Exam 1 Flashcards
Name of Dr. Rubinstein’s Puppy
Legend
What embryonic derivatives does epithelium come from
All 3. Ectoderm, mesoderm, endoderm
What type of epithelium lines the small intestine
simple columnar
What are the three types of endocytosis
- Phagocytosis - ingestion of large particles into phagosomes.
- Receptor-mediated endocytosis
- Fluid phase endocytosis (pinocytosis)
What are the two types of exocytosis
- Regulated exocytosis - signal before the secretory vesicles fuse with the membrane.
- Constituitive secretion - secretory vesicles continuously fuse with the plasma membrane.
Names of the 2 surfaces of an epithelial cell
Apical (top), basal (bottom)
Types of transport through an epithelium (2 types)
Transcellular (larger molecules, through the cell)
Paracellular (between cells, smaller, and regulated by tight junctions)
What causes Cystic Fibrosis
apical Cl chanels do not open, disrupting polarity in epithelium and thickening the mucous layer covering the epithelia.
Protein is misfolded and never makes it to the cell membrane, it is retained in the ER.
What is in the basement membrane
The basal lamina (top layer, known as lamina densa), which contains laminin, fibronectin, type IV collagen, proteoglycans
The reticular lamina (lower) which contains type III collagen (reticular fibers)
lamina lucida is the top layer, which contains adhesive glycoproteins (integrins) - links to anchor proteins at hemidesmosomes and focal adhesions
What are the adhesive proteins that link the basal lamina to anchor proteins on the epithelial cell at hemidesmosomes and focal adhesions
Integrins
What do microvilli do and what are they made of
increase surface area, contain a core of actin filaments that attach to the terminal web, where they interact with horizontal actin filaments. Villin anchors actin filaments in the tip. Actin and myosin interact at the terminal web to form a contractive matrix, causing the microvilli to spread.
What are sterocillia (villi), what do they do, and where are they found
Epididymis, proximal part of ductus deference, and sesory cells of the innear ear. Actin filament core, interconnected by cytoplasmic bridges.
What are motile cilia (true cilia), and what do they do
Have a 9+2 pattern of microtubules, dynein is motor protein by splitting ATP, has synchronous movement
Monocilia
Have a 9+0 arrangement of microtubule pairs, they are immotile cilia that can function as mechanoreceptors that respond to fluid displacement, may create left-right assymetry
What are the types of glands and what do they do
Endocrine - no duct - secreted dirrectly into connective tissue and diffuses into blood
Exocrine - duct system
Unicellular (goblet cell containing mucinogen, a hydrophilic glycoprotein)
Multicellular
Simple (single duct) or compound
What are actin filaments and what do they do
Form core of microvilli, provide cell motility by polymerizing, form contractile ring for cell division
What are intermediate filaments and what do they do
Stable tissue specific, maintain cell integrity by linking to intercellular junctions (so cells do not rupture when stretched). They do not change length, and make up keratins, vimentin, neurofilaments, and lamins. They attach to desmosomes.
What are microtubules and what do they do
Treadmill by maintaining a constant length while polymerizing and depolymerizing. Polarize the organelles, form mitotic spindle and core of cilia. They move using kinesin and dynein.
Zonula Occludens (Tight Junction)
Semipermeable barrier between apical and basolateral membranes, Linked to actin filaments in the terminal web by claudin/occludin. Tight junction membranes are linked by the cadherins occludin and claudin that are bound to several classes of ZO proteins that are linked to actin.
Can seal of the apical surface of the cell from the basal and lateral borders, so that cell polarity is possible.
Zonula adherens
lower than the zonula occludens. Linked to actin filaments in the terminal web by cadherins. Cadherins are calcium dependent.
Desmosome (Macula adherens)
Anchors intermediate filademtns, linked by cadherins (desmocollins and desmogleins).
Gap Junctions
Form connexon channels that permit cell to cell communication. No link to anchor proteins, allow free flow of ions and messengers between cells.
Hemidesmosome
Links cells to matrix, uses integrins linked to intermediate filaments. Use integrins instead of cadherins for adhesive proteins.
Focal Adhesions
Links cells to matrix, using integrins linked to actin microfilaments. Molecular basis for cell migration. Integrins connect to fibronectin.
Explain the secretory pathway in a cell
Begins at RER, vesicular transport to the Golgi apparatus, vesicular transport either directly to the cell surface or into secretory vesicles, with these then moving to the cell surface upon a signaling event.
The Golgi complex distributes everything
Why does RER stain blue in H&E
abundant, negatively charged mRNA associated with it
How do proteins get to the ER
membrane and secretory proteins have signal sequences, that are recognized by Signal Recognition Particles (SRPs). They stop translationand bind to a docking protein in t he RER, where the SRP falls off and translation continues.
