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FOM > Exam 4 > Flashcards

Exam 4 Flashcards

1
Q

Locus

A

A segment of DNA at a specific location

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2
Q

Alleles

A

Alternative possible versions of a gene

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3
Q

Wild type

A

Single prevailing allele, present in the majority of individuals in a population

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4
Q

Variants or mutants

A

The other versions of alleles that are not wild type

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5
Q

Polymorphic alleles or polymorphisms

A

Variant alleles are said to show polymorphism which affect disease susceptibility 

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6
Q

Genotype

A

An entire set of alleles in a genome, or the set of alleles at a specific locus

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7
Q

Phenotype

A

Observable expression of a genotype as a morphological, clinical, cellular, biochemical, or other trait 

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8
Q

Homozygous and heterozygous

A

Homozygous: An individuals two alleles are functionally identical at a locus

Heterozygous: two alleles are functionally different add a locus 

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9
Q

Hemizygous

A

When an individual only has one allele of a gene

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10
Q

Compound heterozygotes

A

Individuals with two heterogeneous recessive alleles at a particular locus that can cause genetic disease

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11
Q

Pedigree

A

Graphical representation of the family tree

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12
Q

Kindred

A

Extended family

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13
Q

Proband vs consultand

A

The first affected person who is brought to clinical attention

Vs

The person who brings the phenotype to clinical attention 

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14
Q

 Mosaicism

A

 Phenotype may only be expressed in a subset of cells, typically 50-50

Ex: muscular dystrophy

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15
Q

Pure dominant

A

When both homozygous and heterozygous shown identical severity of phenotype

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16
Q

Semidominance/ Incomplete dominance

A

A disease is more severe in homozygotes compared to heterozygotes

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17
Q

Codominance

A

Two different variant alleles are expressed together

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18
Q

 Penetrance

A

The probability that a mutant gene will have any phenotypic expression— Anything less than 100% is reduced penetrance

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19
Q

Expressivity

A

The severity of expression of the phenotype among individuals with the same disease causing phenotype— Usually variable expressivity 

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20
Q

Modifier genes

A

Segregating variant alleles, distinct from the disease causing genes, can also influence penetrance and variable expressivity 

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21
Q

Neurofibromatosis (NF1)

A

NF1 is an autosomal dominant disease and is a common disease of the nervous system/eyes

 Always exert some kind of disease phenotype in heterozygotes (100% penetrance) But the severity varies greatly (Variable expressivity due to different mutations) 

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22
Q

Allelic heterogeneity

A

The occurrence of more than one allele at a locus— ex. Thalassemia

Different mutations at the same gene making it more or less severe

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23
Q

Locus heterogeneity

A

The association of more than one locus with a clinical phenotype— ex. Thalassemia from a-globin or b-globin

Different genes give the same phenotype

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24
Q

Clinical or phenotypic heterogeneity

A

The association of more than one phenotype with mutations at a single locus — ex. B-Thalassemia and sickle cell result from the same b-globin gene mutation

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25
Q

Examples for allelic heterogeneity

A

CTFR

PKU

a/b-thalassemia

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26
Q

Examples of locus heterogeneity

A

Hyperphenylalaninemias

rentinitis pigmentosa

Familial hypercholesterolemia

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27
Q

Examples of phenotypic/clinical heterogeneity

A

RET gene — Encoding receptor tyrosine kinase

• colonic ganglia, Hirschsprung disease
• Cancer of thyroid and adrenal glands
• both 

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28
Q

Hemachromatosis

A

• mutation in the HFE gene
• Sex influenced autosomal recessive disorder
• Iron overload and damage to the heart, liver, pancreas
• Reduced penetrance in women, because low iron levels, menstruation, and lower alc intake

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29
Q

Consanguinity 

A

When parents are closely related (second cousins or closer) causing autosomal recessive mutant alleles to be more prominent

Ex. Xeroderma pigmentosum

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30
Q

Inbreeding

A

Consanguinity at population-level. Individuals from a small population tend to choose their mates from within the same population— shared gene alleles from ancestors

Ex. Tay-Sachs, Ashkenazi Jews 

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31
Q

Autosomal dominant inheritance

A

• phenotype usually appears in every generation, any child of an affected parent has a 50% risk for inheriting the trait 

• exceptions include fresh mutations in a gamete of a phenotypically normal parent

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32
Q

Incomplete dominant inheritance example

A

 Achondroplasia— (dwarfism) Homozygotes tend to show a more severe phenotype

Familial hypercholesterolemia

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33
Q

New mutations in autosomal dominant disorders

A

Mutations most commonly arise in the gametes of the parents (Sperm, eggs) And the likelihood of new mutations rises dramatically with the age of the parents 

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34
Q

Male limited precocious puberty

A

Mutation in the LCGR which becomes constitutively active in the absence of its hormone ligand: puberty around age 4 

• on an autosomal chromosome

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35
Q

 Manifesting heterozygotes

A

When female heterozygotes for an X-linked recessive disease demonstrate a disease phenotype

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36
Q

Unbalanced X inactivation

A

the proportion of mutant genes expressed is significantly different than 50% (not following typical mosaicism)

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37
Q

X-linked dominant inheritance

A

 all of the daughters but none of the sons of an affected male will have the disease

 typically semi dominant— Different levels of severity

Male lethality can occur— never affected male in pedigree 

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38
Q

Y-linked dominant disorders

A

• SRY genes are important— sex determination genes
• Y-linked disorders involve infertility/reproductive abnormalities
• there is one form of male deafness associated with Y chromosome

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39
Q

Unstable repeat expansion disorders and pre-mutation alleles

A

Huntington disease, fragile X, myotonic muscular dystrophy, and Friedreich ataxia 

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40
Q

Transgenerational epigenetic inheritance

A

Non-gene based inheritance, environmental such as diet. May involve small non-coding RNAs

Changes in metabolism, susceptibility to diseases such as type two diabetes

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41
Q

Gluconeogenesis

A

The liver uses amino acids, lactate, and glycerol to produce glucose, which it exports to the blood

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42
Q

Gluconeogenesis substrates come from

A

• Anaerobic glycolysis using lactate
• muscle protein degradation (Ser, Ala)
• Lipolysis leading to glycerol

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43
Q

The key regulatory steps of glycolysis enzymes

A

Glucokinase, PFK1, pyruvate kinase (PK-L)

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44
Q

The key regulatory steps of gluconeogenesis

A

Glucose-6-phosphatase, fructose-1,6-bisphosphate, PEP carboxylase

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45
Q

Oxaloacetate and gluconeogenesis 

A

OAA —> Malate

OAA —> Asparate

^ Used to remove OAA from the mitochondria to Create PEP and CO2 from carboxykinase and GTP (PEP—> glucose after that)

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46
Q

When is malate-OAA transfer used vs Aspartate-OAA transfer?

A

Malate-OAA requires an abundance of reduced NADH (Asp-OAA doesn’t require anything) so it is used when there is a lot of NADH 

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47
Q

Oxaloacetate —PEP-CK—> PEP

A

Phosphoenolpyruvate carboxykinase (PEP-CK) is a key regulatory step in gluconeogenesis, regulated by transcription

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48
Q

Transcriptional regulation of PEP-CK

A
  1. Insulin response element (IRE)
  2. Glucocorticoid response element (GRE)
  3. Thyroid response element (TRE)
  4. Two cAMP response elements (CREI and CREII)
  5. TATA box

^^^ in that order

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49
Q

PEP-CK and steroid hormones binding its transcriptional receptors

A

1. Cortisol bunds to the GRE (agonist)

  1. Glucagon -> cAMP -> PKA -> binds CREII (agonist)
  2. Insulin prevents FOX01 binding to IRE (antagonist—inhibits PEP-CK expression)
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50
Q

 insulin and PEP-CK 

A

Insulin —> INS1 —> PI3K —> Akt (PKB) —> phosphorylates FOX01 preventing it from binding to IRE

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51
Q

TORC2 and CREB

A

when they bind they create PGC1alpha and PEP-CK expression to increase gluconeogenesis

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52
Q

Regulation of TORC2

A

AMPK (Energy sensor, AMP kinase) gets phosphorylated by LKB1, which in turn phosphorylates TORC2, preventing its nuclear localization. This prevents transcription of gluconeogenesis genes and decreases hepatic glucose production

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53
Q

PKA phosphorylation in the liver

A
  1. Inhibits pyruvate kinase in the fasted state
  2. PK phosphorylation of CREB activates transcription of PEP-CK



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54
Q

Fructose 2,6- bisphosphate as an activator/inhibitor

A

Allosterically activates PFK1, and allosterically inhibits fructose 1,6-bisphosphate (drives towards glycolysis)

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55
Q

glucose 6-phosphatase vs Glucokinase

A

g-6-p always outcompetes and sends glucose out to cells with hexokinase

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56
Q

Energetics of gluconeogenesis

A

11 high energy phosphate bonds are consumed (a lot of energy), but this is required for RBC‘s 

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57
Q

High-protein meal with no carbs

A

Insulin and glucagon both increase. Insulin promotes storage of dietary amino acids as proteins, and glucagon promotes the conversion of dietary amino acids into glucose. Blood glucose levels stay the same after eating

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58
Q

PEP-CK disorder

A

Inherited loss of function mutations that are rare. Early death, fatty liver, FTT 

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59
Q

Functions of the cell membrane

A
  1. Mechanical structure
  2. Selective permeability
  3. Transport
  4. Markers and signaling
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60
Q

