphingomyelin (lipidic component of cellular membranes) due to deficiency of sphingomyelinase A = infantile, neuro + visceral accumulation B = survive to adulthood, organomegaly w/o SNC involvement
108
Mutations in Niemann-Pick disease Type C?
Mutations in NPC1 (membrane bound) and NPC2 (soluble) Accumulation of cholesterol and ganglioside in nervous system
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What is Gaucher’s dz?
Autosomal recessive disorder -> mutation in glucocerebrosidase (cleaves glucose residue from ceramide) = accumulation of glucocerebrosides in phagocytes and +/- SNC = formed from catabolism of glycolipids derived from cell membranes of senescent leukocytes and GR
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What are the types in Gaucher’s dz?
Type 1 = chronic nonneuropathic, ++monocyte system, splenic and skeletal Type 2 = acute neuropathic gaucher = die young, no enzyme activity Type 3 = systemic and progressive SNC dz (intermediaire) Morpho = distended phacocytic cells (gaucher cells = spleen, liver, MO, NL, PP, tonsils) with fibrillary cytoplasm, PAS+ Aggregation of a-synuclein from impairment in autophagy
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Mucopolysaccharidoses = deficiencies, variants, morpho
Deficiencies in enzymes involved in degradation of mucopolysaccharides (glycosaminoglycans) = +++ ECM, joints, connective tissue 11 variants = Hurler syndrome (MPS I-H) defect in a-L-iduronidase, Hunter syndrome (X-linked) - MPS II Morpho = mucopolysaccharides in mononuclear phagocytic cells, endothelial cells, intimal smooth muscle cells, fibroblasts = BALLOON CELLS (PAS +)
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Steps of normal glycogen metabolism
Glycogen = storage form of glucose Conversion of glucose to glucose-6-phosphate (I) by hexokinase (glucokinase) -> conversion to glucose-1-phosphate by phosphoglucomutase -> conversion to uridine disphosphoglucose -> formation of highly branched large polymer (glucose molecules linked by a-1,4-glucosides bonds) -> glycogen chain elongates by addition of glucose molecules by glycogen synthetases Degradation = phosphorylase in liver and muscle split glucose-1-phosphate from glycogen until 4 glucose residues on each branch -> limit dextrin -> can be further degraded by debranching enzyme (III) Glycogen also degraded in lysosomes by acid-alpha-glucosidase (if deficient can’t be accessed by cytoplasmic phosphorylase
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What are the subgroups of glycogen storage dz?
HEPATIC FORMS (chien) = alteration of glycogen degradation = accumule + hypoglycemia (liver phosphorylate or debranching enzyme) (Von Gierke dz (glucose-6-phosphate) MYOPATHIC FORMS (chevaux) - glycogen used as energy during physical activity (ATP generated from glycolysis -> lactate) -> store glycogen -> muscle weakness -> associated with deficiency of acid alpha-glucosidase (type II or Pompe dz, cardiomegaly) and lack of branching enzyme
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What is a karyotype test (in chromosomal dz)
Arrest in dividing cells in metaphase with mitotic spindle inhibitors (colcemid) and stain giemsa (G-banding)
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What are the different structural changes in chromsomes?
- Deletion (loss interstitial = 2 breaks, terminal = 1 break) - Ring chromosomes = breaks both ends with fusion at damaged ends = serious consequences - Inversion = 2 breaks in 1 chromosome with reincorporation of inverted segment (paracentric 1 arm, péricentric breaks opposite sides of centromere) = possible développement normal - Isochromosome = one arm lost and 2e dupliqué = 2 short or long arms = monosomy for genes on short arms and trisomy for genes on long arms - Translocation = segment of chromosome transferred to another —> balanced reciprocal translocation = 1 break in each of 2 chromosomes with exchange = likely phenotypically normal because no loss of material but increase risk of producing abnormal gametes —> robertsonian translocation (centric fusion) = translocation between 2 acrocentric chromosomes = possible normal
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When does the cytogenic disorders involving sex chromosomes happen?
Inactivation occurs at random among all the cells of the blastocyts about day 5,5 of embryonic life
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Role of gene XIST?
Gene involved in X inactivation LncRNA retained in nucleus coats X chromosome and initiates gene-silencing process by chromatin mod/DNA methylation Regardless of the number of X chromosome presence of Y determine male sex
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Role of gene SRY and MSY
SRY = testicular development Male-Sp Y region (MSY) = testis/spermatogenesis genes Y deletion = azoospermia
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Consequences of more X chromosomes
Greater the number of X chromosomes, greater intellectual disability
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What is Klinefelter syndrome?
Male hypogonadism (2 ou + X, 1 ou + Y) Cause +++ nondisjunction during meiotic divisions in one of the parents, mosaic also possible
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What is Tuner syndrome
Complete or partial monosomy of X chromosome (missing entire X, structural anomaly +++ on short arm) Genes involved = SHOX (not inactive, short stature) Hypogonadism in phenotypic females
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What is the mechanism of trinucleotide-repeat mutations?
Loss of fct by transcription silencing -> repeats are in the noncoding part of the gene
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What is a coding vs non coding region?
Coding = involve CAG repeats coding for polyglutamine tracts Expansion of polyglutamine can lead to toxic gain of fct
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How are future generations impacted with fragile X syndrome?
Clinical features worsen with each successive generation
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What is gonadal mosaicism?
Patients with autosomal dominant disease have healthy parent = new mutation in egg or sperm = mutation postzygotically during early development (gametes carry mutation but somatic cells ok)
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Mechanism of PCR
Heat stable DNA polymerase, thermal cycling, target DNA (<1000bp), designed primer
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What is Sanger sequencing?
Single PCR product mixed with DNA polymerase, primer, nucleotides labeled with fluo tags = rx produce ladder of DNA molecules of all possible lengths labeled with a tag
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What is Nexgen sequencing?
PCR using primer for many different genomic regions = more Se than Sanger = identify mutations in only a small % of individual sequencing reads
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What is the single-bas primer extension?
= ID mutation in Sp nucleotide position PCR product hybridizes one base upstream of target Very Se but only 1bp of data
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What is restriction fragment length analysis?
Digestion of DNA with endonuclease Useful when mutation always occur at an invariant nucleotide position
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When to use real-time PCR?
Used to monitor the frequency of cancer cells bearing characteristic genetic lesions or infectious load of certain virus
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Use of FISH (fluorescence in situ hybridization)
Useful for numeric abnormalities of chromsomes (aneuploidy), subtle microdeletions, complex translocations
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Detection of epigenetic alterations
Treat DNA with sodium bisulfite : converts unmethylated cytosine to uracil which acts like thymine -> discriminate unmethylated DNA from methylated DNA by sequencing

Nutrition (13 decks)

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