Any protein without a signal sequence is moved to the cytoplasm.
Proteins that stay inthe ER have retention signals, interacting with receptors in the ER that prevent them from leaving.
Functions of the ER
Protein folding (possible toxic gain of function by aggregation, Parkinsons, Alzheimers), glycosylation (addition of carbohydrate), sorting, quality control, degredation, and integrating responses to cellular stresses
How is protein folding accomplished
folding enzymes
molecular chaperones that bind to newly made proteins and stop them from aggregating. As the protein folds, chaperone binding sites are hidden.
Chaperones as clinical targets
In parkinsons, there is aggregation of proteins, so if more chaperone can be introduced and overexpressed, it can cause the mutated protein to fold correctly more often
Drugs that correct folding defects
Read-through editors: read through premature stop codon
Correctors - help to fold the protein properly
Potentiators - improve the function of the misfolded protein after it is made
ER-Associated Degredation
Misfolded protein complexed with ubiquitin is transported out of the ER, where it is degraded by the proteosome
Things that cause accumulationof unfolded proteins
hypoxia, glucose deprivation, calcium abberations, viral infection, cancers (chaperone limited), misfolding mutations
How to proteins get to the Golgi
Transport vesicles bud from the ER, moving on microtubules to the Golgi where they fuse with the cisternae.
Functions of the Golgi apparatus
Glycosylation (adding carbohydrates), Lipid biosynthesis, proteolytic processing, secretion and sorting
How does the Golgi make lysosomal enzymes, and what happens when it goes wrong
A mannose 6 phosphate is added, allowing them to go to lysosomes. In lysosomal storage diseases, enzymes are secreted because this M6P is not added.
Signaling for secretory granules to fuse with the membrane
Signal causes an influx of calcium, leading to massive degraulation and release of contents
What is vesicle/membrane fusion catalyzed by
SNARE proteins, one on the vesicle (vSNARE), one on the target membrane (tSNARE)
Botox cleaves SNARE proteins, preventing neurotransmitter release
General structure of the endocytic system
Early endosomes are mildly acidic, here they either recycle to the cell surface or deliver contents to more acidic late endosomes, late endosomes (site of mebrane degredation MVB) send material to lysosomes
High Cholesterol caused by failure of endocytosis
LDL cannot bind to a cell receptor with a mutation and is not endocytosed. Therefore, LDL is present in blood at a high level.
H&E Staining
Hematoxylin is a basic stain and stains strong acid containing material blue
Eosin is an acidic stain and stains basic substances (such as proteins) red
Endothelium vs. mesothelium
Endothelium lines blood vessels, mesothelium lines body cavities
simple Squamous Epithelia and where they are found
thin, nucleus bulging out into the lumen. Found in alveoli of the lung
found in mesothelium
Simple cuboidal epithelia and where they are found
tall and wide, found in liver, endocrine and exocrine glands, and kidney
simple columnar epithelia and where they are found
tall, in endocrine and exocrine glands, lining of intestine
stratified squamous epithelia and where they are found
basal layer is cuboidal, top layer squamous. Found in skin, digestive tract, vagina.
Stratified cuboidal epithelia and where they are found
Rare. found in larger ducts of some exocrine glands
stratified and pseudostratified columnar epithelia and where they are found
stratified - anorectal region, very large exocrine ducts
psuedo - tall cells that span whole membrane and short that do not. Lines the trachea, bronchi, and ducts of epididymis.
Transitional epithelium and where it is found
Accomodates strethcing, lines bladder, ureter
Fibronectin
binds basal lamina components to integrins on the cell membrane
What is the darkly staining line near the surface of epithelial cells
The terminal web, and array of actin filaments that connects to the actin in the microvilli
Names and order of junctions found at the apicolateral border of the cell
- zonula occludens
- zonula adherens (belt desmosomes)
- macula adherens (spot desmosomes, desmosomes)
Calcium Influx and Gap Junctions
Causes gap junctions to close immediately, so neighboring cells cannot be damaged.
Progenitor cells
Transit amplifying, arise from stem cells and divide rapidly to produce daughter cells tha differentiate to generate and maintain tissues
Totipotent vs. pluripotent vs. multipotent
toti: zygote, can make all tissues, including placenta
pluri: all embryonic tissues, not placenta
multipotent - can make multiple cell types in tissue
2 types of stem cell asymmetry
divisional asymmetry - “stemness” factor only into one daughter cell
environmental asymmetry - nice provides signals that help stem cells retain self-renewal
HSC’s
Hematopoetic stem cells, in bone marrow, are very rare and hard to identify
In the current view, Long term reconstituting cells devide into short term reconstituting cells. These STR’s become a common myeloid (everything other than immune) progenitor or a common lymphoid progenitor.