Electrochemical gradient of the lipid bilayer

A
  1. e- gradient, charge not even
  2. Chemical gradient, pH not even
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61
Q

Simple diffusion

A

No ATP required, gases, hydrophobic molecules, small polar molecules

Ex. CO2, 02, Benzene, H2O, ethanol

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62
Q

Aquaporin

A

Water channel that allows the movement of larger amounts of water

They also facilitate the reabsorption of water in the kidney collecting ducts 

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63
Q

Human AQP2 and nephrogenic diabetes insipidus (NDI)

A

Disease due to kidney pathology, where APQ2 doesn’t work

APQ2 normally is single file and diffusion limited, governed by water-protein interactions

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64
Q

Facilitative transporter

A

Moves molecules from higher concentration to lower concentration by binding the desired molecule to be moved 

Transport proteins can be saturated and have a Vmax

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65
Q

Gated channels

A

• Opens both sides of the membrane simultaneously to move substrate down electrochemical gradient

• can occur selectively (Ex. Cations or anions), or gated by voltage, ligand, light, temperature

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66
Q

ligand gated Cl- channel

A

ABD and R domains—> PKA Phosphorylates R group causing confirmational change—> opening of channel and influx of Cl- out of the cell

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67
Q

Dysfunction of CFTR (Cl- ligand gated channel) leading to cystic fibrosis

A

• CFTR mutation of F508
• Secretion of Cl- in sweat is very high in CF patients  because reabsorption of Cl- is low

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68
Q

Typical ion distributions across the plasma membrane

A

• Na+ high in extracellular
• Ca2+ high in extracellular
• Cl- high in extracellular
• K+ high in cytoplasm

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69
Q

Classes of ATPases

A

P class: located on plasma membranes, or auto phosphorylated during catalysis, ex: sodium potassium pump

V class: Located in secretory vesicles like synaptosomes, Transport H+ into vesicle 

F class: located in mitochondria, ATP is formed here (think: F0 and F1 from skildum) 12 H+ —> 3 ATP

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70
Q

Sodium potassium pump

A

3 Na+ out

2 K+ in

— Regulated by ATP, phosphorylation causes confirmational change on pump

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71
Q

Secondary active transport of glucose

A

Symporter: sodium goes passively down gradient, creating energy to move glucose from low concentration—> high concentration

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72
Q

HCO3- and Cl-

A

Anti-porter: bicarbonate-chloride via AE1 pushing chlorine into the cell and bicarb out of the cell

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73
Q

Digoxin

A

Plant used to treat heart failure by inhibiting sodium potassium pump

— Causes dysfunction in the sodium potassium pump: too much intracellular Na+ leads to Na/Ca exchanger malfunction, leading to too much Ca2+ in the cell causing contractions

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74
Q

ATP binding cassette transporters (ABC transporters)

A

Increased efflux and decreased influx caused by MDR1 transport protein-1

— Commonly and cancer cells to get rid of anticancer drugs

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75
Q

Types of endocytosis

A
  1. Phagocytosis (cell eating)
  2. Pinocytosis (cell drinking)
  3. Receptor mediated endocytosis (Receptor binding to molecule you want to trigger endocytosis) 
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76
Q

Cholesterol uptake by receptor mediated endocytosis

A

ApoB-100 on LDL particle binds to receptor triggering endocytosis, LDL receptor is maintained while endosome gets degraded

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77
Q

Duchennes Muscular Dystrophy

A

Mosaic expression of x-inactivation gene

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78
Q

Hemophilia A

A

X-linked recessive disease: females are carriers, males cannot pass to sons

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79
Q

Rett Syndrome

A

X-linked dominant syndrome — male lethality (homozygous female lethality)

Symptoms: neurological, 6-18mo, spastic, ataxic, autism, seizures

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80
Q

Mutational mosaicism

A

Can occur in germlines or somatic cells. One cell mutates and spreads, not ALL cells mutated

Childhood cancers and OI

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81
Q

Mitochondrial DNA

A

• Maternally passed down

• demonstrate mosaicism by having a wide range of severity based on how many mutant mitochondria end up in the germ cells

• There is a threshold for phenotypic expression between normal and diseased

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82
Q

What type of SNP’s are important for precision medicine?

A

• actionable genetic variants

• Genomics diversity in three main categories: efficacy disrupters
1.)  polymorphisms in enzymes
2.) Drug transporters
3.) Drug targets

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83
Q

Benefits of precision medicine

A
  1. Determine individuals risks of developing certain diseases
  2. Find biological markers to aid in prevention and diagnosis
    
  3. Find the most effective therapy for different people
  4. Identify solutions to health disparities
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84
Q

Clinically actionable SNP

A

Testing for an SNP to determine drug dosing and safety

Example: 6-mercaptopurine in Acute lymphoblastic leukemia and NUDT15/TMPT mutated SNPs 

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85
Q

Homozygous deficiency in TPMT or NUDT15 change of treatment

A

Typically require 10% or less of the standard PURIXAN dose (mercaptopurine)

(ALL)

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86
Q

Heterozygous deficiency in TPMT and or NUDT15

A

Reduce the PURIXAN dose based on tolerability. Most patients with heterozygous deficiency tolerate recommended mercaptopurine doses 

(ALL)

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87
Q

Example of functional testing

A

Prior to treatment with methylene blue, patient must be tested for G6PD deficiency (more susceptible to oxidative stress, acute hemolytic anemia)

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88
Q

Pharmacogenomics

A

The study of how an individuals genetic inheritance affects the body‘s response to drugs

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89
Q

Benefits of pharmacogenomics 

A

• reduce or eliminate side effects
•  Access to targeted therapies
• Increase effectiveness of treatments
• Tailored to the individual

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90
Q

Types of genetic testing

A
  1. Functional tests (phenotype)
  2. Direct sequencing (genotype)
  3. PCR, quantitative RT-PCR, digital droplet PCR
  4. Deep sequencing (NGS) (need to confirm disease relevance with functional studies) 
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91
Q

Actionable SNP’s

A

Have actionable genetic variants, including polymorphisms in enzymes, drug transporters, and drug targets

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92
Q

Types of metabolizers

A
  1. Poor metabolizer (too slow/not at all)
  2. Extensive metabolizer (just right)
  3. Ultra rapid metabolizer (too fast)
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93
Q

Poor metabolizer

A

Has a genetic predisposition or polymorphism that blocks the metabolism of certain drugs. They may overdose on less because it cannot be metabolized

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94
Q

Ultra rapid metabolizer

A

(Rare, less than 10% of the population) they metabolize the drug too fast to gain any benefit from the medication

Erroneously labeled “drug addicts”

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95
Q

Important cytochrome P450

A

CYP3A4 metabolizes many drugs/detoxification. Located in liver and intestines

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96
Q

Genotype versus phenotype in the context of precision medicine

A

Genotype: PCR, SNP’s, Genomic variation

Phenotype: blood tests, functional tests, enzymatic expression

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97
Q

Etiology 

A

Initial causes of a disease (Genetic, environmental, chance)

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98
Q

Pathogenesis

A

How do the etiologies produce the disease? (Sequence of events)

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99
Q

Morphologic changes

A

Observable structural alterations that are characteristic of a disease (diagnostic) 

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100
Q

Clinical manifestations

A

Functional abnormalities that determine signs, symptoms, clinical course, and outcome of a disease

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101
Q

Four aspects of disease constitute the core of pathology

A

1. Etiology
2. Pathogenesis
3. Morphologic changes
4. Clinical manifestations

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102
Q

Cellular adaption

A
  1. Hypertrophy: increase in cell size
  2. Hyperplasia: increase in cell number
  3. Atrophy: decrease in cell size and/or number
  4. Metaplasia: change from one cell type to another (Particularly in endothelial cells)
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103
Q

Hypertrophy

A

Driven by increased workload, typically due to hypertension in heart, can be due to hormones (uterus)

Increase in cytoplasm size and occasionally nuclear enlargement

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104
Q

Hyperplasia

A

Driven by hormones and growth factors

Common example is endometrial hyperplasia with a larger epithelial area with more glands 

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105
Q

Metaplasia

A

Occurs as a response to chronic stress and irritation from an altered environment

• Squamous epithelium replacing columnar ciliated epithelium (smoker’s airway)

• Metaplastic bone formation in soft tissue after trauma (connective tissue)

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106
Q

Reason for metaplasia?

