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Flashcards in Week1 Part2 Deck (146):
1

define screening

used to identify those at a high probability of disease, not for diagnosis and done on healthy people (asymptomatic)

2

define diagnostic testing

used to establish diagnosis, administered to individuals suspected to be sick

3

questions, clinical exam, lab tests, genetic tests, and x-rays are all examples of

screening tests

4

what is the purpose (2) of screening

delay onset of disease, prolong survival

5

What are the three requirements for screening?

suitable disease, suitable test, suitable screening program

6

what is a suitable disease

a disease that has serious consequences, progressive, effective treatment, detectable

7

what is the natural history of disease (4 stages)

biological onset-->detectable by screening-->symptoms develop-->death

8

what is primary prevention

prevent disease before it starts (before biological onset)

9

what is secondary prevention

delay symptoms (after biological onset, before symptoms develop)

10

what is tertiary prevention

aims to delay death (symptoms already present)

11

what is detectable pre-clinical phase of disease

screening for disease before symptoms arise

12

what is lead time

the amount of time you gain by catching a disease before symptoms appear

13

validity

does the test measure what its supposed to measure

14

reliability

does the test give them same result over and over

15

internal validity

does the test measure what its supposed to measure

16

external validity

are the results generalizable

17

how do you calculate test sensitivity

TP/(TP+FN)

18

how do you calculate test specificity

TN/(TN+FP)

19

what is the relationship between validity, specificity and sensitivity

a valid test will have a high specificity and sensitivity

20

if specificity increase what occurs to false positive rates

false positive rates decrease

21

if sensitivity increases what occurs false negative rates?

false negative rates decrease

22

when is sensitivity favored over specificity?

to prevent disease transmission

23

when is specificity favored over sensitivity?

TPfor fatal diseases with no treatment. don't want to tell someone they have HIV if they done

24

what is the eqn for accuracy of a screening test

(TP+TN)/(TP+FP+TN+FN)

25

eqn for positive predictive value

(TP)/(TP+FP)

26

eqn for negative predictive value

(TN)/(TN+FN)

27

what is erythropoeisis

the formation of RBCs

28

Where does erythropoeisis occur?

bone marrow of sternum, ribs, and pelvis

29

what is the main difference between erythroid cells in the bone marrow vs. in circulation

erythroid cells in circulation lack a nucleus

30

what is the color change associated with maturing eryhthroid cells? why?

as they mature the cytoplasm changes from blue to orange due to increased Hb being present

31

how long does it take an erythroid cell to mature in the marrow?

7 days with 2-5 cell divisions

32

what are reticulocytes?

the first stage of immature RBC to enter circulation and not have a nuclues

33

how long do reticulocytes circulate for? how many are produced/second

-1-2 days
-2 million reticulocytes produced per second

34

what is the lifespan of a mature RBC?

120 days

35

EPO: role, produced?,MOA

stimulate RBC production, produced in kidneys, binds EPO receptors on progenitor cells that differentiate into RBC

36

what is anemia

a lack of RBCs or a decreased amount of Hb in each RBC

37

What are the two most essential enzymes present in RBCs? why are they important?

Recall: RBCs dont have a nucleus so they need to fend for themselves (proteins, stored up RNA) or die. G6PD of the PPP ensures a steady supply of NADPH to compat free radicals. Pyruvate Kinase of glycolysis (PEP-->Pyruvate) to ensure adequate ATP production

38

how are old/damaged RBCs removed?

macrophages of reticuloendothelial system found in liver, spleen, and bone marrow

39

what is the structure of a RBC? how does this relate to function

biconcave disk (7 um). Large SA:V ratio for gas exchange

40

Do RBCs have organelles?

No! has stores of lipids, proteins, and carbs that were made when it still had nucleus

41

describe the lipid bilayer of RBCs

external surface is different in composition than inner surface, but cholesterol is evenly distributed between both layers

42

Role of flipases

movement of molecules (phosphatidylserine and ethanolamine) from the outer membrane to the inner membrane (flip in)

43

role of flopases

takes phospholipids from inner membrane to outer membrane (flop out)

44

Role of scamblases

move phospholipids in both directions in the phospholipid membrane

45

where are spectrin and ankyrin found?

interacting with membrane proteins to provide a system of vertical linkages within the cell/cytoskeleton

46

disruption in membrane composition or cytoskeleton (shape) can cause what in a RBC?

hemolysis

47

the formation of Hb is limited by what?

availability of iron and level of intracellular heme

48

where is heme synthesized?

mitochondria

49

where are globin (alpha, beta, gamma) chains formed?

ribosomes of the cytoplasm

50

what is the range of RBC concentration?