Label-retaining cells are called stem cells
Localize to the endosteal region of the bone marrow, must stay in this niche to retain potency, can migrate in blood to other niches (because of this we can take bone marrow from blood)
How are stem cells separated out
Flow cytometry techniques that separate cells based on flourescently labeled antibodies, followed by fluorescence activated cell sorting, or FACS
MSC’s
Mesenchymal stem cells - multipotent cells derived from many tissues. CAn be injected into the blood stream, and they will migrate to places where we know stem cells exist. They adhere to plastic and have a few markers that are notable.
Induced pluripotent stem cells and their problems
convert differentiated fibroblasts into ES-like cells taht are self-renewing and pluripotent. However, this may promote cancer development
Cancer and Stem Cells
only a small number of cancer cells are capable of producing a new tumor
Could be from transformation of a normal SC through mutation - rare
activation of self-renawal pathways in already cancerous cells
Shown by AML-causing oncogene injected in mice, cell’s gain self-renewal. This self-renewal correlates with gene expression.
Ki67 antigen
expressed at all phases of active cell cycle but not in G0 in resting cells
Cell Cycle restriction point
G1-S boundary. If GF’s are withdrawn before this cells do not divide. However, having passed this the cell is committed.
pRB
protoypical tumor suppressor protein in retinoblastoma. Rb encodes this protein. It represses E2F transctipion factors (inhibited when bound to pRB). Kinases phosphorylate pRB, and it releases E2F.
CDK
Cyclin dependent kinase complexes. These regulate pRB through phosphorylation, and are activated by cyclins.
Cyclin/CDK complexes
These regulate different stages of the cell cycle. Cyclin D/CDK4/6 and cyclin E.CDK2 pushes cells to the restriction point by hyperphosphorylating pRB.
CDK2 vs. CDK4/6
CDK2 is a much better kinase than CDK4/6 and hyperphosphorylates pRB after it is slighlty phosphorylated by 4/6.
pRB remains hyperphosphorylated until the end of mitoses, and is dephosphorylated by phosphatases.
CKI (INK4)
(Inhibitors of CDK4) inhibits cyclin/CDK activity in response to cell stresses
loss leads to cancer
p16INK4a gene
often lost or silenced in cancer cells
causes protective cell cycle arrest in melanomas
features of Apoptosis
Highly ordered, ATP dependent, proteases and nucleases destroy cell, puts everything in vesicles.
Distinct from necrosis, that is cell lysis
Two layers of skin
Epidermis - stratified squamous, keratinized
dermis - connective tissue containing vessels, glands, nerve endings, roots)
Below this there is the superficial fascia, loose connective tissue
Layers of the epidermins and their properties
Stratum basale
Stratum spinosum
Stratum granulosum
stratum lucidum
stratum corneum
stratum basale
cuboidal or columnar, divide frequently. All cells attached to basement membrance by hemidemsosomes.
keratin 5 and 14 proteins that dimerize to form intermediate filaments
stratum spinosum
intercellular spindle bridges attached by desmosomes, extensive intermediate filaments. Membrane-coating granules, or lamellar bodies, spinosum cells produce keratins 1 and 10
stratum granulosum
flattened nucleated keratinocytes multilayeed, keratohyalin granules that make the cells dark.
Synthesizes filaggrin, which induces keratin aggregation
Has many lamellar bodies
Stratum lucidum
Nucleus not visible, dead cells (only in thick epidermis)
stratum corneum
keratin filaments crosslinked with fillabgin. Complex of lipids from lamellar bodies cross links the cell envelope and is highly resistant to degredation. Moist surfaces don’t have a stratum corneum.
Two layers of the dermis
papillary layer (superficial, loose connective tissue)
Reticular layer (ticker and less cellular, Langer’s lines of tension are formed here)
Attachment of epidermis to dermis
dermal papillae are fingerlike projections from the epidermis into the dermis
Basal side: Anchoring fibrils extend from the basal lamina to the collagen (reticular) fibrils of the connective tissue.
Epithelial side: laminin, collagen XVII, and integrins adhese the basal lamina and there are hemidesomsomes.
Four classes of cutaneous mechanoreceptors
Merkel corpuscles, Meissner corpuscles, Pacnian corpuscles, and hair receptors
Pacnian corpuscle
Looks like an onion, central region has nerve process. Found near the junction of the dermis and the hypodermis.
Respond to pressure and vibration and are tickle receptors
Meissner’s corpuscles
smaller than pacnian, found in dermal papillae especially in fingertips.