A

Protective in the short term, metaplasia is often at risk of development into malignancy in long-term (cancer) 

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107
Q

Atrophy

A

Decrease in both size and number of cells due to:

  1. Decreased work load
  2. Denervation
  3. Nutritional deprivation
  4. Decreased blood supply
  5. Pressure (chronic, ulcers)
  6. Loss of endocrine stimulation 
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108
Q

Hypoxia— Decreased ATP

A

Loss of activity of Ca2+ and sodium potassium pumps 

• cells swell, plasma membrane breaks
• Ca2+ Activates proteases, possible lipases, endonucleases, and DNAases
• Switch to anaerobic metabolism— lactic acid 

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109
Q

Free radical (ROS) generation

A

Causes: in redox reactions, UV light, radiation, metals, chemicals, inflammation

Results: Lipid peroxidation, DNA fragmentation, protein cross-linking 

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110
Q

Chemical injury

A

Drug or other chemical, sometimes via toxic metabolite of that drug (CYP)

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111
Q

ER UPR and DNA damage

A

Both can lead to apoptosis if severe

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112
Q

Mitochondrial dysfunction in tissue

A

Failure/abnormal oxidative phosphorylation: Depletion of ATP, generating ROS

Membrane barrier damage releases cytochrome C into cytoplasm and triggers apoptosis

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113
Q

Membrane defects

A

Mitochondrial: loss of ATP production, release of cytochrome C

Plasma membrane: influx of fluid ions, lots of critical metabolites

Lysosomal membrane: leak of lysosomal hydrolyzes in the cytoplasm and digestion of cellular components

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114
Q

Reversible cell injury

A

• Mitochondrial/cell swelling
• plasma membrane blebs (Areas pinching off)
• Nuclear chromatin clumps
• Myelin figures (Phospholipid aggregates) 

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115
Q

Irreversible cell injury

A

• plasma membrane breakdown
• Autolysis from lysosome rupture
• nuclear breakdown: Pyknosis, Karyorrhexis, karyolysis

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116
Q

Pyknosis

A

Condensation of nucleus, appears smaller and darker

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117
Q

Karyorrhexis

A

Fragmentation of the nucleus

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118
Q

Karyolysis

A

Dissolution of the nucleus. Fades and goes away, not able to see with hematoxylin stain

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119
Q

Apoptosis

A

ATP dependent cell program to death

• Minimal surrounding tissue reaction
• caspases activated (cytosolic proteases)

Histologically: deeply is eosinophilic cytoplasm and basophilic nucleus

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120
Q

Intrinsic (mitochondrial) pathway and apoptosis

A

BAX & BAK are proapoptotic and activate when p53 activates due to DNA damage. they regulate initiator caspases to kill the cell

Bcl-2 and Bcl-xL are anti-apoptotic and try to prevent cell death 

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121
Q

Extrinsic (death receptor) pathway

A

Ligand receptor interactions

• FasL binding to Fas (CD95)
• TNF binding to it’s receptor
^^ both activate caspases

• cytotoxic T cell T cell releases granzyme B and perforin into the cell 

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122
Q

Necrosis

A

Extrinsic injury causing plasma membrane damage, with leakage of cellular components

Local inflammatory tissue response (not silent to other cells like apoptosis)

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123
Q

Hypoxia versus ischemia

A

Hypoxia is decreased supply of oxygen, while ischemia is decreased blood supply which leads to hypoxia, loss of nutrients and accumulation of toxic metabolite waste

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124
Q

Reperfusion injury

A

Exacerbate injury, ROS, calcium overload, inflammation, activation of the complement system

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125
Q

Lipofuscin accumulation 

A

Wear and tear pigment, product of lipid peroxidation, seen in heart and liver, yellow brown find granules often perinuclear

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126
Q

Protein accumulations

A

Renal tubes, accumulations of fragments in cytoskeleton, defective intracellular transport, wrestle bodies

All of these look hypereosinophilic

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127
Q

Fat accumulations (steatosis)

A

Primarily liver, heart, skeletal muscle, kidney

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128
Q

Iron accumulation (hemosiderin)

A

Local excess in iron, usually hemorrhage

Systemic excess in iron, hemachromatosis

Chunky, yellow brown granules

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129
Q

Cholesterol accumulation in macrophages

A

Atherosclerosis, xanthomas, cholesterolosis, foamy cells

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130
Q

Dystrophic calcification

A

Seen in areas of necrosis, atherosclerotic plaques, aging, and damaged cardiac valves

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131
Q

 Metastatic calcification

A

Calcium deposition in normal tissue and systemic calcium is elevated

Ex. Hyperparathyroidism, renal failure, Vit D, increased bone resorption

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132
Q

Polyol pathway

A

Glucose > aldehyde > alcohol > ketone > fructose

Occurs in the eye, can increase intraocular pressure and cause Cataracts 

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133
Q

Sucrose goes to:

A

Glucose and fructose via sucrase isolmaltase

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134
Q

How is dietary fructose taken up?

A

GLUT5 in ilium

GLUT2 sometimes in liver, pancreas, and jejunum

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135
Q

Process of fructose to energy

A

Fructokinase creates Fruc-1-P

Aldolase B cleaves it into dihydroxyacetone phosphate and glyceraldehyde

Triose kinase creates glyceraldehyde 3- phosphate : glycolysis

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136
Q

How is excess fructose stored?

A

Fatty acids via pyruvate/TCA cycle/citrate

Glycogen via gluconeogenesis > glycogen synth

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137
Q

UDP-glucose

A

A common intermediate, helps with glycosylation and can be turned into UDP-galactose

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138
Q

How is galactose transported from lumen to blood?

A

GLUT2 and SGLT1 (Na+ and sugar) transporters 

Brush border enzymes lactase can also convert lactose to glucose and galactose

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139
Q

Process of galactose to energy

A

Galactokinase creating galac-1-P

galac-1-P uridyl transferase with UDP-glucose creating UDP-galactose and gluc-1-P

phosphoglucomutase creating gluc-6-P 

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140
Q

How does UDP-glucose become UDP-galactose?

A

Epimerase 

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141
Q

Nonclassical galactosemia

A

Inhibition of galactokinase.

Galactose accumulates and is converted to galactitol through polyol pathway in eyes: cataracts

Treatment: eliminate lactose from diet

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142
Q

Classical galactosemia

A

Inhibition of epimerase or galactose-1-P uridylyltransferase (serious) : FTT, jaundice, hypoglycemia

Treatment: eliminate galactose from diet, prognosis is poor

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143
Q

Products of the pentose phosphate pathway

A

Reduced NADPH and a five carbon sugar. Used for antioxidant defense, and nucleotide biosynthesis

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144
Q

The oxidative phase of the pentose phosphate pathway

A

Creating 2 NADPH, CO2, and ribulose 5-phosphate

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145
Q

The nonoxidative/regenerative  phase of the pentose phosphate pathway

A

Creating xylulose 5-phosphate —> ribulose 5-phosphate —> ribose 5-P —> nucleotide biosynthesis 

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146
Q

Glutathione

A

Tripeptide: glutamate, cysteine, glycine

Purpose: Neutralizes ROS by creating disulfide bonds

NADPH maintains glutathione in the reduced to state (reduced= GSH, oxidized= GSSG)

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147
Q

Transketolase

A

Transfers two carbon groups

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148
Q

Transaldolase

A

Transfers three carbon groups (6–>3+3)

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149
Q

ChREBP

A

Carbohydrate response element binding protein

A transcription factor which is inhibited by phosphorylation by PKA & AMPK 

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150
Q

Xylulose 5-P and ChREBP

A

X5P acts as an allosteric activator of PP2A, which removes the inhibitory phosphate allowing for a translocation of ChREBP to nucleus 

Essentially, X5P promotes transcription of genes that convert carbs to fat

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151
Q

Genes that are upregulated by ChREBP

A

— pyruvate kinase
— malic enzyme
— Citrate lyase
— Acetyl-CoA carboxylase
— Fatty acid synthase

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152
Q

Essential fructosuria

A

Inherited loss of function mutations in fructokinase. Benign, may cause false positive dipstick urine tests for diabetes

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153
Q

Hereditary fructose intolerance

A

Inherited mutations in aldolase B. Much more serious, build up of fruc-1-P with no metabolic fate

This traps all of the cells phosphates, and ATP synthesis is impaired

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154
Q

Lactase deficiency

A

Dietary lactose is not broken down to monosaccharides in the small intestine. Gut bacteria ferments lactose into lactic acid and water enters the lumen of the gut to offset the increase lactate and proton concentration.

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155
Q

Three types of lactase deficiency

A

Primary: autosomal recessive, lactase activity declines over many years

Secondary: damage of brush border of intestinal enterocytes due to intestinal disease

Congenital lactase deficiency: complete absence of lactase

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156
Q

Uridine diphosphate galactose 4-epimerase deficiency 

A

The treatment is to restrict, but not eliminate galactose from the diet because we need UDP galactose for glycosylation reactions and can only get it from the diet

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157
Q

G6PD deficiency

A

X-linked trait, their capacity to regenerate NADPH through the pentose phosphate pathway is limited causing severe ROS rxn.

Acute hemolytic anemia (think: sulfonamides)

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158
Q

Warfarin

A

Rate of elimination is independent of dose, zero order/nonlinear kinetics, Low therapeutic index, causes many adverse drug reactions, weak acid

Oral anticoagulant that decreases concentrations of vitamin K-dependent clotting factors

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159
Q

Two enantiomers of warfarin

A

S: Active, CYP2C9

R: Less active, CYP3A4, CYP2C19, CYP1A2

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160
Q

VKORC1 polymorphism and warfarin

A

PD: A mutation (G WT)

Reduction vitamin K —> increase in warfarin activity

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161
Q

CYP2C9 and warfarin

A

PK: *2, *3 mutations

Lowered metabolism elimination —> increase in warfarin activity

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162
Q

Antacids and warfarin

A

PK

Less absorption (ion trapping) —> less warfarin activity

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163
Q

Salads (greens) and warfarin

A

PD:

increase/decrease absorption Vit K, —> increase/decrease warfarin activity

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164
Q

Aspirin and warfarin

A

PK: lowered plasma binding protein —> increased warfarin

PD: antiplatlet —> increased warfarin activity

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165
Q

Glipizide and warfarin

A

PK:

Substrate of CYP2C9 lowers metabolism elimination —> increased warfarin

Decreased PPB —> increased warfarin

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166
Q

Cimetidine and warfarin

A

PK: inhibitor CYP2C9 decreasing metabolism elimination —> increase warfarin activity

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167
Q

Rifampin and warfarin

A

PK: inducer of CYP2C9 increasing metabolism elimination —> decreased warfarin activity

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168
Q

Four types of enzyme-linked receptors

A
  1. Receptors that are Tyrosine kinases

2. receptors that recruit tyrosine kinases

  1. Receptors that are serine-threonine kinases
  2. Receptor guanylyl cyclases 
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169
Q

Activation of RTKs (receptor tyrosine kinases)

A

Ligand binding dimerizes or oligomerizes RTKs

Relayed along:
1. PLC — Ca2+/PKC
2. Ras/Rho — MAPK

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170
Q

Ligands can be what?