4-6 million/uL

51

What is polcythemia?

increased numbers of red blood cells or increased amount of Hb

52

what are hemoglobinpathies? what are the two we discussed in detail? why are they bad?

qualitative disorders of Hb. Hemoglobin S (sickle cell) and Hemoglobin C disease. these morphological changes DONT impact oxygen carrying capacity, but they are destroyed sooner than 120 days

53

qualitative Red cell abnormalities could include abnormal 1,2,3

Hb, cytoskeleton, enzymes

54

How do Thalassemias appear under a microscope?

small, hyperchromic (less orange/color)

55

how does hereditary spherocytosis appear under a microscope? what is it caused by?

RBC appear as spheres. abnormality in ankyrin band 3 and spectrin genes

56

how does hereditary ellipctocytosis/ovalocytosis appear under a microscope? cause?

RBCs appear as ovals. abnormality in spectrin and ankyrin protein 3.1 genes (spectrin dimer-dimer interactions)

57

how does hereditary pyropoikilocytosis appear under a microscope? cause

RBC looks like heat was added and cells fell apart in blood (this morphological disorder does impact oxygenation b/c cells degrade in circulation). spectrin and ankyrin protein 4.1 genes. spectrin dimer-dimer interactions

58

how does hereditary stomatocytosis appear under microscope? cause?

swelling of RBC. caused by increased intracellular sodium

59

how do G6PD defficencies appear under a microscope? casue (RBC)

looks like RBC have a bite taken out of them (bite cells). due to Hb oxidation

60

how does pyruvate kinase deficiency manifest itself in RBC? why

RBC appear spikey, termed acanthocytes. lack of ATP causes a loss of K and water and accumulation of Na

61

what does in vitro refer to

in a test tube

62

how do proteins know how to fold?

info required to fold is inherent in the primary structure of the protein

63

does protein folding require energy?

no, it is a thermodynamically favorable process

64

what drive protein folding

hydrophobicity (burying of hydrophobic residues, hydrophobic effect) and increasing the disorder of surrounding water molecules

65

What does Levinthal's Paradox State

Proteins cant fold by random sampling of all possible confirmations (it would take too long), folding is therefore a stepwise, ordered event

66

urea does what to proteins?

denatures them

67

what abnormal/detrimental process competes with the normal folding of proteins?

protein aggregation (proteins fold with each other instead of with itself)

68

why is protein aggregation a real problem in vivo?

the intracellular environment is very crowded leaving larger macro-molecules with little room to fold

69

what is the excluded volume effect?

the term used to describe the increased likelihood of protein aggregation due to the minimal intracellular room

70

what four types of polypeptides are especially at risk for protein aggregation?

1. nascent chains synthesized by polysomes
2. nuclear proteins: crowded, highly charged environment
3. mutant proteins
4. unfolded proteins arising from conditions of stress (heat shock)

71

what are the cells 3 solutions to protein aggregation?

1. peptidyl-prolyl cis trans isomerase (PPI)
2. protein disulfide isomerase (PDI)
3. molecular chaperones

72

what do peptidyl-prolyl cis trans isomerase (PPI) do?

catalyze/accelerate folding of proteins by interconverting between cis and trans proline bonds to avoid protein aggregation

73

what do protein disulfide isomerases (PDI) do? where are these proteins found?

catalyzes the quick breakage and reassembly of disulfide bonds as proteins fold so they can quickly find the correct configuration and avoid aggregation. found in the ER

74

what is the role of molecular chaperones

prevent and revers incorrect interactions that may occur in the crowded intracellular environment

75

what are the three classes of chaperones and their sizes

small heat shock protein (14-45kDA), low MW (200kDa)

76

how do small heat shock proteins fxn

ATP independent, form small oligomeric complexes to help fold aggregation hot spots

77

how do small MW chaperones function

ATP dependent that act through cycles of polypeptide release and binding

78

high mw chaperones: alternate name, role/fxn

chaperonins. sequester polypeptide and prevents anggregation through forming the Anfinsen Cage. Protein is release from cage when folded

79

Mutated proteins either fold ____ or ____

incomplete folding

aggregate protein

80

inappropriately Aggregated proteins are typically very _____ and result in a _______

stable

Gain of function (toxicicity)