Respond to light touch. Fingers, toes, lips
Langerhan’s cells
Antigen-presenting cells in skin, between keratinocytes, leave the skin and move to lymphoid organs
melanocytes
melanosome organelles rpduce melanin. Located between the basal and spinosum layers. melanin is secreted in the interstitial space and is taken up by keratinocytes.
Derviced from neural crest tissue. UV stimulated.
Merkel cells
mechanoreceptors in stratum basale, linked to keratinocytes by desomosomes
KLK’s
Cleave desmosomes in a pH dependent manner. Inhibited at high pH of the bodly, but at lower pH surface of skin) Corneal cells are shed
constitutive receptor activity
some receptors stay in the R(a) form instead of the R(i) form even in the absence of ligand binding
5 transmembrane signaling mechanism
- diffuse across membrane (steroid) and act on intracellular receptor
- receptor spans domain, signal binds to EC domain and activates enzymatic activity in the cytoplasmic domain (cytokine receptors)
- Signal binds to EC domain which activates a tyrosine kinase on cyto side
- ion channel opened by signal
- G-protein coupled receptor
steroid receptor mechanism
bind to a protein that releases repressors (like HSP90, heat shock) when the steroid is bound, activates dNA transcription
cytokine receptors
dimerize when activated, then activate separate mobile protein (JAK) molecules, which phosphorylates signal transducers and activates STAT molecules
(Growth hormone, erythropoietin, interferon)
Stat molecule
Signal Transducer and Activation of Transcription
receptor tyrosine kinase
dimerizes and the cytoplasmic domains become phosphorylated, and they catalyze phorphorylation of substrate proteins
(EGF, PDGF, TGFB, insulin)
Ligand Ion Channel
several subunits, ligand binds to site on one of the subunits (neurotransmitters)
structure and activity of G proteins
Have alpha, beta, gamma conformation
dissociate into alpha and beta-gamma
uses binding and hydrolysis of GTP, and ampifies the signal to another protein (usually cAMP
Histamine and epinephrine and G proteins
epinephrine dilation, histamine constriction, in constant opposition
Regulation of the GPCR response
phosphorylation of the receptor weakens sensitivity by Gprotein coupled receptor kinases (GRK’s) - recruits B arrestin
Can either recycle the receptor and remove the arrestin, or degrade the receptor
Ras signaling
Initiated by RTK’s (EGFR binding), dimerization of tyrosine residues phosphorylates the receptor, and two proteins connect like legos to inactive rass, which gets rid of GDP and allows GTP to bind (higher conc. in cell)
Ras is a G protein. It has self GTPase activity as a molecular switch, can hydrolyze its own GTP to turn off.
Ras phosphorylates other things.
Ras and cancer
mutation abolishes Ras GTPase activity so it can’t shut itself off
30% of human cancers have ras mutations
Activating mutaitons in EGFR for Raf (activated by ras) are uncontrolled in cancer
melanomas and the ras pathway
50% of melanomas have activating mutations in B-Raf (right downstream of ras), vemurafenib inhibits this form of B-raf and leaves normal raf alone
However, acquired resistance in some tumor cells show restored ras pathway inactivation, even in the presence of vemurafenib
It does this by activating other Raf proteins (we have more than one) in oncogene bypass
RESTORE OR BYPASS
prefixes: fibro, chondro, osteo
suffixes: blast, cyte
fibro: connective
chondro: cartilage
osteo: bone
blast: young and active
cyte: old and tired
Loose irregular connective tissue
cell types are transient, primarily present benaty the epithelia that lines the body surfaces, and tracts. Surrounds vessels and nerves as well.
Structural element is type 1 collagen
Type 1 collagen
Found in most connective tissue, 90% of all body collagen. Viscous, resistance to stretching
Dense irregular connective tissue
abundant fibers, little ground substance. Present where stresses are high, such as skin. Hollow organs covered by this.
Structural element also type 1 collagen
Dense regular connective tissue
tendons, ligaments in bundles, or alternating parallel perperdicular sheets in cornea or bone.
Two types of connective tissue cells and examples
resident cells: fibroblasts, chondrocytes, osteocytes, adipocytes (all derived from connective tissue stem cell) Mast cells and macerophages are also regarded as long term resident alien cells, as they arise from bone marrow precursors.
transient cells: neutrophils, eosinophils, basophils, monosytes, immune cells.
fibroblast
principal cell of connective tissue, makes collagen, elastic fibers, reticular fibers, and carbohydrates of ground substance.