A
  1. Monomers or multimers
  2. Arrayed on proteoglycans of the ECM or other transmembrane proteins

3. Other transmembrane proteins (like ephrins)

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171
Q

RTKs do what after binding ligands?

A

Autophosphorylate themselves In order to further increase their Kinase activity, and serve as docking sites

172
Q

Which phosphatidylinositol cannot be cleaved into IP3 and DAG by PLC?

A

PI(3,4,5)P3

It instead serves as an anchor point for the assembly of other signaling platforms

173
Q

PTEN

A

Phosphatase that converts PI(3,4,5)P3 back into PI(4,5)P2

it is an important inhibitor of PI(3,4,5)P3 associated signaling platforms

174
Q

RTK and Ras—MAPK

A

RTK -> GEFs of Ras -> Ras activation -> MAPK pathway (serine threonine kinase cascade) -> cell proliferation or differentiation gene expression (important for cancer)

175
Q

ERK1/2 and ERK5

A

Growth factors, hormones, Ras

Growth, survival, differentiation, development

ERK5 is similar, can be acted on by stress

176
Q

p38

A

Inflammatory cytokines and stress (Rho)

Inflammation, apoptosis, growth, differentiation 

177
Q

JNK

A

Cell and environmental stress (Rac)

Inflammation, apoptosis, growth, differentiation

178
Q

RTK and PI 3-kinase — PKB/Akt

A

Binding of growth and survival factors to RTK‘s can turn on PI3K which can lead to the phosphorylation and activation of PKB/Akt which can activate a number of targets with pro-survival and growth functions

179
Q

mTOR signaling pathway integrates:

A

A serine threonine kinase that functions in dual complexes, and integrates: metabolic status and growth control

• Growth factors
• Energy status
• Oxygen
• Amino acids

180
Q

mTOR signaling pathway regulates:

A

Cell survival and growth processes:

• angiogenesis
• Cell growth
• nutrient uptake and utilization
• Metabolism
• Cytoskeletal organization

181
Q

GPCR signaling:

A

• adenylate cyclase (cAMP/PKA)
• Phospholipase C (Ca2+ and PKC)
• Rho monomeric G proteins (cytoskeleton & MAPK)

182
Q

RTK signaling:

A

• PI3-K (PKB/Akt)
• Phospholipase C (Ca2+ and PKC)
• Ras and Rho g-proteins (MAPK and cytoskeleton) 

183
Q

Receptors that recruit tyrosine kinases

A

Integrins: FAK and Src

Many: Src

Cytokine receptors: Jak

184
Q

Integrins, FAK, and Src 

A

Associated with focal adhesions to modulate numerous signaling pathways

185
Q

Src tyrosine kinase activity activated by:

A

It’s unfolding after the binding of a ligand to its SH2 and or SH3 domain

SH2: Autophosphorylation ligand
SH3: Proline motif on beta-arrestin bound to the receptor

186
Q

Cytokine receptors and Jak-STAT

A

• Responds to cytokines and hormones promoting Jak, which auto phosphorylates to increase its activity and then phosphorylate the receptor
• STAT proteins bind to the receptors, and are also phosphorylated by Jak
• STAT moves into the nucleus where it can turn on target genes 

187
Q

TGF-beta: serine-threonine kinases

A

Transforming growth factor beta: Super family of signaling molecules (TGF-b, activins, BMPs)

They regulate the number of processes required for cell function by phosphorylating SMAD

188
Q

Receptors that are guanylyl cyclases 

A

Single pass transmembrane proteins with extracellular binding site for signal molecule and an intracellular guanylyl cyclase catalytic domain

• bind ANP/AMP ligands-> cyclase domain -> cGMP-dependent serine-threonine kinases and PKG
• intracellular mediator

189
Q

NPR-A

A

ANP/BNP

• regulate salt and water balance, stimulates the kidneys to secrete sodium and water, induces the smooth muscle cells in the blood vessel walls to relax
^^^ lower blood pressure 

190
Q

Four major signaling pathways are associated with proteolytic events:

A
  1. Notch
  2. Wnt
  3. Hedgehog
  4. NF-kB
191
Q

Notch

A

• signaling pathway in early development
• Delta and jagged ligands bind and trigger proteolysis of notch on both sides of the plasma membrane (let’s tail enter cytosol)
^^^ transcription regulator

192
Q

Wnt of Frizzled family

A

• secreted signal molecules that act as a local mediators to control development
• Associated with colorectal cancer
• They signal through Dvl (disheveled)


193
Q

Frizzled family

A

Seven pass transmembrane proteins, which are atypical members of the GPCR family

194
Q

In the absence of Wnt

A

Protein degradation of beta-catenin

195
Q

In the presence of Wnt

A

Wnt binding couples and activates frizzled-LRP Which binds and activates disheveled (Dvl)

• this inhibits the degradation complex of beta-catenins, so they can move into the nucleus and displace repressor proteins to activate Wnt via TCF/Lef1 

196
Q

Hedgehog signaling

A

Patched(Ptch1) and smoothened(SMO) release signals from hedgehog to GLI to influence cell proliferation


197
Q

Dysfunction of hedgehog signaling can give rise to:

A

Cyclopia

198
Q

Absence of hedgehog

A

Patched inhibits smoothened, GLI is phosphorylated and partially cleaved, fragment moves into nucleus and access repressor of hedgehog

199
Q

Presence of hedgehog

A

HH binding to patched blocks inhibition of SMO, allowing full length GLI to move into nucleus and activate hedgehog target gene transcription

Occurs near primary cilium 

200
Q

NF-kB

A

Gene regulatory proteins that play major roles in stress and inflammation

IkB: Inhibitory protein

201
Q

Nuclear hormone receptor parts

A

A/B: Active domain

C: DNA binding domain

D: Hinge domain

E/F: Ligand binding domain

202
Q

Broad behaviors of NRs

A

Steroid hormone receptors in the cytoplasm

Retinoid/thyroid/vitamin D receptors in nuclei

Orphan receptors: unknown

203
Q

NO mediated vasodilation

A

Cooperative event involving endothelial cells and the surrounding smooth muscle cells

IP3 -> Ca2+ -> calmodulin -> NO synthase -> NO -> guanylyl cyclase -> cyclic AMP -> PKG -> muscle relaxation

204
Q

Neuronal nitric oxide synthase

A

• Long-term potentiation
• Cardiac function
• Peristalsis
• Sexual arousal

205
Q

Endothelial nitric oxide synthase

A

• vascular tone
• Insulin secretion
• Airway tone
• Regulation of cardiac function and angiogenesis
• Embryonic heart development

206
Q

Inducible nitric oxide synthase

A

• in response to attack by parasites, bacterial infection, tumor growth
• Causes septic shock, autoimmune conditions

207
Q

Nitrodilators

A

Drugs that mimic the actions of endogenous NO by releasing NO or forming it within tissues. These drugs act on the vascular smooth muscle to cause relaxation

Endothelial independent vasodilators

208
Q

Gap junctions

A

Connexons Which are hexameric hemi-channels composed of protein connexin

Regulated to open or close the passage between cells

209
Q

Malfunction in gap junctions

A

Heart arrhythmias

210
Q

Pleiotropy

A

Phenotypic expression can create a wide range of issues, differentiation 

211
Q

Fructose 1,6-bisphosphatase deficiency:

A

Autosomal recessive disorder exacerbated by metabolic stress, injury, and infection

Liver reverts to glycogenolysis for energy

212
Q

PEP carboxykinase deficiency

A

RARE. Early death, fatty liver, infant death

213
Q

Transcriptional regulation of lipogenesis

A
  1. ChoRE: bunds ChREBP from glucose
  2. LXRE
  3. SRE: binds SREBP1C from insulin
  4. E-Box: binds BAF60C from insulin

= lipogenesis (in that order)

214
Q

Polymorphic chromosomal markers

A

• markers that can distinguish between individuals and between carriers and non-carriers of a disease gene
• Used to detect, map, clone
• Most common markers are “DNA sequence variants”

215
Q

Using polymorphisms in human and medical genetics

A

Researching a particular region of a chromosome, prenatal diagnosis of genetic disease, forensic applications, and genomics-based personalized medicine

216
Q

Indel

A

And insertion or deletion of a nucleotide base

217
Q

Restriction fragment length polymorphism (RFLP) 

A

• allelic variant that abolishes or generates a restriction endonuclease recognition site or changes the size of an RFLP
• biomarker, not the cause of a dysfunctional gene

218
Q

Variable number of tandem repeats VNTR/ Simple sequence length polymorphism’s SSLP’s

A

Tandem repeats, polymorphic in size between chromosomes and individuals, can be used as genomic markers

• Analyzed by PCR

219
Q

Single nucleotide polymorphisms (SNPs)

A

• Single base substitution, insertion, deletion
• Detected by sequencing a particular region from different individuals who may have polymorphisms
• True SNP must have at least 1% frequency 

