Exam 1 Flashcards
1
Q
Type IX Collagen. Tissue distribution, synthesizing cells, function, organization?
A
- Tissue distribution: hyaline cartilage2. Synthesizing cells: chondroblasts3. Function: binds collagen fibrils to one another4. Organization: fibril-associated
1
Q
Discuss what is occurring at the cellular level in Cystic Fibrosis?
A
- CFTR is a chloride channel, also regulates Na and HCO3– In CF, CFTR is not put up on the cell surface as a result of defect in glycosylation- Chloride and Na not brought into the cell, leads to salty sweat- Airway: normal mucous has sodium extracted from it, chloride gets added and water is taken out. In CFTR, sodium and water are extracted from it making it viscous and dehydrated. - Also leads to viscous secretions in intestines, pancreas and bile duct. Ductus deferens becomes obstructed too.
2
Q
Where is desmin found?
A
- Found in striated muscle and non-vascular smooth muscle
2
Q
What is Von Gierke’s disease?
A
- Defect in Glucose-6-phosphatase or the G-6-phosphate transporter and results in glycogen accumulation in the cytoplasm and nucleus of affected cells- Symptoms include: hepatomegaly, hypoglycemia and increased lactate production
2
Q
What molecules are required in order for endocytosis to occur?
A
- Calcium and ATP
3
Q
What can overexpression of MDR-1 proteins cause? Clinical relevance?
A
- Cancer cells to become resistant to cytotoxic drugs- This is targeted intervention with RNA interference and pharmacologic inhibitors
4
Q
Function of primary/non-motile monocilium
A
- Chemosensors, osmoreceptors, mechanoreceptors- Pivotal role in normal tissue morphogenesis- Seen in fibroblast and epithelial cells of collecting tubule
4
Q
Structure of zonula occludens (aka tight junctions)
A
- Cytoskeletal element = actin- Intracellular anchor proteins = ZO proteins (1,2,3)- Cell adhesion molecules = Claudins and occludins
5
Q
Basic structures of the ECM
A
1.) Ground substance- Glycosaminoglycans/mucopolysaccharides- Proteoglycans- Multiadhesive Glycoproteins- Water2.) Fibers/CT- Collagen- Reticular (type III collagen)- Elastic
5
Q
A 38 yo female presents to a cosmetic surgeon complaining of excessive facial wrinkles. The physician explains that she is an excellent candidate for botox injections as a means to diminish wrinkles by weakening facial muscle contractions. How does botulinum toxin mediate its effect?A. Proteolysis of coating proteinsB. Stabilization of microtubulesC. Proteolysis of SNARE proteinsD. Disrupts endocytosis of released neurotransmitter
A
- C
5
Q
What would happen to ceruloplasmin serum level in Wilson’s disease? Explain
A
- ATP7B is a copper transporter in the Golgi membrane, takes copper from cytoplasm into Golgi. Apoceruloplasmin in Golgi is protein not bound with Cu. When Cu is present, apoceruloplasmin binds it and forms ceruloplasmin, which then can be secreted into plasma.- In Wilson’s, copper transporter is defective, not moving Cu into Golgi, don’t form ceruloplasmin, therefore it decreases.
5
Q
What stain would be indicated to identify extracellular deposits of amyloid?
A
- Congo red
6
Q
Nissl. What has affinity for it? What is the color imparted from this dye? Medical application?
A
- Color = blue- Ribosomes (typically neurologic tissue) have affinity for this dye- No specific medical application indicated
7
Q
What inhibits polymerization of actin?
A
- Cytochalasin B
8
Q
Discuss difference between the basal lamina and basement membrane. What is the composition?
A
1.) Lamina lucida: composed of laminin, entactin, integrins and dystroglycans (integrins and dystroglycans are transmembrane receptors for laminin)2.) Lamina densa: composed of type IV collagen, fibronectin and perlecan3.) Lamina fibroreticularis: composed of fibronectin and types I and II collagen- Basal lamina = lamina lucida + lamina densa- Basement membrane = basal lamina + lamina fibroreticularis
8
Q
What are MAPs?
A
- Microtubule-associated proteins- Function to stabilize microtubules
9
Q
Discuss unique findings of proelastin
A
- Proelastin is a component of elastic fibers- Contains unique amino acids desmosine and isodesmosine
9
Q
Lifespan of mitochondria? How do they reproduce?
A
- Short life span of ~ 10 days- Reproduce by fission, can also fuse with one another
9
Q
Describe clathrin-mediated endocytosis
A
1.) Occurs at clathrin-coated pits2.) Coated pits have cargo receptors (could be specific receptors – ie. LDL), adaptin associates with intracellular portion of cargo receptor, coated vesicles form, 3.) Dynamin GTPases is used to pinch off vesicle, vesicles become quickly uncoated after formed4.) Uncoated vesicles fuse at target5.) Recycling of synaptic vesicles
10
Q
Location of transitional/urothelium
A
- Ureters- Urinary bladder- Urethra
10
Q
Principle amino acids that make up collagen?
A
- Principly glycine (every 3rd AA)- Also hydroxyproline and hydroxylysine (both specific to collagen)
11
Q
Junctional complexes that anchor cells to matrix
A
- Focal adhesions- Hemidesmosomes
11
Q
Difference between pump and carrier?
A
- Pump requires direct expenditure of energy- Carrier doesn’t require direct expenditure of energy
12
Q
What does inactivation of the gene for perlecan result in?
A
- Defective skeletal development
13
Describe structure
- Membranous organelle- Forms intracellular network of cisternae (fluid-filled tubules)- Continuous (in most cases) with outer membrane of nuclear envelope- Polyribosomes attached
14
Deleterious effects of elevated intracellular calcium?
- Membrane damage- Nuclear damage- Decrease in ATP concentration
15
Clinical relevance of MAPs
- Tau is an example of a microtubule-associated protein- In Alzheimer’s disease, the amount and type of tau is modified and the microtubule binding affinity is lost. Consequently, tau pairs accumulate in the cytoplasm of the neuron impairing its function
15
Two forms of chromatin
a.) Heterochromatin: condensed, coiled, transcriptionally inactive chromatinb.) Euchromatin: decondensed, uncoiled, transcriptionally active chromatin
16
Discuss Ehlers-Danlos types IV, VI and VII. What is the defect and what are the clinical consequences?
1.) Type IV- Defect: mutation in Col3A1 gene encoding type III collagen (aka reticular fibers)- Clinical: varicose veins, aortic rupture, intestinal rupture2.) Type VI- Defect: defective hydroxylation of lysine destabilizes strength of collagen- Clinical: hyperelasticity of skin, rupture of eyeball3.) Type VII- Defect: mutations in Col1A1 and Col1A2 genes encoding type I collagen- Clinical: joint dislocation and hypermobility of joints
16
List exogenous and endogenous pigments found in cells
1.) Exogenousa.) Caroteneb.) Inhaled dust/carbon particlesc.) Tattoo pigments2.) Endogenousa.) Hemoglobinb.) Hemosiderinc.) Bilirubind.) Melanine.) Lipofuscin
17
Discuss segregation of organelles in mitosis
- Cell undergoing division must enlarge its existing organelles, which divide and are distributed in the daughter cells
18
Discuss structure and function of centrosome and centrioles
- Centrosome (aka MTOC: microtubule-organizing center) are specialized cytoplasmic regions near nuclei containing two centrioles (which are organelles) and amorphous pericentriolar material. MTOC is a conductor of microtubule: number, polarity, direction, orientation, organization)- Centrioles oriented perpendicular to one another, comprised of microtubules in 9 x 3 arrangement. Centrioles replicated to form procentrioles which in turn become basal bodies required to form microtubules associated with cilia and flagella- Function: form mitotic spindle in mitosis
18
Examples of proteins that perform enzymatic reactions at cell’s apical surface
- Digestive enzymes on epithelial cells of small intestine- Lactase in GI system, cleaves lactose into galactose and glucose
18
Iron hematoxylin. What has affinity for it? What is the color imparted from this dye? Medical application?
- Color = dark blue to black- Nuclear elements, chromosomes, mitochondria, centrioles and muscle striation have affinity for this dye- No specific medical application indicated
19
What is a specific cell marker for Kaposi sarcoma?
- D2-40 and lymphatic endothelium
20
Marfan syndrome. Defect and clinical consequences?
- Defect: mutation of the fibrillin 1 gene on c/s 15- Clinical: aortic aneurysm or rupture, myopia (near-sighted), detached lens, skeletal defects: long thin arms, legs, toes, fingers, pectus excavatum, scoliosis
21
Describe methods of protein transportation between compartments within cell
1.) Coated vesicle transporta.) Clathrinb.) COPII = anterograde transport from ER to cis Golgic.) COPI = retrograde transport from cis Golgi back to ER.2.) SNARE proteins- These proteins associate with vesicles (v-SNAREs), t-SNAREs associate with targets- Examples = synaptotagmin and synaptophysin- SNARE proteins allow vesicle to recognize its target domain- Example of NT movement- SNAP25/syntaxin associates with secretory vesicle containing neurotransmitter- Vesicle bound to SNAP25, associates with VAMP/synaptobrevin at cell membrane and bulk release of NT occurs
21
What are exosomes?