Stellate with long processes and spindle nuclei. Less active fibroblasts are fibrocytes.
myofibroblast
same lineage as fibroblasts, contain actin and myosin thick filaments, allowing for contraction in injuries
chondroblasts and chondrocytes
produce type II collagen in cartilage
osteoblasts and osteocytes
produce the type I collagen in bone, along with other bone ECM
white fat vs. brown fat
white fat is an adipobyte containing a single large fat vacuole. Brown fat has many small vacuoles and uncoupled mitochondria (UCP-1 protein)
Macrophages
phagocytize particles (put them in phagosomes), derived from monocytes. Can also serve as antigen presenting cells.
oval with round nuclei, have many lysosomes as well as RER, golgi, and mitochondria
mast cells
chemical mediators in connective tissue, have many granules containing things such as histamine. IgE binds and the exocytotic event begins.
Oval shaped with round nuclei
Type II collagen
dominant collagen in hyaline and elastic cartilage, resistant to compression
Type III collagen
forms reticular fibers, found in blood vessel walls. Loose network of thin fibers, smaller than collagen I.
Found in spleen, thymus, lymph nodes
Type IV collagen
major component of basal and external lamina, assembles into mesh instead of fibrils (unlike other collagen), partly due to interruptions in helical structure and interweaving with laminin. Support and filtration barrier
Steps in collagen synthesis (up to cell excretion)
type 1 colalgen in RER facors coiling of an alpha chain of collagen into a tight helix. 3 alpha chains are wounding into a triple helix, and then there is crosslinking of the component alpha chains by disulfide and hydrogen bonds. This resulting triple helix is procollagen. They are assembled into secretory vesibles and secreted into the extracellular space.
collagen formation (post-procollagen secretion)
staggered head to tail procollagen molecules line up in side to side arrays to form fibrils of collagen, with covalent cross linking.
Reticular fibers
Thin collagen fibers are coated with glycoproteins. Composed of type III collagen. In the spleen and lymph nodes, the reticular cell synthesizes this type III collagen.
Elastic fibers
major component is elastin, initially synthesized as a soluble precursor molecule. Elastin molecules form random coils instead of helicies.
Found in the vertebral column and in arteries
Three groups of ground substances
- Glycosaminoglycan molecules (GAGS)
- Proteoglycans
- multiadhesive glycoproteins
GAG’s
Glycosaminoglycan molecules, covalently bound to proteoglycans, long, unbranched dissacharide chains, witha high negative charge. Gives tissue turgor.
proteoglycans
large macromolecules made of core protein and GAGs. form gels with water, giving tissues rugor. Can also be binding for signal molecules
proteoglycan monomers attach to a backdone of hyaluronan to form proteoglycan aggregates
multiadhesive glycoproteins
stabilize the ECM, fibronectin and laminin are examples of these, posses binding sites for ECM proteins
cause of Osteogenesis Imperfecta
mutation of one of two genes coding for alpha chains in type I collagen
Ehlers-Danlos syndrome
skin hyperextensibility, defect in a gene coding for alpha chains in Type V collagen
Alport syndrome
abnormally permeable kidneys
defect in type IV collagen, major component of basal lamina
Marfan syndrome
long extremities, dilated aorta, dislocated lenses
defect in gibrillin 1, resulting in disrupted elastic fiber formation
Scurvy
vitamin C deficiency state. lack of hydroxalyation of proline and lysine in collagen. These stabilize collagen
What type of collagen fibers form the basal lamina? The reticular lamina?
Basal: type IV
Reticular: type III
Is blood considered a tissue?