220
Q

Haplotypes

A

Haploid genotypes, can be any combination of alleles, loci, or markers on the same chromosome but commonly refers to groups of nearby alleles or markers on a chromosome that are inherited together

• Haplotype blocks are large sets of SNPs that are co-segregating in the human population (created haplotype maps) 

221
Q

Haplotype size determining ancestry

A

A larger haplotype block suggests that the particular alleles arose relatively recently in human history

222
Q

Prader Willi syndrome

A

• PW gene is maternally imprinted. When a deletion or other mutation occurs in the expressed allele no PW gene product is made and thus the result is the syndrome
• snoRNA (SNORD116) mutation

223
Q

Angelman syndrome

A

• AS gene is paternally imprinted. When a deletion or other mutation occurs in the expressed allele, no AS gene product is made and thus the result is the syndrome
• UBE3A mutation

224
Q

Three molecular genetics subtypes of PWS

A

— 65-75% of PWS is caused by paternal 15q11-q13 deletions

— 20-30% of PWS is caused by maternal uniparental disomy 15

— 1-3% of PWS is caused by an imprinting defect

Phenotype is likely due to Hypothalamic dysfunction

225
Q

Uniparental disomy (UPD)

A

Occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent

226
Q

Clinical cytogenics

A

The study of chromosomes, their structure and their inheritance, as applied to medical genetics

227
Q

Karyotyping

A

To detect a chromosomal abnormality, one can start with large defects visible on whole chromosomes :all 46 chromosomes 

228
Q

How do we identify chromosomes?

A
  1. Banding
  2. Centromeric position
  3. Size
  4. Morphology
  5. Chromosome markers
229
Q

Metacentric

A

Central centromere and equal size arms (normal) 

230
Q

Submetacentric

A

Off-center centromere and different size arms

231
Q

Acrocentric

A

Centromere near one end, creates satellites connected to the centromere by a stalk 

232
Q

Telocentric

A

Single arm, only in mice

233
Q

FISH

A

• molecular cytogenetics
• Multi-chromatic fluorescent probes can target chromosomes, chromosome regions, or genes 
• combinations of FISH probes= Spectral karyotyping/SKY 

234
Q

The four phases of the cell cycle

A

G1, S (DNA synth), G2, M (mitosis)

235
Q

Mitosis: prophase

A

• Replicated daughter centrosomes move apart
• Chromosomes begin to condense
• Nuclear envelope breaks down

236
Q

Mitosis: prometaphase

A

• bipolar spindle becomes apparent
• Microtubules attach to kinetochores
• Chromosome/nuclear events continue

237
Q

Mitosis: metaphase

A

• Maximally condensed chromosomes align on a disk like plate

238
Q

Mitosis: anaphase

A

• daughter chromosomes separate and begin to move apart, toward opposite spindle poles

239
Q

Mitosis: telophase

A

• plasma membrane begins to constrict around the spindle midline via contractile actin and myosin pinching
• Chromosomes begin to decondense
• Nuclear envelope begins to reform

240
Q

Mitosis: cytokinesis

A

•Cell pinches into two daughter cells

241
Q

Condensin and cohesin complexes

A

Related complex is composed of SMC and associated proteins

Cohesins: Encompass adjacent daughter chromatids so that they remain attached to each other throughout G2, prophase, prometaphase, and metaphase (proteolyzed at the onset of anaphase)

Condensin: Activate it in prophase, causes chromosome compaction

242
Q

The centrosome cycle

A
  1. Grow in G2 — daughter centrioles
  2. Split and move apart to form spindle poles in M-phase
    ^^ microtubule driven, Kinesins and Dyneins
243
Q

Nuclear envelope breakdown and reformation

A

• Lamin filaments phosphorylated by CDK1, causing them to depolarize— nuclear envelope vesiculates and scatters throughout cytoplasm

• Dephosphorylation of lamin, Envelope vesicles and Lamins aggregate around the chromatin of each daughter cell. Begin fusion and reform nuclear envelope

244
Q

Spindle microtubules include:

A

• kinetochore microtubules: opposite directions
• interpolation microtubules: overlap and interact, affects spindle pole distances
• astral microtubules: migrate away from spindles

245
Q

Kinetochore

A

A complex of proteins that assembles on centromeric DNA

Functions:
• attachment points for spindle microtubules
• Sensing alignment of chromosomes in metaphase
• Separation of daughter chromosomes in anaphase

246
Q

What is a kinetochore made of?

A

• CENP-A: A specialized histone that defines centromeric chromatin and mediates binding of kinetochores to DNA
• linkers to microtubules
• Microtubule motor proteins
• Sensors and signaling proteins— responsive to binding + tension 

247
Q

Chromosomes aligning on a metaphase plate

A

• kinesins push chromosomes away from spindle poles
• microtubule depolymerization at the kinetochore pulls chromosomes toward poles
• Microtubule flux, tubulin subunits are removed at the (-) end, pulls microtubules and attached chromosomes toward poles

248
Q

Separation of daughter chromatids in anaphase

A

APC/C Induces proteolysis of securin, activating separase, which proteolyzes shugoshin and cohesin at the centromere region, allowing the pulling forces of the spindle to begin separation of daughter chromatids

249
Q

How is APC/C activated?

A

At the metaphase-anaphase transition by association with Cdc20 — Tags securin for destruction

250
Q

Anaphase A/anaphase B

A

A: Pulling force is separating sister chromatids (towards separate poles)

B: pushing of spindle poles farther apart by interpolar microtubules

251
Q

Cytokinesis

A

• A central spindle assembly forms at the overlap of interpolar and astral microtubules (Recruits and activates Ect2, a GEF for RhoA)

• Activated RhoA reorganizes actin microfilaments to form a contractile ring— pinching cell into two daughter cells

252
Q

Monopolar spindle assembly (defects)

A

Causes defects in centrosomal proteins (tubulin), microtubule motor proteins, kinase dependent effects

253
Q

Multipolar spindle assembly— Centrosome amplification

A

• cytokinesis failure from previous division cycle
• Mitotic slippage— checkpoint bypass
• centrioles over duplication, fragmentation, or fusion
• cell-cell fusion 

254
Q

Major cell cycle driver reactions

A
  1. Phosphorylation/dephosphorylation
  2. Regulated proteolysis— Irreversible
255
Q

Cyclin dependent kinases (CDKs)

A

Kinase family that phosphorylates numerous cell targets— Denoted by numbers

Regulated by:
• Cyclins
• Activating and inhibitory kinases and phosphatases
• CKIs 

256
Q

Cyclins

A

A family of regulatory proteins that help control CDK activity— Denoted by letters

• Different Cyclins function in different stages of the cell cycle
• influence CDK substrate specificity

257
Q

Cyclin-dependent kinase inhibitors (CKIs)

A

”brakes” for CDK

• proteins that can inhibit CDK activity
• Can have complex regulatory roles

258
Q

Different cyclins/CDKs and cell cycle stages 

A

G1: cyclin D, CDK4/6

G1/S: cyclin E, CDK2

S: cyclin A, CDK2/1

M: cyclin B, CDK1

259
Q

Cell division decisions based off of environmental effectors

A

• growth factors (Enzyme linked receptors)

• Hormones (G protein coupled receptors)

• Contact signaling (integrins, integrin-linked kinases)

• Stress (DNA damage, p53)

260
Q

The targets of M-Cdk include:

A
  1. Condensins
  2. Centrosomal proteins
  3. Nuclear pore complexes and lamins
  4. Proteins associated with Golgi and ER, promoting their fragmentation
  5. APC/C: a ubiquitin ligase
261
Q

Two crucial proteosomal targets of APC/C

A
  1. Securin : Initiate anaphase
  2. Mitotic cyclins : Negative feedback loop where M-Cdk leads to its own inactivation via activation of APC/C
262
Q

How to achieve mitotic exit:

A

Destruction of cyclins abolishes CDK activity, this is necessary to reset the cell so another cycle can be initiated if conditions are appropriate

— Low cyclin needed for helicase loading in order to lyse another round of division

263
Q

Why does proteolysis provide directionality?

A

It is irreversible, so it prevents the cycle from going backwards.

Proteolysis facilitates:
1.) entry into the S phase by destruction of CKI
2.) onset of anaphase by destruction of securins
3.) mitotic exit by destruction of cyclin B

264
Q

p53

A

• heavily involved in cell checkpoints throughout the cycle, tumor supressor gene — p53 limits its own quantity by upregulating Mdm2: ubiquination ligase that targets p53 (neg feedback)

1.) Upregulates CKI to hold the cycle progression to allow DNA repair

2.) Upregulates Bax (proapoptotic) if DNA damage unrepairable

265
Q

DNA damage leading to p53 activation and p21 inhibition of CDK activity

A

Damage -> ATM/ATRK -> Chk1/2 -> phosphorylates p53 increasing free amount (not bound to Mdm2) -> increase CKIs -> cell arrest to fix damage -> BAX -> apoptosis

266
Q

Bub/MAD2: Spindle assembly checkpoint

A

Inhibits APC/C blocking anaphase initiation and mitotic exit, so cohesions cannot release from one another, makes the cell “stuck” until alignment is completed

267
Q

Oncogenes

A

“Gas”

stimulate proliferation of cell division

268
Q

Tumor suppressor genes

A

“Brakes”

Inhibits proliferation in cell division

269
Q

Growth factor signaling

A

Growth factor, RTK, G proteins, ERK MAPK —> signals immediate/early response genes

Second wave: delayed response genes, Cyclone D, CDK4/6, pRb/EZF, DNA proteins made (cyclin E, cyclin A), S phase and division begins

270
Q

What drives cells into M phase?