- Secretory products can be released from cells into the EC environment with the products limited by a membrane. Eg. Reticulocytes discard the transferring receptor in this manner- Some tumors release exosomes
21
A 38 yo male was administered a volatile gaseous anesthetic and succinylcholine prior to surgery. During the procedure, the pt went into tachycardia and development muscle rigidity and became febrile (temp = 108degF). Pt was diagnosed with malignant hyperthermia and treated with cooling blankets, rapid saline infusion IV and dantrolene. Explain what was occurring.
- Halothane (anesthetic) promotes excessive leak of calcium across the ryanodine-1 receptor in the sarcoplasmic reticulum. - Result = increased muscle rigidity from EC coupling and increased contraction in muscle. Increase in body temp is due to increased activity of SR-Calcium pump which moves calcium back from sarcoplasm into SR
22
What protein in the plasma membrane is defective in Dubin-Johnson syndrome?
- Mutations in ATP binding region of MDR-2, therefore impaired transcription and mislocalization of the MDR-2 protein
22
Where are inhaled dust/carbon particles found? Condition associated with this?
- Macrophages in lungs phagocytize dust- Anthracosis is accumulation of carbon particles in lungs and regional lymph nodes. Harmless
23
Describe multivesicular bodies
- Located bw early and late endosomal compartments- pH 5.0-6.2 (aided by membrane-bound proton-ATPases)- Contain large amounts of membrane and vesicles- Eventually fuse with late endosomes, also have secretory role via exosomes- Migrate along microtubules
24
List detailed steps of mitosis
1.) Prophase- chromatids condense, tetrads/bivalents seen, kinetochore forms on centromere, cytoplasmic microtubules disassemble, centriolar pairs migrate to opposite ends of cell2.) Prometaphase- nuclear envelope starts to disappear, mitotic apparatus is becoming organized and microtubules are beginning to attach to kinetochores, chromatids start to become organized at equator of cell, nucleoli disappeared by early prometaphase3.) Metaphase- chromatids located at equator of cell4.) Anaphase- chromatids separate from one another and are referred to as chromosomes, chromatids have their cohesion complex enzymatically degraded by the APC (anaphase promoting complex)5.) Telophase- nuclear membrane reporms, nucleoli reappear, chromosomes unwind into chromatin6.) Cytokinesis- division of cytoplasm
25
Describe physical characteristics of mitochondria
- Comprised of mainly protein, some lipids, small quantities of RNA and mtDNA- Outer membrane: permeable d/t large porins, contains translocator protein- Inner membrane: selectively permeable d/t high conc of cardiolipin, contains enzymes for ETS with translocator proteins- Intermembrane space b/w membranes- Inner membrane invaginates to for cristae (shelf-like in hepatocytes, cardiac and sk muscle cells; tubular in steroid-secreting cells where mitochondria participate in synthesis of steroid hormones)- Matrix contains enzymes for Krebs, beta-oxidation and also matrix granules (phospholipoprotein, calcium, mag)
26
What are clue cells?
- stipling appearance on vaginal epithelium that indicate bacterial vaginal infection- specifically, vaginal epithelial cells are coated with coccobacilli
26
Describe co-translational translocation of polypeptides
- Polypeptide in ribosome contains signal recognition sequence- Signal recognition particle binds to sequence bringing ribosome containing polypeptide to the membrane of the ER. Signal recognition particle binds to receptor- Polypeptide is positioned and fed into ER- Signal peptidase cleaves signal recognition sequence releasing mature protein into ER lumen
26
What is occurring at the cellular level in Duchenne’s and Becker’s muscular dystrophy?
- Dystroglycans (extracellular) and dystrophin (intracellular) are structural proteins that anchor cells plasma membrane to underlying cytoskeleton.- Dystrophins are not present in DMD
27
Silver methods. What has affinity for it? What is the color imparted from this dye? Medical application?
- Color = black- Intermediate filaments of nerve cells, glial cells and reticular fibers have affinity for this dye- No specific medical application indicated
29
Gap junctions (nexus). Structure, function and location?
- Structure: formed by connexon protein structure, which is a hollow cylinder composed of six TM proteins called connexins- Function: electrical and chemical communication bw cells- Location: most tissues, esp. cardiac muscle, smooth muscle and hepatocytes
30
Function of telomerase
- In somatic cells, telomere length decreases with every cell division. When too short, cell loses its capacity to divide- Germinal / stem cells contain telomerase that maintains length of telomere thus sustaining the capacity of cells to divide- Most tumor cells express telomerase
30
Is the rER basophilic or acidophilic?
- Basophilic
30
Describe 4 methods of vesicular transports across plasmalemma. Which is ingestion, which is secretion?
1.) Endocytosis: ingestion2.) Exocytosis: secretion3.) Porocytosis: secretion4.) Exosomes: secretion
30
Difference in utility of frozen vs non-frozen tissue sections?
- Frozen tissue useful when need for urgent diagnosis is urgent (unexpected nodule from surgery, presence of metastasis beyond proposed resection field). Section prepared and evaluated within 10 minutes. Fine detail is lost
31
Clinical relevance of macula adherens
- Pemphigus (skin disease): pts develop antibodies against desmoglein 3 of desmogleins. This disrupts desmosomes that connect skin cells to one another producing a blistering of skin
32
Trypan blue. What has affinity for it? What is the color imparted from this dye? Medical application?
- Color = blue- Macrophages have affinity for this dye- No specific medical application indicated
33
What is ER stress?
- Accumulation of unfolded/misfolded proteins in the ER cisterna
34
H&E. What has affinity for it? What is the color imparted from this dye? Medical application?
- H&E = hematoxylin, basic (blue) and eosin, acid (pink)- RNA, DNA, ribosomes and rER are basophilic and have affinity for hematoxylin- Secretory vesicles, sER, lysosomes, mitochondria and type I collagen are acidophilic have affinity for eosin- Medical application = coagulative necrosis
36
Location of keratinized stratified squamous epithelium
- Epidermis of skin
37
Structure of multiadhesive glycoproteins?
- Have three primary binding sites:- 1.) one for integrins (cell adhesion molecules)- 2.) one for collagen fibers- 3.) one for proteoglycans
38
Exocytosis. What is secreted using this method? Describe where in the cell this occurs? What pathways are used? Energy/substrate requirement?
- Used to secrete proteins/enzymes, hormones and NTs- Secretory vesicles are formed by Golgi, fuse with PM. Trafficking within the cell is dictated by COPs (COat ProteinS) - Two pathways: a.) constitutive: continuous process as product being secreted is synthesized and directly secreted, ie. not stored. b.) regulated: secreted product is stored in vesicles until signal causes product to be secreted- Calcium and ATP
38
Where are tattoo pigments stored?
- Macrophages of dermis
39
Lysosomes. Function, location? Example of lysosomal hydrolase transport
Function?- Transport of hydrolases (with enzymatic activity greater at acidic pH) and other chemicals that are able to digest most biologic molecules. Location?- Found in most cells, but especially abundant in professional phagocytic cells such as neutrophils and macrophagesExample?- Lysosomal hydrolase precursor is tagged when it arrives from ER in Golgi with mannose- As it moves through cisternae of Golgi, it reaches trans Golgi. Packaged into vesicle.- M6P (mannose-6-phosphate) receptor recognizes it in vesicle and transported to lysosome- Defect in M6P synthesis leads to lysosomal storage disease
39
What is FISH?
- Fluorescent in situ hybridization
40
Clinical relevance of lamins
- Mutations associated with cardiomyopathy- Two forms of progeria, a disease that rapidly accelerates aging
41
Effect of colchicine on mitosis
- Arrests dividing cells at metaphase
41
What are heart failure cells?
- Macrophages indicative of CHF
42
28-yo male complains of muscle pain, fatigue within a few minutes of exercise. Continuation of exercise leads to muscle spams. He mentions that his urine is dark after colored spams. Lab studies and tests revealed elevated CK, absence of myophosphorylase activity and lack of lactate production during and ischemic forearm test. a.) What is the name of this disorder?b.) Why the myoglobinuria?c.) Why is CK elevated?d.) Why is lactate production absent?e.) What is the cytoplasmic inclusion seen in the following image? What stain is appropriate?
a.) McArdle’s (glycogen storage disease)b.) Necrosis of muscle and myoglobinc.) Lysis/breakdown of muscle tissued.) No CHO precursor in order to produce lactate, glycogen isn’t degradede.) Glycogen. Stained with PAS reaction
43
Histology of Golgi – describe
- Neither acidophilic or basophilic. Pale-staining area of cytoplasm may be seen in H&E.
44
What is metaplasia?
