MCM Lectures 19-22 Flashcards
What is the apical most junction found between epithelial cells? This junction is maintained by what proteins?
Tight junction, occludins and claudins
Cell to cell junctions anchored by actin filaments
Adherens
Cell to cell junctions anchored by intermediate filaments
Desmosomes
Cell to matrix junctions anchored by intermediate filaments
Hemidesmosomes
Anchoring junction. That mediates cell to cell connections using actin
Cadherin
Anchoring junction. That mediates cell to matrix connections
Integrin
Classical cadherins and desmosomal cadherins are both examples of what kind of junction
Homophilic
Classical cadherin junctions require calcium to function while nonclassical cadherins do not. What are examples of nonclassical cadherins?
Desmoglein, desmocollin, hemidesmosome
Cells of similar type are able to stick together with highly selective regulation (especially important during development) thanks to a process dependent on what Homophilic cell adhesion molecules?
Cadherin
Anchoring protein that help link classical cadherins to the cytoskeleton (important in wnt pathways)
Beta-catenin
This structure is found just inferior to tight junctions between epithelial cells (adjacent to contractile actin)
Adhesion belt (zonula adheren)
hydrophilic medications are fast acting. what is an example of a hydrophilic medication?
epinephrine
the same hormone may elicit different responses in different tissue when bound to GPCRs. For examples, epinephrine causes what to happen in bronchial tissue, smooth muscle, and cardiac muscle?
bronchial- relax
smooth muscle- relax
cardiac muscle- contract
these two beta agonists are used to treat airway constricting conditions
albuterol, epinephrine
fatal drop in blood pressure can occur with too much vasodilation which is why these two medications should not be taken together
viagra- cGMP phosphodiesterase inhibitor
nitroglycerine- smooth muscle relaxation/vasodilation
antihistimines bind GPCReceptors which normally bind what?
the AA histidine
what 4 regulatory proteins cause a differentiated adult cell to revert to pluripotency?
sox2, oct4, nanog, lin28
what is a stem cell?
self renewing, slow dividing, primitive cell that gives rise to more specialized cell types through differentiation
term for a cells ability to give rise to all cells of an organism including embryonic and extra embryonic tissues.
totipotency (zygote)
term for a cells ability to give rise to all cells of the embryo and thus all adult tissues
pluripotency (ES cells)
term for a cells ability to give rise to different cell types within a given lineage
multipotency (adult stem cells)
term for a set of cells that is programmed to have a fixed number of divisions controlled by short range signals
founder stem cells
cell population that is mixed with stem cells yet divides frequently to leave basal layer and become incorporated more superficially (divide a limited number of times)
transit amplifying cells
divisional asymmetry describes the process of stem cell division where one daughter cell retain stem cell characteristics while the other has the ability to differentiate. this describes which theory of stem cell renewal?
asymmetric division
environmental asymmetry describes the process of stem cell division where both daughter cells are identical and environment alters one so it has the ability to differentiate. this describes which theory of stem cell renewal?
independent choice
theory of stem cell division stating an original strand of DNA is preserved generation to generation (second cell gets newly synthesized DNA) to prevent errors
immortal strand hypothesis
pluripotent stem cells can be obtained from which part of an embryo at which stage in development?
inner cell mass of the blastocyst
what is a teratoma?
embryonic stem cells alone (when they are not part of an embryo) are incapable of generating a body in full. the lack of organization leads to tumor formation that involves many different tissue types involved.
whats required to differentiate a cultured ES cell into an adipocyte? a neuron?
fat- RA, insulin, thyroid hormone
neuron- RA
what are advantages / disadvantages to using multi potent stem cells to treat a patient?
no immune response to patients own tissue however they have limited ability (cannot become ANY cell type) and limited longevity
what are advantages / disadvantages to using embryonic stem cells (via somatic cell nuclear transfer) to treat a patient?
they are pluripotent (live long and can become anything) however immune rejection is possible if they were obtained via IVF and can be hard to coax
what is SCNT?
somatic cell nuclear transfer is when the nucleus of a somatic cell is used to replace an oocyte nucleus to generate ES cells to be used in therapy
where are adult stem cells found
bone marrow, cord blood, skeletal and heart muscle, skin, colon, liver, prostate, mammary gland, eye, ear, fat
whats the name of the process which allows lost limb tissue in a newt that is differentiated muscle tissue to reenter cell cycle after cutting off a limb, de differentiate and become ES cells that can proliferate and form a new limb
regeneration
where does hematopoiesis occur in a developing fetus?
trimester 1- yolk sac
trimester 2- liver and spleen
trimester 3- bone marrow
where does hematopoiesis occur in an adult?
long bones: tibia, vertebra, pelvis, sternum, ribs, femur
more hematopoiesis occurs in which type of bone marrow?
red marrow
what are the components of red marrow?
bone, endothelial, hematopoeitic, sinusoids that allow mature blood cells to enter circulation
what is the primary component of yellow bone marrow?
adipocytes
what cells in bone marrow are responsible for producing short range regulatory molecules to induce colony stimulating factors?
stromal (reticular) cells
Hemoglobin has how many subunits? Each subunit contains what structure which actually binds oxygen?