A

Cyclin B binding to CDK1, but it is phosphorylated at both activating and inhibitory sites by CAK and Wee1 — low activity

Removal of inhibitory phosphate by Cdc25 activates CDK1 

CAK activates, Wee1 inhibits M phase

271
Q

Three key cofactors for enzymes in amino acid metabolism:

A
  1. Pyridoxal phosphate (PLP) B6
    — Transamination, deamination, carbon chain transfers
  2. Tetrahydrofolate (FH4) folic acid
    — One carbon transfers
  3. Tetrahydrobiopterin (BH4)
    — Ring hydroxylation’s, redox cofactor, used for Phe —> Tyr 
272
Q

Essential amino acids, required from the diet:

A

M. V. Pitthall

Methionine, valine, phenylalanine, isoleucyl, tryptophan, threonine, histidine, arginine*, leucine, lysine

273
Q

Amino acids produced from glycolytic intermediates

A

Alanine via pyruvate

Serine via 3-phosphoglycerate

Cysteine and glycine via serine 

274
Q

Amino acids derived from the TCA cycle intermediate

A

From alpha-ketoglutarate:
1. Glutamate
2. Glutamine
3. Arginine
4. Proline

From oxaloacetate:
1. Aspartate
2. Asparagine

275
Q

Two ways glutamate can be produced from alpha-ketoglutarate:

A

1.) oxidative deamination by glutamate dehydrogenase using NADP and creating NADPH and ammonium

2.) Transamination by aspartate aminotransferase

276
Q

Amino acids can be degraded into TCA cycle intermediate and ketone bodies 

A

K. L. WIFTY

G. SCAWT

277
Q

Branched chain amino acids

A

Valine, isoleucine, leucine 

278
Q

Rate limiting step in branched chain amino acid degradation

A

Branched chain alpha-keto acid dehydrogenase

This enzyme has a similar organization to PDH:
E1: decarboxylation, TPP
E2: acyl transferase, Lipoate & CoA
E3: redox FAD and NAD+

279
Q

Degradation of phenylalanine

A

The first step is synthesis of tyrosine, phenylalanine hydroxylase hydroxylates the ring of Phe, which requires BH4 as redox cofactor

280
Q

Cysteine vs. cystine

A

Cystine is two cysteines creating a disulfide bond— this is the oxidized form of cysteine and is hydrophobic 

281
Q

Cystinuria

A

Inherited autosomal recessive disorder in the amino acid carrier for cysteine and basic amino acids (Lys, Arg, Orthinine)

• Causes cysteine kidney stones
• Type A transporter: SLC3A1
• Type B transporter: SLC7A9

282
Q

Maple syrup urine disease MSUD

A

Loss of function in the E1 subunits of branched chain alpha-keto acid dehydrogenase— no oxidative decarboxylation

 symptoms: convulsions, vomiting, maple syrup odor in urine

Labs: elevated plasma and urine Val, iso, leu, and keto acids

Treatment: BCAA diet

283
Q

Classic MSUD

A

Complete loss of enzymatic activity: need branched chain AA free diet

284
Q

Intermittent and mild MSUD

A

Some residual enzymatic activity, treated with oral thiamine (B1) to have cofactor in surplus

285
Q

Familial autism and seizures

A

Unregulated catabolism of branched chain AAs, mutations were found in BCKDK

Treatment: high BCAA diet — However, not the best treatment because BCAA metabolism causes ROS (shouldn’t oversupply the problem just to maintain BCAA synthesis in body)

286
Q

Phenylketonuria PKU

A

Defect in phenylalanine hydroxylase, prevents tyrosine biosynthesis. Instead, creates phenyllactate (toxic intermediate)

Symptoms: seizures, cognitive delay, light complexion, mousy odor
Diagnosis: newborn screening
Treatment: Phe restricted diet

287
Q

What does excess phenylalanine do to large neutral amino acid transporters?

A

Acts as a competitive inhibitor, decreasing tyrosine and tryptophan intake and use

• impaired melanin/myelin/protein synthesis
• Impaired glucose metabolism
• Amyloid- like plaque formation
• oxidative stress damage
• Epigenetic alterations

288
Q

Nonclassical PKU

A

Defects in tetrahydrobiopterin Metabolism, dihydropyridine reductase can mimic PKU

Phenylalanine restricted diet— restrict toxicity, but you need Phe for protein synthesis

289
Q

Tyrosinemia type I

A

Loss of function mutation of fumaryloacetoacetate hydrolase (FAH) Resulting in accumulation of succinylacetone leading to liver failure. Most severe

Diagnosis: succinylacetone in blood and urine

Treatment: Nitosinone: slows catabolism of tyrosine

290
Q

Tyrosinemia type II

A

Increased levels of Tyrosine, mutation of tyrosine aminotransferase (Normally clips off amine group)

Diagnosis: patient develops plaques on the hands and feet, corneal ulcers, and mental delays
Treatment: synthetic diet low in Phe and Tyr

291
Q

Tyrosinemia type III

A

Loss of function mutation in the 4-hydroxyphenylpyruvate dioxygenase

Symptoms: intellectual disability, seizures, intermittent ataxia. Rarest and severe

292
Q

Alcaptonuria

A

Deficiency in homogentisate oxidase Leading to dark colored urine, ochronosis, and homogentistic acid in urine

Diagnosis: Patients are asymptomatic until middle age, when they develop arthritis, back pain, renal calculi

293
Q

Uses of serine

A

1.) donation of one carbon to tetrahydrofolate (FH4)

2.) converted to pyruvate

3.) protein synthesis (storage)

294
Q

Excess glycine is converted to:

A

Glyoxylate through transaminatjon or oxidative deamination. Metabolites of this can be oxidized to CO2 or excreted in urine

295
Q

What pathway involves tandem receptors associated with primary cilia?

A

Hedgehog signaling

296
Q

What pathway involves the proteolytic release of the cytoplasmic tail of a transmembrane receptor tail, which then migrates into the nucleus to regulate genes involved with lateral inhibition or cooperatively between neighboring cells?

A

Notch signaling

297
Q

What pathway is associated with small, hydrophobic signaling molecules that can trigger multiple waves of gene expression responses?

A

Nuclear hormone signaling

298
Q

What pathway is associated with enhancing protein kinase G activity through phosphodiesterase inhibition?

A

NO signaling

299
Q

What signaling pathway leads to polyp formation and increased risk of colorectal cancer when the function of a proteolysis inducing complex that includes the APC protein is compromised?

A

Wnt signaling

300
Q

What pathway is associated with inflammation and stress, and is activated by TNF signaling?

A

NF-kB signaling

301
Q

The two positive feedback loops that result in a switch-like activation of cyclin B — CDK1 (M-cyclin/CDK) involve:

A

Activation of CDC25 phosphatase and inhibition of Wee1 kinase

302
Q

What stage of cell cycle (decision of a cell to commit to division or leave the cycle) impacted by growth factors, contact signaling, and stress?

A

G1

303
Q

What situation would lead to active Bub/MAD signaling metaphase arrest?

A

Kinetochores unattached to microtubules in M-phase

304
Q

Which protein is upregulated by p53 and binds to cyclin-CDK complexes to inhibit their activity?

A

The CKI p21

305
Q

A loss of function mutation in which protein could potentially lead to unregulated cell division and cancer promotion?

A

p53

306
Q

Specialized chromosomal region required for the accurate segregation of a replicated pair of chromatids among daughter cells

A

Kintechores (line up on metaphase plate)

307
Q

What pathway is an important transducer of cytokine signaling, and involves the recruitment of tyrosine kinases when activated?

A

JAK-STAT pathway

308
Q

What pathway involves phosphorylation of an inositol phospholipid followed by activation of kinases that promote self survival?

A

PI3K-protein kinase B/AKT pathway

309
Q

What pathway includes a large family of ligands that bind and activate receptors with serine- threonine kinase activity?

A

TGF-beta / SMAD pathway

310
Q

What pathway is known to encompass multiple parallel pathways, each consisting of three kinase cascades that are important regulators of cell proliferation, differentiation, and stress response?

A

MAP kinase pathway

311
Q

What pathway regulates salt and water balance through the activation of protein kinase G?

A

Natriuretic peptide/ cGMP pathway

312
Q

What pathway functions to integrate metabolic status with growth control?