- transformation of native epithelium into another epithelial type
44
List of exogenous pigments
- Carotene- Inhaled/carbon dust particles- Tattoo pigments
44
What is hemochromatosis?
- Severe accumulation of iron (compared to hemosiderosis) due to a genetic defect resulting in excessive iron absorption or transfusion
45
Differentiate between what is occurring at cis vs trans Golgi
- Cis: transport vesicles carrying newly synthesized proteins from ER to Golgi are being formed for movement through Golgi- Trans: secretory granules, lysosomes and membrane protein-transporting vesicles are being formed
45
What conditions cause accumulation of stored food inclusions within the cell?
- Glycogen accumulation = glycogen storage diseases eg. McArdle disease- Lipid accumulation = lipid storage disease and fatty liver
47
What is Kartagenar syndrome?
- Defect in dynein arms lead to immotile cilia and flagella. These individuals are prone to respiratory infections, bronchiectasis and infertility in men.- Triad seen in these pts: bronchiectasis, situs inversus and chronic sinusitis
48
What is hemosiderin? Color? Location? Clinical relevance?
- Iron-containing pigment- Color = brown- Found in macrophages of spleen and liver- Clinical relevance = hemosiderosis, hemochromatosis, heart failure cells
49
Osmic acid. What has affinity for it? What is the color imparted from this dye? Medical application?
- Color = black- Lipids have affinity for this dye- No specific medical application indicated
50
Discuss mutations in dysferlin gene, clinical relevance and organelle implicated
- Membrane protein-transporting vesicles containing dysferlin and important in repair of microperforations formed in skeletal muscle PM during contraction / relaxation.- In repair process, dysferlin-containing vesicles are shipped from Golgi to cytosolic leaflet of sarcolemma where they accumulate and reseal microperforations in a calcium-dependent manner- In mutated gene, damage membrane is not resealed and muscle degenerates- Results in three types of muscular dystrophy (miyoshi myopathy, limb-girdle muscular dystrophy type 2b and distal myopathy tibialis anterior muscle onset). All forms are characterized by muscle weakness and atrophy of distal (principally) leg or proximal limb muscles
50
What happens to the material after the lysosome has completed its action?
- Digested material diffused out of lysosomes into cytoplasm OR- Residual bodies (undigested wastes) form. Waste product can be eliminated from cell via exocytosis or waste accumulates as cell ages. Eg. Lipofuscin in cardiac and nerve cells.
51
What are microvilli?
- Extensions of apical surface plasma membrane- Contain proteins (actin microfilaments plus others) that allow for movement by their interaction with terminal web containing myosin II and tropomyosin – separation or bringing together or microvilli- Increase absorption
52
What is chromatin?
- DNA coiled around basic histones. Basic structural unit of chromatin is the nucleosome, which has 4 pairs of histone proteins.
54
Characteristics of epithelium
- Cover body’s external and internal surfaces and lines body tubes- Has apical, lateral and basal domains- Anchored to basal lamina- Avascular- Can be glandular
54
What is carotene? Condition associated with excessive amounts?
- Fat-soluble pigment that imparts yellow-orange color- Carotenemia
55
What are the functions of translocator proteins?
- Move proteins from cytoplasm to peroxisomes and mitochondria
56
Function of sER
1.) cholesterol homeostasis via HMG-CoA reductase2.) steroid synthesis3.) synthesis of phospholipids4.) glycogenolysis (G-6-phosphatase is located on intraluminal side of ER membrane5.) detoxification of drugs6.) storage, release and uptake of calcium ions in striated muscle – known as sarcoplasmic reticulum here
57
Clinical relevance of defect in kinesin
- Defect in kinesin motor has been shown to decrease transport of serotonin receptors. Implicated in development of anxiety disorders
58
What is released via porocytosis?
- Quantal release of NTs
59
What inhibits proteasomes?
- Abnormal prions- Bortezomib (used in treating multiple myeloma) causes partial inhibition of proteasomes. Proteasome inhibition decreases degradation of pro-apoptotic factors that then promotes apoptosis of cancer cells.
60
Where is cytokeratin found?
- Found in epithelial cells
60
Function of cholesterol
- Strengthen lipid bilayer and make it less deformable. Less permeable to small, water-soluble molecules
60
Markers for breast cancer?
- Estrogen receptors- HER2/neu (aka ErbB2) receptors- Carcinoembryonic antigen
61
What is hemosiderosis?
- Increased deposition of hemosiderin in tissues and organs- Seen with: increased absorption of iron in diet, impaired use of iron by body, hemolytic anemias and transfusions
62
Compare and contrast cytoplasm and cytosol
- Cytoplasm: part of cell external to nucleus that suspends organelles and inclusions- Cytosol/cytoplasmic matrix: portion of cytoplasm devoid of organelles and inclusions
63
Discuss epithelial cell layer types
1.) Simple: one layer with all cells residing on basement membrane2.) Stratified: a.) 2 or more layersb.) Transitional epithelium (urothelium = specialized type of stratified)3.) Pseudostratified: all cells (one layer) reside on BM, but nuclei at various levels in tissue section giving it a stratified appearance
63
Where is nuclear lamin found?
- Nuclei of all cells
64
Name and describe long-range transport proteins of vesicles using microtubules
1.) Kinesin. Moves vesicles toward periphery2.) Dynein. Moves vesicles toward nucleus
65
List general groups of cellular inclusions
- Stored foods- Pigments- Crystalline
66
Staining of actin
- Phallacidin conjugated with green fluorescein dye
66
Function of rER?
- Synthesis of proteins for secretion, membrane proteins and lysosomal proteins- Synthesis of enzymes associated with sER- Modification of proteins (glycosylation and to assist with protein folding)
67
Function of intermediate filaments
- Structural support
68
Type V Collagen. Tissue distribution, synthesizing cells, function, organization?
1. Tissue distribution: dermis, tendon, bone, fibrocartilage2. Synthesizing cells: fibroblasts, mesenchymal cells3. Function: participates in type I collagen function4. Organization: fibril-forming
69
List steps of mitosis/M-phase
- Prophase- Prometaphase- Metaphase- Anaphase- Telophase- Cytokinesis
69
4 endosomal compartments
1.) Early endosomes2.) Recycling endosomes3.) Multivesicular bodies4.) Late Endosomes• Differ by cytoplasmic location, luminal pH, possess unique molecular markers
70
Function of CHOs in plasma membrane
- CHOs are attached to lipids and proteins forming glycolipids and glycoproteins respectively- Have negative charges which repel other negatively charged substances – keep RBCs aapart- React with regulatory molecules- Play a role in cell-cell and cell-matrix recognition and adhesion- Protection
70
Verhoeff. What has affinity for it? What is the color imparted from this dye? Medical application?
- Color = black- Elastic fibers have affinity for this dye- Medical application = Marfan syndrome
71
Scurvy. Defect and clinical consequences?
- Defect: tropocollagen molecules cannot aggregate into fibrils due to decreased hydroxylation of proline caused by deficiency in vitamin C- Clinical: gum ulceration and hemorrhages
71
Mutation in gene for myosin causes what?
- Severe form of cardiomyopathy
72
Clinical relevance of mitochondria
- Mutations in mitochondrial DNA implicated in DM, deafness, heart dz, Alzheimers Parkinsons and LHON- MERRF: myoclonic epilepsy with ragged red fibers histologically recognized by red appearing mitochondria imparted by using modified trichrome stain. Mitochondria harbor parking lot inclusions and assume peculiar shapes and have cristal disruption. Symptoms of this disorder: myoclonus, seizures and ataxia
73
Where are GFAPs found?
- Glial fibrillary acidic proteins are found in astrocytes
75
Function of versican
- Important in cell-cell and cell-ECM interactions
76
Function of transitional epithelium
- Aka urothelium- Barrier- Protection- Distension
76
What endocytotic processes require actin?
- Macropinocytosis- Phagocytosis
77
Characteristics of ground substance. Function
Characteristics: - Amorphous intercellular material that is transparent, colorless and homogenous, hydrated, fills space b/w cells and fibers, viscousFunction:- Acts as lubricant, barrier and provides structure, diffusion medium for metabolites
78
What are the molecules that make up ground substance?
-Glycosaminoglycans/mucopolysaccharides- Proteoglycans- Multiadhesive Glycoproteins- Water
79
What does shape of nucleus say?
- Can help identify cell type- Also used to classify neoplasms along spectrum. Well-differentiated are typically benign, where non-differentiated is a hallmark typically of malignancy
79
Functions of microtubules
- Supports cytoplasm and gives cell shape- Organelle support- Cell division- Motility of cilia and flagella- Does long range transport of vesicles by microtubule motor proteins, which are ATPases
79
Proteasome. Location, function?
- ATP-dependent protease that is located in the cytoplasm and nucleus- Function: proteolysis of regulatory proteins, malformed/denatured/damaged proteins and antigenic proteins
79
What is Wilson’s disease?