81

proteins that do not fold properly are generally _____ and result in _____

unstable

loss of fxn (accumulation of non-functional proteins or decreased levels of protein)

82

Sickle cell disease is an example of what type of protein folding? GOF or LOF

HbS aggregation, GOF

83

Cystic fibrosis is an example of what type of protein folding? GOF or LOF

Incomplete folding of CF transmembrane conductance regulator. LOF

84

are chaperones extracellular, intracellular, both?

only intracellular

85

What is systemic amyloidosis

extracellular deposition and accumulation of insoluble protein, evade chaperones in extracellular space

86

what is a prion?

an infectious agent composed of misfolded protein, this is an example of a GOF mutation

87

why are prions so deadly?

prions can convert normal folded proteins to misfolded proteins

88

what are localized amyloids? what is a common example of disease they cause

protein aggregations that develop near site of the original protein production. Alzheimers disease is caused by beta amyloid plaques

89

contrast role of foldases and chaperones

Foldases: speed up rate of protein folding
chaperones: decrease rate of protein aggregation

90

aggregated proteins are dominated by what secondary structure?

beta sheets

91

in sporadic AD, amyloid plaque formation follows:

abnormal post-translational modification of precursor proteins

92

what are two exceptions to the "flow" of the central dogma?

The production of DNA from RNA with reverse transcriptase. non-coding RNA that can function on its own w/o producing a protein

93

what two major biological processes depend on coordinated regulation of gene expression

homeostasis and development

94

what are the steps from DNA to protein in eukaryotic cells?

DNA>Transcription to RNA>RNA processing>export of mature RNA into cytoplasm>translation>post-translational modifications

95

compare eukaryotes to prokaryotes: nucleus, genome, histones,introns, transcription/translation

Euk: have nucleus, germ line cells are haploid, somatic cells are diploid, have histones, have introns, transcription and tranlation are separate processes

Pro: no nuclues, haploid genome, no histones, no introns, T+T are coupled

96

what type of RNA is capped at the 5' end?

mRNA

97

what are 4 mechanisms to regulate gene expression

physically modify DNA, chemically modify DNA, transcriptional regulation by proteins, post-transcriptional regulation

98

Physical modifications of DNA include (3).. and an example

DNA/gene loss: when RBC eject their nucleus

DNA/gene amplification: often seen in cancer

DNA rearrangement: segments of DNA are moved from one place to another so different proteins are made (production of antibodies by B cells). note this is not alternative splicing because the DNA is being altered not mRNA

99

what is a type of chemical modification to DNA, which residue is modified? what is the effect?

methylation. cytosine. methylated sections of DNA are less transcribed.

100

what are CpG islands?

regions in DNA that are hotspots for methylation. (p indicates a phosphodiester bond connecting C and G) these sequences are palindromic. meaning the C of the complementary is also methylated

101

how is X-inactivation attained in females?

methylation!

102

what is genomic imprinting. how can it be attained?

one copy of a gene is silenced due to parental origin. could be a result of methylation.

103

what role do histones play in gene expression

histones ca regulate chromatin condensation. the more condensed chromatin is, the less transcription occurs

104

how do transcription factors regulate gene expression?

in order for transcription to occur in eukaryotes, a multi-unit transcriptional apparatus must assemble. this apparatus includes TFs

105

Uniquely, a steroid hormone receptor is a...

Transcription factor, and when activated transcription is altered

106

what are 5 forms of post-transcriptional regulation

alternative splicing, alternative polyadenylation, mRNA editing (changing mRNA after it is made), mRNA transport, mRNA stability

107

what is mRNA transport and how does it impact gene expression. give an example

in eukaryotes mRNA must travel out of the nucleus before being translated. if the RNA is not allowed to leave, no protein is made.
HIV RNA produced in the nucleus must be assisted out of the nucleus

108

what is mRNA stability and how does i impact gene expression?

proteins can bind to mRNA and prevent their degradation.

109

Give an example of translational regulation

the translation of globin mRNA is regulated by heme. if heme is not present, globin is not translated. this causes iron deficiency anemia

110

as red blood cells mature what occurs to their histones?

histones condense chromatin and prevent their transcriptions

111

How does HIV work? how does it kill?

HIV infects and kills T lymphocytes (destroys immune system). people with HIV/AIDS generally die from opportunistic infections

112

why is it so difficult to cure/treat HIV?