Yes
Difference between plasma (non RBC component of blood) and serum
Serum has lost clotting factors, they are in the blood cell portion
Major proteins found in plasma
Fibrinogen (synthesized in the liver, help clotting)
Albumin (75% of all protein)
Globulins (antibodies)
albumin
75% of all protein in plasma, major contributor to osmotic pressure that maintains intravascular volume
binds bilirubin, fatty acids, drugs, metals
Erythrocytes
Rich in ribosomes during infancy (reticulocytes)
33% hemoglobin in RBC’s
Cytoskeletal network of spectrin and actin, ankyrin makes connection, prevents shear
Elliptocytosis
Defects in elastin, RBCs cannot “bounce back”
spherocytosis
defects in spectrin and ankyrin, lose membrane steadily (blebbing) and become smaller and lose biconcave shape
platelets
have an active cytoskeleton, integrin receptors that can bind to fibronectin, cause a liquid to turn into a gel
2 types of leukocytes
myeloid cells and lymphocytes
(leukocytes are White Blood Cells)
3 types of granulocytes
basophil, neutrophil, eosinophil
Neutrophils
Very inactive chromatin, nucleus constricted in different regions connected by thin strands of chromatin, short living, major phagocytic cells
granules contain toxic substances, such as myeloperoxidase
Most frequent WBC, much more than basophil and eosinophil
Eosinophils
Release cytokins and granule cells into EC space in response to cytokines
Role in antiviral and antibacterial, defend aganinst parasites
Contain MBP (Major Basic Protein), eosinophil peroxidase, eosinophil cationic protein (ECP) and Eosinophil-derived neurotoxin (EDN)
Basophils
Express IgE receptors, host defense, play a role in allergy, have extremely dense and dark staining granules
Monocytes
precursor cells of the mononuclear phagocytic system, become macrophages
kidney shaped nucleus
express different scavenger receptors on the surface to recognize pathogens
Gaucher’s disease
lysosomal deficiency, cell can’t break down damaged blood cells
Give macrophages a ruffled appearance because they cannot break down the dead material
Lymphocytes
B cells (precursors to plasma cells and memory cells, produce and secrete antibody)
T cells (help make antibody, destroy abnormal cells)
NK cells (destroy abnormal cells)
B and T cells are histologically unremarkable
NK cells are larger with visible granules
Regulated motility and adhesion are critical to leukocyte function
Selectins, chemoattractants, and integrits cause diapedisis, tissues displacy selectins when they want the cell to come to its surface
actin nucleation and brancing
diapedesis
transendothelial migration by leukocytes
actin nucleation and branching
GTPases drive a treadmilling process, acting as molecular switches
Wiskott-Aldrich syndrome
failure to stimulate actin polymerization, neutrophils are deficient in phagocytosis, T cells do not polarize
Two types of hematopoesis
Primitive (embryonic) - 5-10 times the size of mature erythrocyte, occurs in the yolk sac in blood islands, these then migrate to the liver, which is chief at 3 months.
Definitive (adult), occurs in bone marrow (medullary hematopoiesis, between the sinuses in the marrow stroma) and within the liver and spleen (in conditions of stress), (extramedullary hematopoesis)
Colony stimulating factors
regulators of hematopoiesis
myeloproliferative disorders
JAK2 (Janus Kinase 2) mediates the EPO signals, mutation causes it to phosphorylate STAT5 without EPO, abnormal RBC production called polycythemia vera
CFU
Colony forming unit - monocytes and granulocytes derive from a common precursor
5 stages of myelopoesis and their forms for granulocytes
myoblast (large, euchromatic nucleus)
promyelocyte (large nuclei, granules start)
myelocyte (3 types can be distinguished based on granules, nucleus starts to become indented, last time that mitosis can happen)
metamyelocyte (smaller nucleus, clear granules)
band cell (nucleus is horseshoe shaped, cytoplasm similar to mature form)
How long do neutrophils last in the circulation
about 24 hours, most time is spent in the bone marrow before this
Erythropoeisis
Basophilic erythroblast: Deep blue cytoplasm due to ribosomes
polychromatic erythroblast - transcription slowing, starts to be eosinophilic due to proteino
orthochromatic erythroblast - nucleus pushed to one side, cytoplasm eosinophilic
reticulocyte - nucleus extruded
Megakaryocytes
Sit near vascular channels, protrude through the sinusoids, blood shear force stimulates the cell to form bulbs and pinch off to form platelets
Suffix for deficiency of a cell in the peripheral blood
-penia
suffixes for excess of cells
- cytosis
- philia
- emia
Bohr Effect
Conformational change in Hb that releases oxygen into the hypoxic tissue
What do the secondary granules of eosinophils contain
MBP (Major Basic Protein) and peroxidase
Monocytes and inflammatory response
exit a blood vessel at the site of inflammation, transform into a macrophage. Chemotax toward factors such as N-formyl peptides
APC
antigen-presenting cell
What elements do platelets release
serotonin and thromboplastin, released by granules
Glanzmann’s thrombasthenia
severe reduction in platelet aggregation mutation in integrin so it can no longer bind to fibrinogen
Structure of bone marrow
nutrient arteries enter through bone foramina. They give rise to sinusoids (thin walled vessels in the endosteum. Sinusoids are oriented in a radial direction, downs the central longitudinal vein in the long axis of the bone. Hematopoetic cells are between the sinuses
Walls of the sinusoids
endothelial cell layer, basement membrane, and a reticular cell layer (adventitial cells). These adventitial cells create microenvironments in the marrow that nurture specific hematopoetic lineages.
Reticular cells can become adipose cells (yellow bone marrow, found in adults)
GATA1 protein
needed for the maturation of red blood cells, but also is active at earlier steps in the hemopoietic pathway
Thrombopoetin
Tpo stimulates the proliferation of the megakaryoblast
How do eosinophils and basophils moderate each other
Basophils release chemotactic agents that attract eosinophils, which neutralize histamine and produce a factor that inhibits degranulation, neutralizing the effect.