- AR disorder caused by mutation in protein pump for copper in trans-Golgi network of liver cells. - Result= impaired biliary excretion of copper. Kayser-Fleicher rings surrounding iris can sometimes be seen, which is copper deposition in Descemet’s membrane
79
What is immunocyto/histo-chemistry? Discuss two methods and sensitivity of each? Clinical utility?
- Technique that uses antibody tagged with marker (eg. Fluorophore) directed to specific antigen in tissue- Encompasses direct method (antigen conjugates with tagged antibody), which is less sensitive as you have 1:1 conjugation and indirect method (antigen conjugates with more antibodies), which is the more sensitive method- Utility: categorization of tumor origin and analysis of cancer markers. Eg. Cytokeratin presence indicates epithelial cell origin.
80
What foreign substance utilizes non-coated-mediated endocytosis to gain access to the cell?
- Cholera and Shiga toxins
81
What is perlecan? Function?
- Major proteoglycan type found in basement membranes and CT- Function = cell adhesion, proliferation, glomerular filtration, development and growth factor binding
83
Location of simple cuboidal epithelium
- Thyroid follicles- Renal tubules- Ducts of glands
85
What occurs at lipid bilayer to indicate cell death? Why?
- Phosphatidylserine is normally located in the cytosolic lipid monolayer- When translocated to the extracellular lipid monolayer, it marks cell as dead- This signals neighbouring cells to phagocytose and digest the dead cell
85
What endocytotic pathway is implicated in atherosclerosis? Why?
- Clathrin-mediated endocytosis- Cholesterol in form of LDL is taken up by cell in this process. When there is a decrease or defect in LDL receptor, atherosclerosis is thought to occur
86
Components of cytoskeleton
- Microtubules- Microfilaments- Thick filaments- Intermediate filaments
87
Drugs that inhibit polymerization of microtubules
- Colchicine, vinblastine, vincristine- Taxol inhibits depolymerization
88
Clinical relevance of neurofilaments?
- Mutations are associated with neuropathies
89
Where are neurofilaments found?
- Type of intermediate filament found in most nerve cells
90
Where is vimentin found?
- Many mesodermal tissues including Fibroblasts and Chondroblasts
92
Two processes of cell death
1.) Apoptosis – programmed cell death2.) Necrosis – premature cell death
93
How is epithelium classified? Discuss
1.) Cell layers: simple, stratified (transitional), pseudostatified2.) Shape of cells: squamous, cuboidal (uncommon as stratified), columnar (always look at highest cell layer)3.) Specialization of apical domain or degree of keratinization
93
Describe late endosomes
- Located near Golgi apparatus and nucleus- pH ~ 5.0 (aided by membrane-bound proton-ATPases)- These fuse with or mature into lysosomes. Aka prelysosomes
93
Define acid and basic dyes. Define acidophilic and basophilic
- Acid dye: chemical with a net negative charge. Acidophilic structures and components of cells possessing net positive charge will have an affinity for acid dyes- Basic dye: chemical with a net positive charge. Basophilic structures and components of cells possessing net negative charge will have an affinity for basic dyes
95
Function of simple cuboidal epithelium
- Absorption- Secretion- Barrier- Conduit
97
Elastic fibers. Function, attributes/characteristics, synthesizing cells, molecular composition
1.) Function: imparts tissue with elasticity2.) Attributes: slender and branched, densely arranged in bundles, nonfibrous elastic tissue arranged in fenestrated sheets (blood vessels), turnover is poor3.) Synthesizing cells: fibroblasts, smooth muscle cells, chondroblasts4.) Molecular composition: three components needed to form elastic fibers: a.) proelastin (tropoelastin = cleaved form), b.) microfibril-associated glycoprotein and c.) fibrillin (1&2)
99
Describe details of interphase
a.) G1- most variable in length, replication of centrioles begins here, has checkpoints: G1 DNA-damage checkpoint, restrictionb.) S- DNA synthesis with or without division of nucleus (tetraploid, octaploid cardiomyocytes), centriole replication continues, S DNA-damage checkpointc.) G2- accumulation of ATP for mitosis, synthesis of tubulin to form microtubules, centriole replication complete, checkpoints: unreplicated DNA, G2 DNA-damaged.) G0- Seen in non-dividing cells such as striated muscle and most neurons\*\* Cell cycle is driven by cyclin-cdk complexes
99
Describe unfolded protein response. Why does this occur?
- Unfolded protein response occurs as a result of ER stress- Chaperone synthesis increases in attempt to repair unfolded/misfolded proteins- There is decreased synthesis of proteins- Misfolded proteins are exported from ER to the cytosol where they are tagged for degradation by proteasomes (ubiquitin)- Caspases are activated that can lead to apoptosis if issues aren’t dealt with
101
A newborn male was born with complete syndactyly of digits three and four. To correct the problem, surgery was performed at 6 months of age. How was apoptosis implicated?
- Apoptosis is crucial in many developmental process. They need to occur between digits, otherwise polydactyly can occur.
101
What is occurring at the cellular level in Creutzfeldt-Jakob disease?
- CJD occurs when PrP (normal prior protein), which is a cell-surface glycosylated GIP anchored protein (in lipid rafts) on neurons is converted into an abnormal variant.- The variant forms cross-linked filaments and is resistant to proteolysis- In addition, variant accelerates conversion of other proteins to its form- Normal proteins may be neuroprotective against ischemia, control circadian rhythms and serve to organize myelin sheath- Symptoms: ataxia, dementia and paralysis
102
What is Zellweger syndrome?
- Defect in import of peroxisomal enzymes to peroxisome- Due to defective import protein on unit membrane of peroxisome
103
Function of digoxin
- Digoxin partially inhibits Na/K pump leading to decreased activity of Ca/Na transporter, leading to an increase in sarcoplasmic Ca ion concentration, which improved cardiac pump performance
105
Types of proteoglycans
1.) Syndecan2.) Perlecan3.) Decorin4.) Versican5.) Aggrecan
107
What are multiadhesive glycoproteins?
- Glycoproteins that molecularly tether cell to EC elements
108
What are targeting signals and what is their function?
- Targeting signals are sequences of AAs in protein that direct proteins to their target compartments by binding to receptors that are specific for the organelles. Escort factors may deliver protein to the target organelle
109
Are ribosomes found in erythrocytes?
- Only in immature erythrocytes
110
Feulgen reaction. What has affinity for it? What is the color imparted from this dye? Medical application?
- Color = magenta (purplish-pink)- DNA has affinity for it- Medical application = nuclear changes in cancer
111
What exogenous molecules block the electron transport system?
- CO and CN
112
Defects in primary cilia results in what pathologies?
- Polycystic kidney disease, polydactyly, vision and hearing loss
114
What cell types synthesize reticular fibers? In what tissues are reticular fibers found?
- Fibrocytes, reticulocytes, smooth myocytes and Schwann cells- Tissues: spleen, liver, lymph nodes, smooth muscle, skin and lung
115
Achondroplasia at the cellular level
- FGF binds FGFR3 (fibroblast growth factor) and is endocytosed- Both ligand and receptor are usually targeted for lysosomal degradation as a means to terminate signaling- In achondroplasia, lysosomal targeting is degraded as there is a mutation in FGFR3. Instead, FGFR3 (still active) is recycled to plasmalemma and amplifies FGF signaling. Result = abnormal bone growth leading to most common cause of dwarfism.
116
Name the steps required, chemical used if applicable and purpose of each step in preparing tissue for light microscopic examination
1.) Fixation: formalin, gluaraldehyde. Preserves normal tissue architecture after death by fixating, coagulating and/or precipitating proteins.2.) Dehydration: graded series of ethanol (to 100%). Removes water from tissue specimen and replaces with alcohol.3.) Clearing: xylene. Prepares tissue for embedding medium.4.) Embedding: paraffin. Tissue infiltrated with paraffin so that it is hard enough to section5.) Sectioning: tissue cut into section with microtome.6.) Mounting: paraffin section is placed on glass microscope slide7.) Staining: impart contrast to tissue structures for distinguishing under microscope
117
What foreign substance utilizes caveolae-mediated endocytosis?
- Simian virus 40
119
Location of nonkeratinized stratified squamous epithelium
- Esophagus- Distal anal canal- Vagina
119
Structure of hemidesmosomes
- Cytoskeletal element = intermediate filament, mainly cytokeratin in epithelial tissue- Intracellular anchor proteins = intracellular attachment plaque, plectin and BP230- Cell adhesion molecules = integrin family and type XVII collagen (aka BPAG2 transmembrane protein) interacts with ECM of basal lamina
120
Where are crystalline inclusions found?
- Cells of Leydig (crystal of Reinke) of testis- Sertoli (inclusion of Charcot-Bottcher) cells of testis
122
Function of focal adhesions
- Anchor cell to matrix
123
What pigment is implicated in Parkinson’s disease?
- Neuromelanin contained in membranes within dopa cells in substantia nigra
124
What is atlastin? What does increased amounts of atlastin lead to? Atlas deficiency?