4
Heme (with a Fe2+ atom)
Each subunit of hemoglobin includes how many alpha helices and beta sheets?
8 alpha helices, 0 beta sheets (because those are sticky!)
Adult hemoglobin has what 4 subunits? What are the subunits of fetal hemoglobin?
Adult- alpha2, beta2 (and a little bit of alpha2, delta2)
Fetal- alpha2, gamma2
Sickle cell anemia occurs when theres a mutation in HbS gene. What is the Amino acid substitution that occurs?
Glutamate to valine at position #6 in beta globin subunit
This condition occurs when red blood cells are misshapen due to a single AA mutation in beta globin. This impedes circulation leading to hemolytic anemia.
Sickle cell anemia
Which amino acid residue in heme interacts with the iron atom allowing oxygen to bind and thus a conformational change to occur?
Proximal histidine (F8 position) when oxygen binds it becomes planar
What effect do each of the following molecules have on the hemoglobin oxygen dissociation curve? 23BPG, H+, CO2, HbF
23BPG: shift right (reduce O2 affinity)
H +: shift right (Bohr Effect)
CO2: shift right
HbF: shift left
Most proteins found in blood plasma are made in what organ?
Liver
Term for the percent of blood that is made up by cells
Hematocrit
This enzyme senses low oxygen levels in order to stimulate RBC production
HIF (hypoxia inducible factor), and transferrin can do this as well
Erythropoietin (EPO) binds a receptor that begins which cell signaling cascade To increase differentiation into RBCs?
JAK STAT
A deficiency of iron can lead to what? deficiency in b12 or folate leads to what?
Microcytic anemia, macrocytic anemia (megaloblastic anemia))
This enzyme made by parietal cells in the stomach protects vit B12 from digestion so that it can fulfill its duty as a coenzyme in DNA synthesis
Intrinsic factor
What type of anemia is acquired when we lose intrinsic factor?
Pernicious anemia
How much oxygen can 1 gram of hemoglobin transport?
1.34 mL O2/ g Hb
What is the difference between oxygen capacity and oxygen content?
Capacity- total O2 that can be carried in blood assuming every heme is bound
Content- amount of oxygen actually being carried by our blood (capacity x % saturation)
This value is measured by pulse oximetry and tells us the % of available spots on heme that are taken up by a molecule of O2
Oxygen saturation
What state of iron is used in heme synthesis?
Fe2+ (because dietary 3+ has TOO HIGH an affinity for oxygen and wouldn’t be able to unload at tissues)
Anemia can result from what?
Folate/B12/iron deficiency, bone marrow damage, kidney damage
What is the condition where one has too many RBC’s in circulation? Why is this dangerous?
Polycythemia, blood viscosity increases and heart must work harder
What condition(s) result in primary polycythemia? secondary polycythemia?
Primary- bone marrow overproduction of RBC, TPO receptor mutation
Secondary- in response to low O2 because of altitude or heart/lung disease
Most of our Iron is stored in what molecule
Ferritin (water. Soluble)
If iron absorption is high in the intestine then we are at risk for what condition? If absorption is low?
High absorption= Fe overloading
Low absorption= Fe deficient
What intestinal lumen protein is required to convert Fe3+ to Fe2+?
Duodenal cytochrome b (Bcytb)
DMT1 is a transport protein on the apical side of intestinal epithelium used to transport Fe2+ into the cell. What protein is required to move this Fe2+ from the cell into circulation?
Ferroportin (requires ferroxidase)
After entry into circulation, Fe2+ is converted back to 3+ and bound to what transport protein that will carry it to the bone marrow for use in heme synthesis?
Transferrin
How much of our tranferrin is normally bound to iron? What lab test is used to determine this?
30%, TIBC (total iron binding capacity)
iron deficiency causes TIBC (total iron binding capacity) values to increase or decrease? What does iron deficiency do to transferrin saturation?
Increase binding capacity, decrease transferrin saturation
What condition results from 1 subunit in hemoglobin converting its iron to 3+ resulting in tighter binding of oxygen to the remaining 3 subunits and leading to hypoxia?
Methemoglobin
What can cause iron deficiency?
Menstruation, aspirin abuse, GI ulcers
What disease is caused By organ dysfunction due to iron overload (due to dysregulation of iron uptake)?
Herediary hemochromatosis (Leads to cirrhosis, arthritis, skin pigmentation, cardiomyopathy)
Folic acid is composed of what 3 parts?
Pteridine ring, PABA, glutamate chain
Dietary folic acid is in what form? It can be reduced by what enzyme to make THF?