A

mTOR pathway

313
Q

Spectral (waveform) Doppler

A

Used to measure velocity of blood flow by frequency shift of the echoes

• Pulse wave: Used for cardiac, exact spot sampling is viewed

• continuous wave: all RBCs in entire spectrum viewed (mitral valve stenosis) 

314
Q

Doppler

A

Shows estimate blood flow moving through veins and arteries using sound waves

Remember: cos (90)=0, hold parallel

Colorful Doppler: blue is flow away from the probe, red/orange is flow towards the probe

315
Q

M-mode

A

Time motion display of ultrasound wave along Chodron ultrasound line. Mono dimensional view displayed along an axis (heart)

316
Q

B – mode

A

Two dimensional image display composed of bright dots representing the ultrasound echoes

• Perpendicular probe is best

15-60fps, 60=cardiac, 15=abdominal

317
Q

Piezoelectric crystals

A

Converts kinetic/mechanical energy into electrical energy which could be interpreted by the ultrasound machine and appear as light in a picture

318
Q

Temporal resolution

A

The frame rate fps, Anything >40 is not distinguishable by the human eye

319
Q

When using a Doppler:

A

High PRF: talks more, listens less: use in a high flow areas such as the carotid where delicate hearing is not necessary

Low PRF: Listens more, more sensitive: use in low flow areas such as the testicles

320
Q

Artifacts in ultrasound

A

1.) High attenuation
2.) low attenuation
3.) gas scatter
4.) refraction
5.)  reverb
6.) Mirror image

321
Q

High attenuation

A

dense objects produce white picture, with a shadow

322
Q

Low attenuation

A

creates echo enhancement posteriorly, used as a window to visualize anatomy

323
Q

Gas scatter

A

bowel gas, must push through it to overcome it

324
Q

Refraction

A

sound gets redirected creating an edge artifact/lateral cystic shattering

325
Q

Reverb

A

equidistant arcs that come from the top of the transducer

326
Q

Mirror image

A

sound glances off diaphragm, returning to probe with a longer flight time. Typically interpreted as more liver seen in the chest (good, means chest is dry)

327
Q

Echogenicity of the body

A

• Cortex of the kidney is slightly less echogenic than the liver
• diaphragm is most echogenic, Followed by the kidney/renal pelvis, liver parenchymal, renal cortex, and hepatic vein (Basically anechoic from blood) 

328
Q

Adjusting depth and gain

A

Always adjust depth first— CCW is shallower, CW is deeper

Gain is adjusted with an AO knob and sliders

329
Q

Different arrays

A

1.) convex array: sometimes called large footprint curve

2.) Phased array: also known as cardiac transducer, single crystal, wide array however what is in the center is seen the best

3.) Linear array: no splaying, good for superficial what you see is what you get, also called the vascular probe

330
Q

Change in chromosome structure

A

Balanced: results in the same amount of genetic material, may or may not result in phenotype

Unbalanced: usually leads to a clinical phenotype due to inappropriate gene dosage

331
Q

BCR – ABL Philadelphia chromosome

A

Chronic Myelogenous leukemia CML, caused by 9 and 22 reciprocal translocation. This translocation is specific for hematopoietic cancers because expression is driven by B-cell receptor promoters

332
Q

Abnormal chromosome segregation caused by nondisjunction

A

Aneuploidy (down syndrome, Klinefelter syndrome), Uniparental disomy 

333
Q

Down syndrome

A

Trisomy 21, most common chromosomal birth defect, increased risk to 1 out of 15 in women over 45, eightfold risk of recurrence if you have a downs child already, disease likely caused by increased gene dosage

334
Q

Sex linked disorders

A

• Trisomy X (females)
• Klinefelter syndrome (second x in males)
• Turner syndrome (x deletion— hemizygous)

335
Q

Amniocentesis

A

Invasive technique, removal of amniotic fluid transabdominally by syringe, fetal cells are cultured for diagnostic tests

Most common in the United States

336
Q

Cordocentesis

A

Invasive technique, removal of fetal blood from the umbilical cord, more often used when the other methods have failed or are ambiguous

337
Q

Chorionic villus sampling (CVS)

A

Invasive technique, biopsy of tissue from the villous area of the chorion, can occur 4 to 5 weeks before amniocentesis— earlier read out

More common in Europe

338
Q

Noninvasive techniques

A

• maternal serum screening
• Ultrasound
• Radiography
• MRI
• NSG/deep sequencing

339
Q

First and second trimester screening for trisomy 21

A

• increased nuchal translucency
• decreased PAPP-A
• Increased free beta hCG
• decreased uE3
• Decreased AFP
• Increased hCG
• Increased inhibin A

340
Q

First and second trimester screening for neural tube defects

A

Significant increase in AFP in second trimester

341
Q

Ultrasound is used to determine:

A

Fetal age, sex, gross abnormalities, and viability

342
Q

Ultrasonic indicator of trisomy 21

A

Nuchal translucency (neck thickness) is increased greatly and can be detected at 10 to 14 weeks

343
Q

Ultrasonic detection of neural tube defect such as spina bifida

A

Meningomyelocele sac protruding through the skin

344
Q

Genetic testing: carrier detection

A

Heterozygote screening

tested by clinical manifestation in the carrier, biochemical abnormality, and DNA analysis

345
Q

Categories of genetic tests

A
  1. Carrier detection
  2. Pre-symptomatic diagnosis
  3. Prenatal and newborn testing and diagnosis
346
Q

Examples of biochemical abnormalities in heterozygous carrier detection

A

Tay-Sachs: hydrolase enzyme activity

DMD female carriers: Serum creatine kinase levels

347
Q

Examples of using pre-symptomatic genetic testing

A
  1. Huntington disease
  2. Tuberous sclerosis
  3. Familial hypercholesterolemia
  4. Familial adenomatous polyposis (ACP gene)
  5. Breast cancer (BRCA 1/2) 
348
Q

Adaptive immune response

A

Antigen specific response, long-term protective immunity

349
Q

What cells are included in adaptive immunity?

A

Natural killer T cells, CD4 T cells, CD8 Tcells, B cells

350
Q

Cellular versus humoral adaptive immunity

A

Cellular is the T cells, humoral is the B cells—humoral=fluid 

351
Q

Which cells are antigen presenting?

A
  1. DC cells
  2. Macrophages
  3. Thymic epithelial
  4. B cells
352
Q

Dendritic cells (DCs) 

A

Long motile protrusions resemble dendrites of nerve cells, critical for the initiation of the immune response, capture antigen by phagocytosis and endocytosis, present antigen and active naïve T cell 

Express high levels of peptide: major histocompatibility complexes, co-stimulatory molecules, and produce cytokines 

353
Q

DCs vs macrophages

A

Macrophages are resident tissue APCs (stay in their tissue), and DCs are in tissue but home to the lymph node (roam)

354
Q

Major histocompatibility complex (MHC)

A

Tells a T cell whether a cell/tissue is self versus non-self (recognition)

The MHC is a group of genes that code for proteins on the surface of cells to facilitate immune system recognition of foreign materials

355
Q

Polygenic MHC’s

A

Encoded by multiple genes: isotopes

MHC class I: HLA-A, -B, -C (one long chain, one short chain)

MHC class II: HLA-DP, -DQ, -DR (two long chains)

(Class one has one letter, class two has two letters) 

356
Q

Polymorphic MHC’s

A

Genes can have various alleles. Includes polymorphism (one gene with different alleles) and polgeny (multiple genes without alleles)

357
Q

MHC class and cell type

A

T cells: MHC class I

B cells: MHC class I and II

Macrophages: MHC class I and II

358
Q

Thymic convolution

A

The thymus shrinks with age, and the T cells mature here. Capacity to produce T cells decreases with age which is why we vaccinate young children 

359
Q

T cell maturation

A

Positive selection: recognizes the antigen

Negative selection: recognizes self — self tolerance (too strong = autoimmune) 

360
Q

T cell development: rule of eight

A

MHC II x CD4+ (and T helper cells) = 8

MHC I x CD8+ (and cytotoxic T lymphocytes) = 8

361
Q

The two signals of T cell activation

A
  1. MHC signal
  2. Co-stimulation/inhibition

If only one signal, T cell becomes anergic (non-responsive to that antigen)

  1. Cytokines to program T cells even further
362
Q

Effector T cell Th1

A

IFN-gamma, macrophages, macrophage activation, autoimmunity, chronic inflammation

363
Q

Effector T cell Th2

A

IL4,5,13, eosinophils, allergy

364
Q

Effector T cell Th17

A

IL17, 22, Neutrophils, extracellular bacteria and fungi, Large contributor to auto immunity and inflammation

365
Q

Effector T cell Tfh

A

IL21, IFN-gamma, IL4, B cells, antibody production, auto antibodies

366
Q

CD8+ cytotoxic T cell lymphocytes (CTLs) cause apoptosis of cells via:

A

Cytoplasmic granules: granzyme B, perforin —> protease, cell death

Fas:FasL: FasL (CD95L) Expressed on surface of T cells, binds Fas on antigen —> apoptosis 

367
Q

Natural killer cells

A

• major role in protection against infected, stressed, and cancer cells
•  Cell killing initiated by absence of self (kill or don’t kill)
• NK cells stimulated by innate cytokines (IFN-alpha, beta, and IL-12)
• Potent producer of IFN-gamma by driving CD4+ cells to become TH1s to make more IFN-gamma

368
Q

Receptors expressed by natural killer cells

A
  1. Activating receptors
  2. Inhibitory receptors

Both expressed simultaneously. Inhibitory (recognizing self) always works over an activating signal (recognizing antigen)

369
Q

Natural killer cells kill via what two mechanisms?

A
  1. Cytoplasmic granule mediated apoptosis (granzyme B, perforin)
  2. Fas:FasL

Same mechanism as CD8 however NK cells know the “self” and do not kill, unlike T cells

370
Q

What is a virus?