- GTPase involved in constructing and shaping the ER- Increased ER membrane fusion and normal Golgi absent- Atlastin deficient = ER that is fragmented. Deficient atlastin linked to hereditary spastic paraplegia - - symptoms = leg stiffness, gait disturbances, mental retardation, extrapyramidal symptoms, dysmorphic features
125
What is a brush border? How to stain for this?
- Striated appearance of well-developed microvilli on epithelia- Contains carbohydrate coat called glycocalyx – PAS (magenta) positive
126
Discuss role of primary cilium in development of kidney pathology
- Defect in polycystin 1 / 2 causes defect in calcium signaling at primary cilium- In normal morphogenesis of kidney epithelial cells, normal polarity of cell occurs in direct of tubule – normal mitotic spindle orientation- In polycystic kidney disease, morphogenesis of epithelial cells occur in planar orientation and there is expansion of the lumen of the tubule causing cyst development – incorrect mitotic spindle orientation
128
Function of simple squamous epithelium
- Blood-brain barrier- Filtration- Exchange
128
Clinical relevance of nexus/gap junctions
- Female infertility- Neuropathy- Deafness- Congenital cataracts- Cardiac arrhythmias
130
List classifications or specializations of the plasmalemma of epithelial cells
- Cilia = motile; monocilia = non-motile = primary cilia; and monocilia = motil = nodal- Flagella- Microvilli- Stereocilia (better term = stereovilli)
131
Is sER acidophilic or basophilic?
- Acidophilic
133
Structure of thick filaments
- Myosin
134
Describe macropinocytosis
- Occurs in thyroid cells as they take up thyroglobulin and in dendritic cells for immune surveillance- Actin-based process- Nonspecific ingestion of fluid and solutes- Can be triggered by bacteria
136
Structure of intermediate filaments
Composed of various molecules depending on tissue:1.) Cytokeratin2.) Desmin3.) Vimentin4.) Neurofilaments5.) Glial fibrillary acidic proteins6.) Nuclear lamins
136
Marfan syndrome commonly leads to a thinning of the elastic fiber layer of the aortic valve. What staining technique would you use to identify this layer from a tissue cross-section?
- Verhoeff
138
What happens to the hydrated state of tissue where there is excessive accumulation of GAGs? No change, decrease and increase?
- Increase
139
Strickler syndrome. Defect and clinical consequences?
- Defect: mutation in Col2A1 gene encoding for type II collagen- Clinical: myopia (near-sighted), hypoplasia of mandible, arthritis
140
Describe proinsulinemia in context of Golgi
- Mutated proinsulin is missorted and placed into constitutive pathway- Prohormone converting enzymes are sorted correctly into regulated pathway- Consequently, there is absence of prohormone coverting enzyme activity in upregulated pathway
141
Describe 4 fates of receptor-ligand complexes. Provide examples.
1.) Receptor is recycled and ligand is degraded or released for cellular use. Example = LDL and its receptor2.) Receptor and ligand are recycled. Example = iron and it transferring receptor3.) Receptor and ligand are degraded. Example = FGFR3 with ligand FGF4.) Receptor and ligand are transported across cell and secreted (transcytosis): how glandular cells secrete antibodies
142
Name specific chemical transport proteins. Function?
- Na/K pump: regulates intracellular volume, electrochemical gradient- Ca/Na transporter- Glucose/sodium co-transport pump utilizing Na/K pump- Multidrug resistant transporters: primary transporter proteins that are ATases. MDR-1 (kidney, liver, intestine and BBB) pumps cytotoxic agents out of cell. MDR-2 transports conjugated (direct) bilirubin. MDR-3 (liver) functions as flippase of PC, flipping to the outer layer of hepatocytes so that it may be excreted into bile
142
List 5 distinct endocytosis methods
1.) Macropinocytosis2.) Clathrin-mediated endocytosis3.) Non-coated-mediated endocytosis4.) Caveolae-mediated endocytosis5.) Phagocytosis
144
Describe selective/non-selective transport through nuclear pores
- Pores are freely permeable to molecules and ions with diameter less than 9 nm- Selective transport of: RNAs, ribosomal subunits, proteins and other larger (greater than 9 nm) molecules and ions- Transports occurs in an energy-dependent GTP manner with Ran, importin, exportin proteins
145
Name lysosomal storage disease. What enzyme is deficient, what metabolite accumulates?
1.) Type II Pompe’s dz: alpha-1,4-glucosidase defiency causing accumulation of glycogen2.) GM1 gangliosidosis: GM1 ganglioside beta galactosidase deficiency causing accumulation of GM1 ganglioside, galactose-containing oligosaccharides3.) GM2 gangliosidosis (Tay Sachs): hexosaminidase-alpha-subunit deficiency causing accumulation of GM2 ganglioside4.) GM2 gangliosidosis (Sandoff): hexosaminidase-beta-subunit deficiency causing accumulation of GM2 ganglioside and globoside5.) Metachromic leukodystrophy: arylsulfatase A deficiency causing accumulation of sulfatide6.) Gaucher: glucocerebrosidase deficiency causing accumulation of glucocerebroside7.) Hurler: alpha-L-iduronidase deficiency causing accumulation of dermatan and heparan sulfate
147
Osteogenesis imperfecta. Defect and clinical consequences?
- Defect: mutations in Col1A1 leads to reduction in the synthesis of type I collagen- Clinical: spontaneous fractures and cardiac insufficiency
149
Clinical relevance of basal lamina and basement membrane?
- Basal lamina prevents spread of epithelial tumors unless broken down- Goodpasture Syndrome = autoimmune dz in which antibodies develop against specific type IV collagen subunit- Developmental failure demonstrated in mouse model if laminin is defective or has deficit
150
Discuss production of proteins for mitochondria
- Small proportion of mitochondrial proteins and oxphos enzymes are produced within the mitochondria- Most are synthesized by free polyribosomes of cytoplasm and are actively imported into mitochondria by translocator proteins
152
Clinical relevance of zonula occludens
1.) Mutation in gene encoding specific claudin in renal epithelium results in excessive loss of mag ions and severe hypomagnesemia leads to neuromuscular symptoms2.) Brain CA can lead to loss of claudin 5 causing breach of blood-brain barrier3.) Loss of claudin 9 shown to cause deafness4.) Cholera amongst other things attacks ZO proteins causing breach of tight junctions and fluid loss5.) Occludins are disrupted by H. pylori
153
Structures of nuclear envelope
1.) Bilayer membrane2.) Perinuclear space3.) Nuclear pores penetrating bilayer
154
Discuss what is occurring at the cellular level in nephrogenic diabetes insipidus
- Aquaporin-2 is expressed in renal collecting tubule cells and reabsorbs water- Vasopressin (ADH) receptor causes translocation of aquaporins to plasmal membrane and increase reabsorption of water across apical surface. - This disorder results when both aquaporin-2 is inactivated by mutations and therefore doesn’t respond to vasopressin signaling- As a result, glucose is concentrated in blood
155
Clinical relevance of proteasome
- Defective ubiquitination of proteins implicated in Parkinson’s disease- Form of CF involves proteasomal degradation of a CFTR ABC transport variant that is slow to fold, but is competent
157
List types of glycoproteins. What are their binding domains and where are they located?
1.) FibronectinBinding domains: integrins, collagen, heparin, heparan sulfate and hyaluronic acidLocation: CT, blood plasma, embryonic tissue2.) LamininBinding domains: integrins, heparan sulfate, collagen (IV) and entactinLocation: basal lamina3.) Nidogen (entactin)Binding domains: laminin and type IV collagenLocation: basal lamina4.) TenascinBinding domains: syndecans and fibronectinLocation: embryonic tissue5.) ChrondronectinBinding domains: collagen II, chondroitin sulfates, hyaluronic acid and integrins of chrondrocytesLocation: cartilage6.) OsteonectinBinding domains: collagen I, proteoglycans, integrins of bone cells (cytes and blasts)Location: bone
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Are lysosomes acidophilic or basophilic?
- Lysosomes are acidophilic
160
List classifications of junctional complexes
1.) Zonula occludens (tight junction)\*2.) Zonula adherens\*3.) Macula adherens4.) Focal adhesions5.) Hemidesmosomes6.) Gap junctions (nexus)\* Belt-like connection that goes around the entire cell
160
3 types of melanin. Color, location, function/clinical relevance
1.) Eumelanin- Color: brown-black pigment- Location: membrane-limited granules in epidermis and pigment layer of retina- Function/relevance: increased production in response to UV radiation and increased in Addison’s disease in response to elevated ACTH. Absent in albinos due to an absence of tyrosinase2.) Neuromelanin- Color: black-brown pigement- Location: neurons, including substantia nigra and locus coeruleus, found in membrane-limited neuromelanin granules- Function/relevance: putative neuroprotective function, depigmentation of dopa cells located in substantia nigra of pts with Parkinson’s disease3.) Phaeomelanin- Color: red pigment- Location: hair- Function/relevance: responsible for red hair color, not protective against UV radiation
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Prussian blue. What has affinity for it? What is the color imparted from this dye? Medical application?