HIV reverse transcriptase has very low fidelity whcih results in a high rate of mutations in the virus. The frequent mutations causes resistance to drugs such as AZT, and avoidance of immune surveillance

113

what is AZT

a drug that targets rverse transcriptase, used to treat HIV

114

Rank the fidelity of RNA pol, DNA pol, and reverse transcriptase

DNA pol>RNA pol>reverse transcriptase

115

what is the new approach to preventing AIDS?

treat the host instead of the virus

116

Antinomycin D: what does it do?

antibiotic that inhibits RNA synthesis (transcription) in both eukaryotes and prokaryotes

117

Rifamycin and rifampicin: what do they do

an antibiotic that inhibits transcription in prokaryotes

118

alpha-amanitin: what does it do?

blocks eukaryotic transcription

119

what is LD50?

the oral does that kills 50% of people

120

what 7 compounds inhibit translation in prokaryotes?

Tetracycline
Chloramphenicol
Erythromycin
Streptomycin
Neomycin
Kanamycin
Gentamycin

121

what 3 compounds inhibit translation in eukaryotes?

Cycloheximide
Diphtheria toxin
ricin

122

what compound inhibits translation in prokaryotes and eukaryotes

puromycin

123

what is the function of snRNPs?

regulate splicing

124

what is systemic lupus erythematosus

an auto-immune disease that targets snRNPs. joint pain, swelling and butterfly rash on cheeks are symptoms

125

what is the only gene expressed in mature mRNA

globin (all globin mRNA is deposited prior to enucleation)

126

what is the most common gene disorder in the world?

thalassemias

127

what is methotrexate used for?

it is a drug for cancer treatment.

128

how do some cancer patients become methotrexate resistant?

cancer cells will amplify gene of the enzyme inhibited by methotrexate

129

What is the actual problem sickle cells cause?

this is not an oxygen carrying problem. the problem is that their sickled shape causes them to be prematurely lysed (life goes from 120 day to 10-20 days) and that their shape prevent them from moving through capillaries.

130

what are the clinical manifestation of sickle cell?

anemia, dyspnea (labored breathing), joint pain, infections (spleen removed)

131

what will lab tests show for a person with sickle cell?

decreased hematocrit, decreased Hb, increased reticulocytes, increased serum iron and bilirubin (products of heme recycling)

132

What are some short term treatments for sickle cell

hydration, oxygenation, exchange transfusion, antibiotics

133

what are some long term treatments for sickle cell

gene therapy, bone marrow transplant

134

what is sickle cell trait? benfit?

a person with one defective beta-globulin gene. a carrier. confers malaria resistance.

135

how does sickle cell anemia arise? what is the mutation

a point mutation of the Beta globulin gene that is located on chromosome 11. this mutation causes a change in AA from glutamate (-) to valine (hydrophobic) at position 6. The hydrophobic residue creates a sticky patch on HbS which polymerizes with other HbS strands into 14 strand fibers

136

What favors the polymerization of HbS?

low oxygen levels (T state!), high concentration of HbS, high composition of HbS (low levels of HbA, HbF)

137

If HbS polymerization is favored by the T state, what allosteric effectors will favor polymerization?

T is deoxy state (low Oxygen affinity) So...a low pH, high CO2 or high BPG will favor polymerization

138

what diagnostic tests can be used to diagnose sickle cell anemia?

Hb electrophoresis, genetic testing (use PCR, restriction enzymes, gel)

139

fetal Hb has which subunits?

alpha and gamma

140

In what DNA repair pathway is PARP1 involved? HOw can it be used to treat cancer?

PARP1 is involved in ssDNA repair (and BER), PARP1 inhibitor is used to treat patients with mutated BRCA1/2 genes (repair of dsDNA). disabling both these pathways promotes cell death

141

what does SMA stand for?

Spinal muscular atrophy

142

How is SMA inherited? GOF or LOF

LOF, autosomal recessive

143

what is the genetic basis of SMA

A loss of SMN Protein caused primarily (95%) by a deletion in of the SMN1 gene or replacing SMN1 with SMN2 gene

144

What is the role of SMN protein

Survival motor neuron protein. Keeps motor neurons in brain and spinal cord alive. A loss of SMN protein causes SMA

145

What are the different types of SMA?

Type I: AKA Werdig-Hoffman Disease, most sever, floppy baby, feeding and breathing problems,

146

What account for the varying severities of SMA?

extra copies of the SMN2 gene can modify the severity. More copies=less severe (SMN2 produces low levels of functional SMN protein)

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