A

•  obligate intracellular parasite
• Can infect all types of cellular life
• Nucleic acid surrounded by a protein shell
• Ultramicroscopic in size
• defined host range of cell types that can support its viral lifecycle, tropism
• Replicate in stepwise fashion, rather than binary fission

371
Q

Tropism

A

Defines the range of cell types that can be infected by a specific virus

372
Q

Virus sizes

A

Mimivirus, herpes Symplex virus are the biggest, smallest includes yellow fever and polio virus

373
Q

Viral structure

A

• Naked or enveloped
• capsid surrounding nucleic acid always

• Icosahedral (box around) or helical nucleocapsid (capsid right on genome)

374
Q

Enveloped virus

A

Has a tegument, an envelope, and spike proteins

375
Q

Coronavirus is a:

A

Non-segmented, enveloped, RNA single strand, helical nucleocapsid, with spike proteins that are large

376
Q

Influenza is a: 

A

Single stranded RNA, segmented, enveloped, helical capsid, with H1N1 spike proteins

377
Q

Structure of bacterial virus

A

Head, collar, tail used for injection of nucleic acid, end plate, tail pins, tail fibers 

378
Q

General viral replication cycle

A

1.) attachment/adsorption

2.) Penetration/injection

3.) Synthesis of nucleic acids and proteins

4.) Assembly and packaging

5.) Released by lysis

379
Q

Antigenic shift

A

Occurs when major changes in antigens occur due to gene reassortment in influenza virus

— Common host infects the same cell at the same time and they recombine with each other 

380
Q

Antigenic drift

A

Occurs when minor changes in antigens occur due to gene mutation in influenza virus

— Point mutations change the virus just enough to make vaccines ineffective 

381
Q

Exponential growth versus one step growth

A

Bacterial: exponential growth from replication per cell

The viral: eclipse and latent period, maturation, assembly and release— big burst of growth

382
Q

Titer

A

Number of infectious units per volume of fluid

383
Q

Plaque assay

A

Analogous to the bacterial colony, one of the most accurate ways to measure virus infectivity and infectious viral particle numbers

Plaques: are clear zones that develop on lines of host cells, the plaque is the absence of cells

384
Q

Effects that animal viruses can have on cells

A

1.) transformation into tumor cell

2.) Death of cell and release of virus

3.) Slow release of virus without death, persistent infection

4.) virus present but not replicating, latent infection (may be lyric eventually)

5.) cell fusion

385
Q

BCS— Class I 

A

 double stranded DNA (+/-) virus

Transcription of minus strand

• classical semiconservative 

386
Q

BCS— Class VII

A

double stranded DNA (+/-) virus

Transcription of minus strand

• transcription followed by reverse transcription 

387
Q

BCS— Class II

A

Single-stranded DNA (+) virus

Synthesis of other strand, double strand of DNA intermediate, transcription of (-) strand

• Classical semi conservative, discard the (-) strand

388
Q

BCS— Class III

A

Double-stranded RNA (+/-)

Transcription of minus strand

• makes ssRNA (+) and transcribe from this to give ssRNA (-) partner

389
Q

BCS— Class IV

A

Single-stranded RNA (+) virus

Used directly as mRNA (no further steps) 

• makes ssRNA (-) and transcribe from this to give ssRNA (+) genome

390
Q

BCS— Class V

A

Single-stranded RNA (-) virus

Transcription of the minus strand

• makes ssRNA (+) and transcribe from this to give ssRNA (-) genome

391
Q

BCS— Class VI

A

Single-stranded RNA (+) retrovirus

Reverse transcription, double-stranded DNA intermediate, transcription of (-) strand

• makes ssRNA (+) genome by transcription of (-) strand to dsDNA

392
Q

Causes of inflammation

A

1.) infection
2.) tissue necrosis
3.) Foreign bodies
4.) immune reaction/hypersensitivity

393
Q

Five Rs of inflammation

A

Recognition: receptors that recognize microbes, and sensors of cell damage, leukocytes/sentinel cells, antibody and complement receptors

Recruitment: of leukocytes

Removal: of the microbes/damaged tissue

Regulation: of the inflammatory response

Repair: of the site of damage

394
Q

 Three major components of the acute inflammatory response

A

1.) vascular changes
2.) Leukocyte recruitment
3.) Leukocyte activation and removal of the offending agent 

395
Q

Signs of inflammation

A

Rubor (redness), Calor (warmth), tumor (swelling) , dolor (pain), Functio laesa (loss of fxn)

396
Q

Vascular changes in acute inflammation

A

Vasodilation: histamine, erythema, increased blood flow

Increased vascular permeability: gaps in between endothelial cells, leakage of fluid causing edema, movement of plasma proteins and inflammatory cells from vascular space to the site of injury an infection

397
Q

Key steps in leukocyte recruitment and migration to the site of injury

A

• margination
• Rolling— selections
• Adhesion— integrins (ICAM & VCAM)
• Migration— PECAM-1 (CD31)

“SIP”

398
Q

Removal of the offending agent

A

• activation of recruited leukocytes
• Phagocytosis
• Destruction of phagocytosed material
• granule enzymes (proteases)

399
Q

Chronic inflammation

A

A response of prolonged duration in which inflammation, tissue injury, and attempts at repair coexist in varying combinations

Caused by persistent infections, hypersensitivity diseases, prolonged exposure to toxic agents in foreign material

400
Q

The dominant cell in most chronic inflammatory reactions

A

Macrophages/Monocytes

401
Q

Lymphocytes

A

• amplify and propagate chronic inflammation
• Generate memory cells, allowing for persistent and severe reactions

CD4+ T lymphocytes promote and influence the nature of the inflammatory reaction

402
Q

Granulomatous inflammation 

A

A pattern of chronic inflammation induced by persistent T cell response in some infections, immune mediated diseases, and foreign bodies

TNF plays a crucial role 

403
Q

Conditions with granulomas

A

Infections: bacterial (TB, bartonella hens., listeria, tertiary syphillis), fungal, and parasitic

Non-infections: immune mediated, vasculitis, foreign bodies, and chronic granulomatous disease

404
Q

Transport of amino acids from the gut into the intestinal epithelial cells is by:

A

Secondary active transport with sodium

405
Q

Key amino acids for protein digestion

A

• glutamate -> alpha ketoglutarate
— The amino group pool of the cell

• Aspartate -> oxaloacetate
— donates nitrogen to the urea cycle

• Alanine -> pyruvate
— A key role in gluconeogenesis, transport nitrogen to liver in the form of alanine

• Glutamine -> glutamate
— transports nitrogen to liver for urea cycle

406
Q

Urea is specific to the breakdown of:

A

Amino acids for energy, diverting to carbs (CO2+H2O) for energy and urea cycle to get rid of the amine groups

407
Q

What promotes mobilization of stored fuels?

A

Glucagon, cortisol, epinephrine, norepinephrine

408
Q

Major transporter of amino acids from muscle to liver

A

Alanine: directly to liver to be used for many different pathways

Glutamine: either straight to the liver, or deposits ammonia in the kidney and leaves as alanine to the liver

409
Q

Alanine glucose cycle

A

Alpha KG and glutamate are common amine exceptors and donors causing transamination reactions

Alanine broken down to carbon for glucose and nitrogen for urea in the liver. Glucose goes back to muscle to create pyruvate to amino transfer to get alanine back

410
Q

three enzymes that can “fix” free ammonium: require energy

A

IN MUSCLE:
1.) Glutamate dehydrogenase (GDH)
2.) glutamine synthase

IN LIVER
3.) Carbamoyl phosphate synthetase I (CPS I) 

411
Q

Two ways alanine enters the urea cycle:

A

Firstly, alanine aminotransferase converts alpha-KG to glutamate. Then:

  1. Glutamate dehydrogenase makes ammonium (NH4+)
  2. Aspartate aminotransferase makes aspartate
412
Q

Order of enzymes in the urea cycle

A

1.) CPS I
2.) Ornithine transcarbamoylase
3.) Citrulline ornithine antiporter
4.) Argininosuccinate synthetase
5.) argininosuccinate lyase
6.) Arginase
7.) NAG synthetase (Activates CPSI)

413
Q

Urea cycle disorders manifest as:

A

— hyperammonaemia
— hyperglutaminaemia
— neural disorders (Seizures, irritability, lethargy, ataxia, FTT, refusal to eat protein)

414
Q

Arginine increases what?

A

Synthesis of N acetyl glutamate (NAG).
NAG acts as an allosteric activator of CPS I 

415
Q

Because arginine is a major regulator of the urea cycle, when arginine builds up:

A

1.) it increases the synthesis of NAG, which activates CPS I
2.) it increases arginase activity (to create urea and ornithine)

416
Q

If ornithine transcarbamoylase (OTC) is inactivated: 

A

This causes leakage to pyrimidine synthesis, which elevates urinary orotic acid

417
Q

HHH syndrome

A

hyperammonaemia, hyperornithaemia, homocitrullinaemia (Comes from carbamoyl phosphate reacting with lysine)

The ornithine/citrulline anti-porter SLC25A15 is defective

418
Q

Nitrogen scavengers

A

1.) arginine —arginosuccinate (2N per)
2.) Benzoic acid (1N per)
3.) Phenylbutyrate (2N per)

These are used to make amino acids as excretable in the urine (more soluble)

419
Q

What is used to treat NAG synthase deficiency?

A

N-carbamoyl glutamate which is an analog of N-acetyl glutamate

420
Q

Using arginine to treat HHH syndrome

A

It generates spermine and creatine, which can be urinated out to eliminate nitrogen (like N scavengering)

421
Q

Rubor, calor, vasodilation

A

Main mediators: Histamine, prostaglandins

422
Q

Tumor, Increase vascular permeability

A

Main mediators: Histamine, serotonin, C3a, C5a, leukotrienes C4 D4 E4

423
Q

Leukocyte recruitment and activation

A

TNF, IL-1, chemokines, C3a, C5a, leukotriene B4

424
Q

Fever

A

IL-1, TNF, prostaglandins

425
Q

dolor/ pain

A

Prostaglandins, bradykinin, substance P

426
Q

Loss of function (functio laesa), Tissue damage

A

Lysosomal enzymes, ROS

FOM (5 decks)

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