- Color = blue- Hemosiderin (ferric iron) has affinity for this dye- Medical application = excessive iron accumulation in hemochromatosis
162
What is in situ hybridization? Clinical utility?
- Use of complementary nucleic acid probes to specifically identify nucleic acid sequence of interest- Utility: used to identify cell infected with virus, specific genes on a chromosome, detect amplification of genes
164
Distinguish between the inner and outer nuclear membranes
Outer: - Studded with ribosomes, which synthesize proteins located on outer membrane, inner membrane or within perinuclear space. This is continuous with rERInner:- closely associated with nuclear lamina
166
Describe events that allow CA cells to become metastatic
1.) Changes in junctional complexes/adhesion- Mutation in E-cadherins- Decreased number of E-cadherins- Catenins that are non-functional or absent- Alteration in integrin numbers or structure2.) Cytoskeleton alteration3.) ECM altered: proteases digest this barrier (synthesis and release of their own proteases or stimulating other cells to release proteases?)4.) Enter blood vessels (evade physical forces and leukocytes)5.) Expression of adhesion molecules: allow CA cells to bind endothelium at distant site and invade/seet into new tissue6.) Following invasion, replication occurs and they form secondary tumor
167
What is the aging pigment? Where is it stored?
- Lipofuscin- Accumulates in long-live cells like neurons and cardiac/skeletal muscle cells
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Two pathways involved in apoptosis
1.) Extrinsic pathway- Fas ligand binds to Fas receptor (known as death receptor)- Adaptor proteins activated intracellularly- Inactive procaspase-8 is cleaved to form activated caspase-8 (executioner caspase)2.) Intrinsic pathway- Cell injury causes release of cytochrome c- Cytochrome c-adaptor protein (Apaf-1) oligomerizes- Inactive procaspase-9 is cleaved to form activated caspase-9 (executioner caspase)
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Type III Collagen. Tissue distribution, synthesizing cells, function, organization?
1. Tissue distribution: spleen, liver, lymph nodes, smooth muscle, skin, lung2. Synthesizing cells: smooth muscle cells, fibroblasts, reticular cells3. Function: maintains structure in expansible organs4. Organization: fibril-forming
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A 38 yo male presents with fatigue and edema. Lab studies reveal urine sediments, urine protein, primary albumin. Biopsy of kidney was obtained and sent to pathology. Membranous nephropathy seen: Prominent spikes of silver-staining matrix projecting from basement membrane lamina densa toward urinary space, which separate and surround deposited immune complexes that lack affinity for silver stain. Electron micrograph shows electron-dense deposits along epithelial side of basement membrane. What is the diagnosis?
- Goodpasture’s Syndrome: autoimmune dz in which antibodies develop against specific type IV collagen subunit.- Leakier kidneys
170
Describe process of phagocytosis
1.) Ingestion of large particles is mediated by zipper-mediated receptors (Fc receptors)2.) This process is dependent on actin, but does not require clathrin3.) Particle packaged into phagosomes4.) Phagosomes fuse with lysosomes where particles are degraded
172
Discuss role of nodal cilia in embryological development. Discuss defect in this
- These cilia are motile (appearance of non-motile) and located in primitive node- Their action directs fluid flow in primitive node from right to left and helps establish left/right axis- Defect = situs inversus and dextrocardia (apex heart to right)
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What is alpha1-antitrypsin deficiency?
- Mutant protein aggregates in ER
175
Golgi apparatus function?
Major sorting and distribution center- Proteins sorted based on chemical moieties such as sequences of AA or attached CHOs- Proteins are modified in Golgi (glycosylation, sulfation, phosphorylation, oligosaccharides previously added are trimmed, proteolytic cleavage of proteins)- Proteins packaged into vesicles
175
Discuss synthesis of phospholipids
- Synthesis of phospholipids occurs principally in cytosolic lipid monolayer of sER. Phospholipid translocators, membrane-bound enzymes catalyze flip-flop of phospholipds from one monolayer to another. Without this, new bilayers couldn’t be synthesized. There is a phospholipid exchange mechanism that allows phospholipids synthesized in ER to be transported and added to the membranes of other organelles
177
A five month old male presents with a constellation of craniofacial congenital malformations. These include a high forehead, large anterior fontanelle, deformed earlobes, micrognathia, and widened nasal bridge. Other findings are hypotonia, depressed deep tendon reflexes, seizures, cataracts and retinal degeneration. Lab results show an elevation of VLCFAs and pipecolic acids in the plasma and a decrease in erythrocyte plasmalogens. What is the most likely diagnosis?
- Zellwegers syndrome
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List of glycosaminoglycans
1.) Dermatan sulfate2.) Chondroitin sulfate3.) Heparan sulfate4.) Keratan sulfate5.) Hyaluronic acid6.) Heparin
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Location of simple squamous epithelium
- Blood vessel (known as endothelium)- Alveolus- Mesothelium
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What endocytotic pathways are triggered by:a.) Salmonella typhimuriumb.) Cholera, Shiga toxinsc.) Simian virus 40
a.) Macropinocytosisb.) Non-coated-mediated endocytosisc.) Caveolae-mediated endocytosis
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Function of pseudostratified ciliated columnar epithelium
- Secretion- Absorption- Barrier- Transport
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Nucleolus. What is it? What are the components of it? Function?
- Organelle within the nucleus that is not membrane bound, serves as location for ribosome synthesis and assembly- Rich in rRNA and protein, size proportional to state of protein synthesis- Three components:a.) Nucleolar-organizer DNA: contains sequence of bases that code for the transcription of rRNAb.) Pars fibrosa: Newly transcribed rRNA just beginning to become complexed with proteinsc.) Pars granulose: maturing subunits or ribosomes
184
List and describe the function nuclear bodies (domains)
1.) Nucleolus2.) Cajal bodies: modifying and assemblying molecular machinery to splice pre-mRNA to mRNA. Molecules here include snRNA, snoRNA, snRNPs.3.) GEMs (Gemini of Cajal bodies): resemble Cajal bodies, may not be distinct. Proposed function is same as Cajal bodies4.) Interchromatin granule clusters (speckles): represent storage depots of snRNAs and proteins. These molecules are released into karyoplasm and become engaged in pre-mRNA splicing.5.) Promyelocytic leukemia bodies (PML): involved in modifying and assemblying proteins tasked with DNA repair and triggering apoptosis. May also engage in repression of transcription and protect against certain viruses.6.) Polymorphic interphase karyosomal association (PIKA). Elusive function, proposed that these bodies are involved in promoting transcription of snRNA.
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23 yo male admitted to hospital for fulminant hepatorenal failure. Pt was jaundiced, Kayser-Fleischer rings absent and pt was confused, combative and unable to cooperate or communicate during exam. Ratio of alk phos to total bili = 0.05, very low value, ceruloplasmin was normal. Microscopic exam of liver biopsy show steatohepatitis and was negative for copper. Pt ultimately died a few days after admission. On autopsy, greenish-yellow appearance on sectioning of the liver with signs of cirrhosis. Copper was 979 ug/gram (normal range: 10-35). What is the diagnosis?
- Wilson’s disease- Ceruloplasmin is normal (normally decreased in Wilson’s)- Kayser-Fleischer rings may or may not be seen in Wilson’s (not in this case)- Biopsy didn’t show copper while pt was alive. Biopsy sample was area that wasn’t affected. Multiple biopsies should have been performed.
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Effect of antilipidemics (eg. Lipitor) on peroxisomes
- Lipitor leads to increased uptake of TGLs and cholesterol by hepatic cells- Increased uptake ramps up beta oxidation of FAs by mitochondria and peroxisomes- Peroxisomes increase in number during chronic administration of antilipidemics
189
What is seen in sER with protracted use of drugs and etoh?
- Volume of sER increases as a result of increased concentration of cytochrome P450 enzymes
191
List types of glycoproteins
1.) Fibronectin2.) Laminin3.) Nidogen (entactin)4.) Tenascin5.) Chrondronectin6.) Osteonectin
192
Location of ciliated simple columnar epithelium
- Uterine tubes
194
Type VII Collagen. Tissue distribution, synthesizing cells, function, organization?
1. Tissue distribution: dermis2. Synthesizing cells: epidermal cells3. Function: anchors lamina densa to lamina reticularis4. Organization: anchoring
195
What is occurring at cellular level in Alzheimer’s disease?
- Abnormal cleavage of Beta-amyloid precursor protein, beta-app into alphabeta peptides, which aggregate and are resistant to proteolysis. This precursor protein is important in neuronal migration in development, synaptic formation and repair, cell signaling, long-term potentiation, memory and cell adhesion.
197
Structural characteristics of junctional complex
- Cytoskeletal element (actin or intermediate microfilaments) – if epithelial tissue, intermediate filament = cytokeratin- Intracellular anchor proteins- Cell adhesion molecules (TM proteins) = CAMs
199
What chemical is used to stain reticular fibers?