How do the mature cells leave the marrow and enter the blood
push against the endothelial cells and push through the aperture into the sinusoids
Fick’s Law of Diffusion
Quantity diffused per time. Net diffusive moemnt is the sum of two opposing unidirectional movements.
Diffusion time varies with the square of the distance.
Proportionality factor is the permeabiity of the compound
Permeability of substances
With the excpetion of water, permeability is related to the lipid solubility
Facilitated diffusion
Protein spans the membrane and the molecule moves through the protein. However, facilitated diffusion is limited by the number of proteins
Osmotic pressure
hydrostatic pressure required to prevent net water flow
van’t Hoff formula
Relationship between osmotic pressure and solute concentration. Doesn’t take much solute to get water to move.
Hyperkalemia
too much extracellular K+. abnormal heart rhythms
Ion concentrations of Na+, K+, Ca2+, and Cl- in the ECF and ICF
Na - 145mM ECF, 15mM ICF
K - 4.5 mM ECF, 120 mM ICF
Ca - 1mM ECF, 100nM ICF
Cl - 120 mM ECF, 6mM ICF
High Na and Ca outside, High K inside
3 professors who went to med school together
Ochs, Rubinstein, and Goldman
Donnan equilibrium
System where all ions except for one (typically large anions) are allowed to passively diffuse until they reach equilibrium
Goldman-Hodgkins-Katz equation
Takes permeability and the concentrations of each ion, average them, and then use that in the Nernst equation
Resting potential
Cell’s resting potentials are typically negative, and can be explained by Na, K, and CL concentrations
Na/K pump
one alpha subunit and one beta subunit
moves 3 Na ions out, and 2 K ions in
30-70% of our energy use can come from this pump
oubain
binds to the 5th conformation of the Na/K pump and gets stuck there
Calcium levels
High outside of the cell, low inside of the cell, high inside the ER
PMCA and SERCA are the Calcium ATPases
The four characteristics of catilage
Flexible extracellular matrix
no vascularization
cells imprisoned in lacunae surrounded by an ECM of their making
Limited amount of proliferation within lacunae, resulting in interstitial growth
How does cartilage form
chondroid precursor cells give rise to chondroblasts. The cartilage mass is surrounded by perichondrium (connective tissue)
Chondroblasts
Secrete type II collagen and some GAG’s to produce extracellular chondroid matrix
Secrete circumferentially, as opposed to osteoblasts which secrete only in one direction
3 types of catilge
hyaline, elastic, fibrocartilage
All contain type II collagen and GAG’s
Hyaline cartilage
Glassy and translucent. Forms the initial models for bones and allows their growth up to puberty.
On the surfaces of bone at the synovial joints. Also in nose, trachea, bronchi.
Elastic cartilage
The ear, epiglottis, has many elastic fibers
Fibrocartilage
has type 1 collagen, as well as type II, giving it greater tensile strength, and is found in spinal column, knee, and ligaments. It lacks a perichondrium and contains less water in the ECM.
What does bone store
Calcium and phosphate
Bone structure
type 1 collagen, as well as ground substance, that is mineralized.
Spaces called lacunae that each contain an osteobyte. There cells have many processes that extend through small tunnels called canliculi
Outer surface of bone covered in periosteum containing osteoprogenitor cells. Outer layer of pereosteum is dense connective tissue, inner layer contains osteoprogenitor cells.
Endosteum
Lining tissue of the compact bone and the trabeculae. Endosteal cells can differentiate into osteoblasts and bone lining cells.
Osteoid
Bone extracellular matrix - secreted by osteoblasts, which are derived from osteoprogenitor cells.
Osteoprogenitor cell differentiation
CBFA-1 and BMP are important factors, these progenitor cells can form many different cell types
hydroxyapatite
calcium and phosphate ions in a crystalline strucutre, ordering of the collagen in the osteoid
osteoclasts
break down bone matrix with the release of calcium, derived from monocytes, and are giant and multinucleated.
Howship’s lacuna
space carved out of bone by an osteoclast
Haversian system
An osteon, consisting of concentric lamellae of bone martix aroudn a cental haversian canal, containing the vascular and nerve supply for the osteon. The long axis of an osteon is parallel to the gdone.
Volkmann’s cannals run parallel to the haversian canal and connect them together. These are channels for blood vessels and nerves, and are not surrounded by concentric lamellae.