Dihydrofolate (DHF), dihydrofolate reductase
What is the biologically active form of folate? It acts by transferring carbon units especially in DNA synthesis
THF (tetrahydrofolate)
With the help of vitamin B12, the inactive stored form of what metabolite can be converted to substrates for making nucleic acids
Folate (inactive form called methyl)
Carbon. Transfer from serine side chain to THF creates N5,10 methylene-THF. The carbon is then gets transferred to catalyze what reaction?
dUMP to dTMP (loss of a C also creates DHF which can be reduced to THF and reused)
What is the role of B12 in preparing folic acid for use in DNA synthesis?
B12 demethylates N5methyl-THF so it can enter folic acid cycle
B12 is necessary for What amino acid conversion?
Homocysteine to methionine
Most often B12 deficiency is from a lack of what essential protein????
Intrinsic factor
Gastric mucosal cells make what protein to bind B12 in the stomach? It gets degraded by proteases in the duodenum
R binders
Lack of B12 or lack of intrinsic factor leads to what type of anemia
Pernicious
In this test we Give radiolabeled B12 while injecting with high dose of B12 to saturate. Binders. If we are absorbing it we lost it in urine got in blood but not to tissues (radioactive urine) if there is none in blood we add IF orally and inspect urine to find radioactivity
Schilling test
Loss of spectrin (autosomal dominant) causes loss of concavity in RBC and what is the result
Hereditary spherocytosis
PK produces ATP at the end of glycolysis. When deficient, RBC’s lack the ability to produce ATP And we get ion build up as well due to lack of function of Na/ATP transporter. What builds up in these cells? What happens to the Hb-O2 dissociation curve?
23BPG builds up and curve shifts right
Result of a mutation from glutamate to valine in beta globin protein
Sickle cell anemia
Phase I of heme synthesis occurs in the mitochondria and involves what reaction
Gly + succinylCoA = ALA
Phase II of heme synthesis involves condensing 2 ALAs to form what product? Where does this. Take place???
4 Prophobilinogen= tetrapyrrole ring, cytosol
Phase III of heme synthesis occurs in the mitochondria involving oxidation reactions to obtain the final product which is what?
Conjugated ring system (protoporphyrin IX) + Fe2+ = heme
Phase 1 of heme synthesis is a decarboxylation that requires what coenzyme?
PLP (B6)
What is jaundice?
State of hyperbilirubinemia due to imbalance of production and excretion of bilirubin
Condition indicated by increased production of unconjugated (direct) bilirubin potentially due to excess hemolysis, internal hemorrhage, G6PO4 dehydrogenase deficiency, incompatible mama-baby blood groups
Pre-hepatic jaundice
What are some findings consistent with pre-hepatic jaundice?
Elevated unconjugated BR, Normal conjugated BR, normal serum ALT and AST, urobilinogen in urine, no direct BR in urine
Condition indicated by impared hepatic uptake, conjugation, or secretion of direct BR presents with general hepatic dysfunction (cirrhosis, hepatitis, Criggler Najjar syndrome, Gilbert Syndrome)
Intra hepatic jaundice
What are some findings in intra-hepatic jaundice cases?
Increase in either conjugated or unconjugated BR, increase serum ALT and AST, normal urobilinogen in urine, conjugated BR in urine
Condition indicated by problems excreting BR can present with decrease bile flow (AKA cholestasis) obstruction to biliary drainage, cholangiocarcinoma, gallstones, infiltrative liver disease, lesions, drugs
Post hepatic jaundice
What findings are consistent with post hepatic jaundice?
Elevated conjugated BR in blood, normal serum AST and ALT, elevated ALP, Elevated bile salts, conjugated BR in urine, no urobilinogen in urine or stercobilinogen in feces
When newborns have elevated unconjugated BR as fetal Hb is broken/replaced with adult Hb, liver can’t conjugate yet, UDP-GT enzyme deficit
Neonatal (physiologic) jaundice
How do we treat neonatal (physiologic) jaundice?
Blue fluorescent light! (Solubilizes BR) or IM inject tin-mesoporphyrin (inhibits heme oxygenase)
Deficincy in what enzyme leads to crigler najjar syndrome? (Hint: leads to hyperBRemia)
UDP-Glucuronyl Transferase
Kiddos with this disease get encephalopathy causing brain damage because of too much BR in the blood
Crigler najjar syndrome
Type I is complete absence of gene
Type II is mutation in gene causing enzyme to function at 10%
What are some treatments for kids with ccrigler najjar syndrome?
Blood transfuse, phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate that complex with BR in gut, liver transplant
Inflammation Of liver can lead to dysfunction, increased BR in blood, urine, skin, and sclera of eyes. What is this called and what could have caused it?
Hapatitis
Virus, alcoholic cirrhosis, liver cancer