- Silver (argyrophilic) and PAS (magenta color)
201
42 yo female presents with mass in her neck. She complains of difficulty breathing and swallowing. PEX reveals palpable, firm, nontendern nodule in thyroid gland area. Lab studies show elevations of thyroxine and triiodothyronine in blood. Biopsy of thyroid gland obtained and sent to path. The pt is diagnosed with papillary thyroid cancer. What histologic features informed the diagnosis?
- Orphan Annie eye nuclei, which refer to clear nuclei
202
List fibers of ECM
1.) Collagen2.) Reticular3.) Elastic
203
What is nucleostemin?
- p53 binding protein found in undifferentiated cells. It decreases as cells become differentiated. Presence in CA cells may play a role in unchecked proliferation.
205
Type IV Collagen. Tissue distribution, synthesizing cells, function, organization?
1. Tissue distribution: basal lamina2. Synthesizing cells: endothelial cells, epithelial cells, Schwann cells and smooth muscle cells3. Function: support of delicate structures and filtration4. Organization: network-forming
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Location of nonciliated simple columnar epithelium
- Stomach, intestines
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What is granulation tissue?
- Tissue that is the hallmark of tissue repair
209
What is syndecan? Function?
- Syndecan is a type of proteoglycan where core protein of molecule is embedded in cell membrane as transmembrane protein- In fibroblasts, syndecan serves as co-receptor for fibroblast growth factor
210
Type XI Collagen. Tissue distribution, synthesizing cells, function, organization?
1. Tissue distribution: hyaline cartilage2. Synthesizing cells: chondroblasts3. Function: participates in type II function4. Organization: fibril-forming
211
Location of pseudostratified ciliated columnar epithelium
- Trachea (has thick basement membrane)- Bronchi- Ducts of male reproductive system (stereocilia)
212
Excessive deposition of collagen
- MI- Keloid/scar formation
214
What anchors the basal lamina to the lamina fibroreticularis?
- Anchoring fibrils of type VII collagen, fibrilin and fibronectin
215
What is lipofuscin? Color? Location? Function/clinical relevance?
- Aka lipochrome pigment, aka wear and tear pigment, aka aging pigment- Color: brownish-yellow pigment that is amalgam of lipids, metals and organic molecules- Location: accumulates in long-live cells like neurons and cardiac/skeletal muscle cells- Function/relevance: accumulation is a measure of cellular stress and is observed in severe malnutrition and cachexia
216
Types of stored foods in cells? Location?
- Glycogen: stored in liver and striated muscles (skeletal and cardiac) cells- Fat: found in adipocytes, hepatocytes, muscles and steroid-secreting cells
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Color of bilirubin pigement? When is it seen elevated?
- Yellow-brown pigment- Elevated in liver and biliary disease, skin and sclera appear yellow – known as jaundice (icterus)
219
Effect of prions on proteasomes?
- Abnormal prions inhibit proteasomes
220
Function of basal lamina and basement membrane?
- Adhesion interface bw epithelium and ECM, molecular filter, regulation of cell differentiation, proliferation, organization and regeneration of cells
221
Structure of proteoglycans
- Linear chains of glycosaminoglycans bound to protein core, majority of weight is attributable to CHOs
222
Junctional complexes that anchor cells together
- Zonula occludens- Zonula adherens- Macula adherens
223
Describe early and recycling endosomes.
- At cell’s periphery- pH 6.2-6.5 (aided by membrane-bound proton-ATPases)- Glucose transport in response to insulin??
224
When is increased eumelanin seen in cells clinically? Absence?
- Increased production in response to UV radiation- Increased in Addison’s disease in response to elevated ACTH- Absent in albinos
226
Functions of proteins in plasmalemma
- Receptors- Transport- Enzymatic control of chemical rxns- Linker proteins for structural support- Cellular ID tags (antigens)- Intercellular junctional complexes
227
What is spinal muscular atrophy?
- Fatal disorder characterized by muscle wasting- Mutation of SMN (survival of motor neurons) gene encodes a defective SMN protein that is localized to the GEMs. Normal protein functions in snRNA production. When defective, death of motor neurons in anterior gray horns of spinal cord results.
228
Function of stratified squamous epithelium
- Barrier- Protection
229
Based on the general blueprint for junctional complexes, what component does integrin represent?A.) Intracellular anchorB.) Cell adhesion moleculeC.) Cytoskeletal element
- Cell adhesion molecule
230
Structure of macula adherens (desmosomes)
- Cytoskeletal element = intermediate filament, mainly cytokeratin in epithelial tissue- Intracellular anchor proteins = intracellular attachment plaque- Cell adhesion molecules = desmoglein and desmocollin (cadherin family)
232
Types of proteins found in plasma membrane
- Peripheral- Integral proteins (including transmembrane proteins)
233
Structure of focal adhesions
- Cytoskeletal element = actin- Intracellular anchor proteins = vinculin, paxillin, talin- Cell adhesion molecules = integrin contacts with fibronectin (adhesive glycoprotein)
234
A mother brings her 10 yo son to pediatrician. She is concerned about his chronic respiratory problems and recurring episodes of ear infections. The PEX reveals swollen nasal mucosa, impaired sense of smell and abnormal lung sounds. Nasal biopsy was obtained and sent to pathology and imaging studies were ordered. Cilium at EM level shows that dynein arms are absent. Imaging studies performed indicate maxillary sinus inflammation, bronchiectasis (dilation of bronchi) and situs inversus with dextrocardia.A.) DiagnosisB.) Explain why bronchiectasis is seenC.) Explain why situs inversus is seen
- A.) Ciliopathy – specifically: Kartagener Syndrome with classic triad - B.) Cilia defective and non-motile, so mucous remains and bacterial infection occurs leads to chronic inflammation and dilatation of bronchi- C.) Nodal cilia are defective and are unable to establish movement of fluid in a left-right direction within the primitive node. As a result, no left/right axis symmetry is established
235
In what order are apical-lateral junctional complexes found?
- Zonula occludens, zonula adherens and macula adherens- In order of apical to basal on the lateral domain
236
List three cellular constituents. Describe briefly
1.) Organelles: structural elements conferring functional attributes to cell. These and are membranous and non-membranous2.) Inclusions: nonliving entities found in cytoplasm and nucleus – stored food, pigements and crystalline3.) Cytoplasmic matrix / cytosol: portion of cytoplasm devoid of organelles and inclusions – typically about 50+% of volume of cell
238
Structure of Golgi apparatus? Location?
- Organelle that is typically located in proximity to nucleus (in polarized cells, located between nucleus and apical face of cell).- Comprise of 3-10 slightly curved flattened membranous sacs (cisternae)- Cis (convex) face presents towards transitional ER- Trans (concave) face is opposite to cis face
239
What is anthracosis?
- Accumulation of carbon particles in lungs and regional lymph nodes. Harmless
240
Is the mitochondria acidophilic or basophilic?
- Acidophilic
241
How does mitochondria regulate apoptosis?
- Release of cytochrome c from mitochondrial activates the apoptotic cascade
243
Functions of microfilaments
1.) Structural support (cell cortical fibers)2.) Forms core of microvilli and sterocilia3.) Movement (muscle contracts, cell migration, short-range transport of organelles)4.) Cytokinesis5.) Formation of filopodia and lamelipodia
244
Is the nucleus basophilic or acidophilic?
- Basophilic d/t presence of negatively charged phosphate groups on nucleic acids
245
Clinical relevance of perlecan
- Enhanced in some types of tumors, promoting proliferation and angiogenesis
246
PAS reaction. What has affinity for it? What is the color imparted from this dye? Medical application?
- PAS = periodic acid Schiff. Color = magenta- CHOs (glycogen, glycoproteins) have affinity for this dye- Medical application = outlines thickened basement membranes in kidney disease, glycogen storage diseases and in alpha1-antitrypsin deficiency in hepatocytes
247
What is a nuclear inclusion body?
- Presence of nuclear inclusion is indicative of disease such as CMV infection
249
What apoptotic strategies are seen with cancer cells?
- Some types of tumor cells evade an immune attack by expressing Fas ligand (FasL) referred to as FasL counterattack. This causes destruction of immune cells by triggering their elimination via apoptosis- Increase anti-apoptotic factors
250
Mallory triple. What has affinity for it? What is the color imparted from this dye? Medical application?
- Color: nuclei = red, muscle = red to orange, collagen = blue, hyaline cartilage = blue- Nuclei, muscle, collagen and hyaline cartilage have affinity for this dye- Medical application = highlighting fibrosis
252
Type XII Collagen. Tissue distribution, synthesizing cells, function, organization?
1. Tissue distribution: tendons, ligaments2. Synthesizing cells: fibroblasts3. Function: binds collagen fibrils to one another4. Organization: fibril-associated
254
What stains elastic fibers?