Two types of bone development
Endochondronal (cartilage model) or Intramembranous *no carilage)
Flat bones develop by intramembranous ossification, bones of weight bearing parts come from endochondronal ossification
Method of Endochondral bone formation
The periosteal collar of bones forms around the diaphysis (shaft) of the cartilage. The cartilage inside begins to calicify. Blood vessels and connective tissues cells invade the cartilage, ossification happens from the senter of the bone (diaphysis) to the ends (epiphysis).
Periarticular chondrocytes
Proliferate and differentiate into columnar chondrocytes that proliferate further and form orderly columns. Regulated by parathyroid hormone
PTHrP
Upregulated by Indian Hedgehog
PTHrP diffuses into the growth plate, where it keeps cells proliferating. When it stops below a certain level, cells stop proliferating.
Cortical bone
Forms the outer surface of bones and does not have cavities for bone marrow or hematopoesis
How do osteoblast signal osteoclasts
Osteoblasts are stimulated by Vitamin D and PTH to secrete factors that cause osteoclast precursors to proliferate. These then differentiate into mononuclear osteoclasts. Osteoclasts resorb some bone in a pit, and osteoblasts replace them to build new bone matrix.
How are lacunae formed
As chondrocytes produce matrix, they become surrounded 360 degrees. They also secrete enzymes that allow them to reposition themselves.
What type of cartilage is in the trachea? What are its components?
Hyaline cartilage, major components are type II collagen and aggrecan. Also contains GAGs
What type of cartilage is the epiglottis?
Elastic cartilage
What type of cartilage is stained by Resorcin-Fuchsin
Elastic cartilage
RNAKL
expressed by osteoclast precursors, leading to increased osteoclastogenesis.
Where are osteocytes found in the osteon
Found in lacunae, which conform to the shape of the cell. They extend processes through canaliculi
How does a solute from the blood vessels reach the osteocytes
flows through vessels in the Volkmann’s canals to the Haversian canals and then to the osteocytes.
How are osteoclast niches acidified
carbonic acid is secreted by clathrin coated lysosomes, which fuse with the ruffled membrane.
What does increased adenyl cyclase do int he intestines in cholera
Makes an abnormally high amount of cAMP, which activates Cl channels, causing the cells to secrete large amounts of CL into the lumen of the intestines
Na follows this gradient of large amounts of ions
osmotic diarrhea in lactose intolerance
lactose stays in the intestinal lumen, where it holds water
What ion channel works to depolarize sterocilia hair cells
The K+ channel,
Where would you find claudins in a normal epithelial cell
Tight Junctions
What would a claudin defect do to hair cells
Impairs the ability of the epithelia to separate the endo- and peri-lymph fluids, so concentration of K+ in the endolymph would be lowered
Non osmotic volume
Colume of a cell that does not pertain to shrinkage or enlargement, the rest can grow and shrink
What will happen to osmotic volume if a cell in 150mM NaCl is placed in 300mM NaCl
Osmotic volume of the cell will shrink in half, however, the concentration of Cl will conversely double in the cell (effectively) so the Ecl would remain unchanged.
What volume and resting potential would a cell acquire if placed in 150 mM NaCl and 300 mM sucrose
The osmotic pressure is doubled, so the new volume decreases again to 60 um. Internal Cl effectively doubles, so the Nernst equation should be recalculated . There is more Cl inside than outside, so the new Ecl is +7.5, up from -10.6
300mM sucrose has the same ionic potential as 150mM NaCl because they generate the same number of ions.
Under what condition would a membrane potential equal a Nernst potential
when it is exclusively permeable to only one ion
Name 6 components of the dermis
Sweat glands and their ducts, blood vessels, merkel, meissner, pacnian (all 3 corpuscles) and hair receptors.
What cell is melanin typically found in
Keratinocytes
Functions of pRB
- Represses E2F transcription factors in non dividing cells
- Regulated by CDK complexes
- CDK’s are activated by cyclins are phosphorylate pRB
- hyperphosphorylating pRB pushes the cell into the cell cycle
What causes the skin’s resistance to mechanical stress
keratin intermediate filaments
What are the 3 major types of ground substance
GAG’s, proteoglycans, and multiadhesive glycoproteins
What is contained int he granules of each of the granulocytes
Neutrophils: peroxidase and lysozyme
Eosinophils: Major basic protein and peroxidase
Basophils: histamine, serotonin
Blue spots in reticulocytes
polyribosomes synthesizing hemoglobin
Several layers of cells reside within epiphyseal disks of developing long bones. Which layer anchors the disk to the bony epiphysis
Cells that are undergoing mitosis
From the diaphysis to the epiphysis, layers:
zone of calcified cartilage, zone of hypertrophy, zone of proliferation, zone of reserve cartilage
Donnan Equilibrium equation
Kout/Kin = Cl(in)/Cl(out)
Or ANY two similarly charged permeable molecules