- Resorcin-fuchsin or Verhoeff stains (black)
256
Describe composition of ribosome and where each of the subunits are synthesized
- Composed of protein and rRNA- rRNA is synthesized in the nucleolus, proteins are imported into the nucleus and associate with rRNA in nucleolus- Subunits are exported to cytoplasm and assembled
258
Clinical relevance of knowing intermediate filament types
- Analysis of neoplastic cells for intermediate filament type allows pathologist to determine type of tumor
259
Describe what is occurring at cellular level with cholera toxin
- Ganglioside GM1 is a glycolipid that serves as a cell receptor for cholera toxin- Toxin enters cell by binding GM1- Causes increased synthesis of cAMP- Causes a substantial efflux of Na ions and water into intestine (for example) – net result = diarrhea
260
Define metachromasia. Stain used?
- Is a phenomenon in which a given stain imparts different colors to the tissue- Stain = toluidine blue
261
Where are stereovilli/cilia found?
- Male reproductive ducts – ductus deferens, ductus epididymus and sensory epithelium in inner ear- Resemble microvilli, with actin filaments, but different protein-protein arrangement
262
Clinical relevance of GFAP
- Aggregates of GFAP known as Rosenthal’s fibers are demonstrated in Alexander disease (a degenerative disease of white brain matter), chronic gliosis and astrocytomas
263
Describe structure of microtubules
- How tubules that are comprised of 13 longitudinally arranged protofilaments, each with subunits known as tubulin dimers- Microtubules polymerize and form ring of gamma-tubulin within a micro-tubule organizing center possessing capping proteins. This polymerization process requires GTP and mag ions
264
Structure and function of glycosaminoglycans
- Linear polymers of disaccharides that have negatively charged carbosyl groups that attract cations, which attract extracellular fluid. Function here = hydrating effect, which allows for compression resistance
265
List 3 secretory pathways from the cell
1.) Exocytosis: bulk secretion2.) Porocytosis: quantal secretion, new model of NT release3.) Exosomes
267
What is the most abundant protein in the body?
- Collagen (20-25% of all protein), specifically type I
268
What is a specific cell marker for cells of epithelial origin?
- Cytokeratins
269
Discuss functional importance of claudins to occludins
- Claudin to occludin ratio determines permeability between epithelial cells- High ratio of claudins to occludins = high permeability- Low ratio of claudins to occludins = low permeability (ie. Blood-brain barrier)
270
Clinical relevance of SNARE proteins
- neurotoxins of tetanus and botilism enter nerve terminals and proteolyse SNARE proteins- this prevents vesicles containing NTs from docking with pre-synaptic membrane of nerve cell
271
What are reticular fibers?
- Reticular fiber are composed of type III collagen
272
Function of simple columnar epithelium
- Absorption- Secretion- Barrier
273
List structures of nucleus
- Nuclear envelope- Nuclear (fibrous) lamina- Nuclear matrix (nucleoplasm)- Chromatin- Nuclear bodies
274
What type of intermediate filament constitutes the Mallory body?
- cytokeratin
275
What amino acid is measured to calculate the concentration of collagen?
- Hydroxyproline or hydroxylysine, both which are specific to collagen- Glycine is principle AA in collagen, but not specific for it
276
What is the molecular composition of motile cilia?
- 9 doublets of microtubules plus central pair of microtubules- Dynein molecules (are ATPases) that extend from doublets to center- Base of cilium = basal bodies (9 triplet sets of microtubules)
276
How does estrogen have an anti-apoptotic effect? Clinical relevance.
- Estrogen has anti-apoptotic effect on osteoblasts- Estrogen causes inactivation of Bad (pro-apoptotic molecule) through phosphorylation- Aging causes decrease in estrogen, no shutting off of Bad and osteoblasts don’t survive as much, therefore bone cell loss, bone matrix loss and osteoporosis
277
Clinical relevance of desmin
- Mutations in desmin are involved in cardiac and skeletal myopathies
278
Type II Collagen. Tissue distribution, synthesizing cells, function, organization?
1. Tissue distribution: hyaline and elastic cartilage2. Synthesizing cells: chondroblasts3. Function: resistance to pressure4. Organization: fibril-forming
279
Functions of peroxisomes
- Beta-oxidation of FFAs- Plasmalogen synthesis (phospholipid found in myelin)- Regulate hydrogen peroxide concentration – catalase break down, amino acid oxidase and hydroxyacid oxidase form hydrogen peroxide- Kill pathogens- Oxidize etoh
280
Clinical relevance of cytokeratin
- Mallory bodies seen in alcoholic liver disease- Epidermolysis bullosa simplex: mutations in keratin 5 or 14 gene prevents keratin from assembling into strong networks. Epidermis of skins becomes fragile and is easily damaged.
281
What are keloids?
- Excessive deposition of collage in scar formation
283
What are lipid rafts? Clinical relevance?
- Lipid rafts are small areas in membranes where sphingolipids and cholesterol are concentrated. These are involed in cell signaling. - Some CA cell types have greater concentration of cholesterol, which correlates with more lipid rafts. Simvastatin (cholesterol inhibitor) has been shown to induce apoptosis by reduction in raft formation in CA cells via down regulation of Akt (cell survival signaling molecule).
284
What is McArdle disease? Symptoms/signs?
- Genetic defect in muscle phosphorylase resulting in accumulation of glycogen and inability to degrade it.- S&S: cramping with exercise, exercise intolerance, myoglobin elevated with strenuous exercise, CK elevated, venous lactate level doesn’t increase with exercise
285
What are Rosenthal’s fibers?
- Aggregates of GFAP and other proteins characteristic of pilocytic astrocytoma
286
Structure of zonula adherens
- Cytoskeletal element = actin- Intracellular anchor proteins = alpha, beta catenins, alpha actinin and vinculin- Cell adhesion molecules = E-cadherin
288
What protein is synthesized on free polyribosomes?
- Free polyribosomes synthesize proteins that are generally for use within the cell (ie. not for export or use elsewhere)- This includes Hb in immature RBCs, many mitochondrial proteins, proteins in peroxisomes
289
Function of endosomes?
- Organelles involved in sorting and identifying molecules for recycling or degradation in lysosomes
290
Clinical relevance of hemidesmosomes
- Bullous pemphigoid: autoantibodies develop against type XVII collagen – BPAG2 = bullous pemphigoid antigen-2. Get separation of epidermis from dermis
291
3 types of lipids in plasmalemma
- Aka plasma membrane1.) Phospholipids (most abundant)2.) Glycolipids3.) Cholesterol
292
Structure of microfilaments
- Comprised of subunits of actin
293
Type I Collagen. Tissue distribution, synthesizing cells, function, organization?
1. Tissue distribution: dermis, tendon, bone, dentin, cementum, fibrocartilage, organ capsules2. Synthesizing cells: fibroblasts, odontoblasts, cementoblasts, osteoblasts, chondroblasts3. Function: resistance to tension4. Organization: fibril-forming
294
Three autophagic pathways
1.) Macroautophagy2.) Microautophagy3.) Chaperone-mediated direct transport
295
Functions of nuclear lamina
- Support of inner membrane- Phosphorylation of lamins causes disassembly of the nuclear envelope during prometaphase of mitosis- Dephosphorylation of lamins causes reassembly of the nuclear envelope during telophase of mitosis
296
Clinical relevance of glycosaminoglycans
- In Grave’s disease, increased deposition of GAGs (hyaluronic acid and chondroitin sulfate) in retroorbital space that causes exophthalmos.- Excess deposition of GAGs in Grave’s also involves skin
297
Functional attributes of ECM
1. Structure2. Defense/protection/barrier3. Nutrition (diffusion of metabolic fuels)4. Diffusion of gases, molecules and ions5. Cell growth and survival6. Cell migration7. Lubrication
298
What structure in the cell is responsible for protein synthesis? Is it basophilic or acidophilic?
- Ribosomes- Basophilic due to presence of negatively charged phosphate groups
299
List steps of cell cycle
- Interphasea.) G1-gap 1b.) S-synthesisc.) G2-gap 2d.) G0-gap not- M-phase
300
Why is smooth ER smooth? Location of it?
- Lacks polyribosomes- Continuous with rER in many cells, not in skeletal muscle
301
Function of zonula occludens?
- Paracellular pathway permits selective movement- Prevent cells from separating from one another- May regulate epithelial proliferation- Essential for establishing functional polarity (think glucose transporters on apical side with sodium pumps only on basolateral domains)
302
In what forms are ribosomes seen?
- Individual granules (ribosomal subunits)- Polyribosomes with mRNA (free in cytoplasm and bound to ER, forming rER)
303
What is basal lamina associated with non-epithelial cells called?
- non-epithelial: muscle, adipocytes and Schwann cells- called external lamina
304
List of endogenous pigments
- Hemoglobin- Hemosiderin- Bilirubin- Melanin- Lipofuscin
305
Describe structure of nuclear lamina
- Specialized region of the nuclear matrix composed of three classes of polypeptides called lamins that are closely associated with the inner nuclear membrane
