Foundations Week 1 Flashcards
Glycogen
branched glucose polymer attached to core protein glycogenin (G)
(mature particles in the nucleus have about 55,000 glucose residues!)
Cytoplasmic disease examples
PKU, sickle cell anemia, hemolytic anemia, glycogen storage diseases
Components of the cytoskeleton
Intermediate filaments, microtubules, and microfilaments
Microfilaments
Contain actin. Involved in muscle contraction, cell movement, intracellular transport/trafficking, maintenance of the cell shape, cytokinesis, etc
Intermediate filaments
Cell “scaffolding.” Involved in the maintenance of cell shape, anchoring of organelles, some cell-to-cell junctions.
Examples: keratin, lamin, desmin, etc
Microtubules
Hollow cylinders (the “9+2” structure). Commonly organized by the centrosome.
Involved in the mitotic spindle, cilia & flagella movement, and intracellular transport
Do membrane carbohydrates span the lipid bilayer?
No, they are only present as modifications to lipids and proteins (on the membrane surface facing away from the cytosol)
Cerebroside
glycolipid + monosaccaharide
Ganglioside
glycolipid + oligosaccharide + sialic acid (an acidic sugar)
Does a uniporter transport ions?
No, only molecules down their concentration gradient without energy input.
Normal lab values for Na+ in the blood?
136-145 mEq/L (mM)
Normal lab values for K+ in the blood?
3.5-5.1 mEq/L (mM)
Normal lab values for Mg2+ in the blood?
1.5-2.0 mEq/L (mM)
Normal lab values for Ca2+ in the blood?
8.4-10.2 mg/dL (2.1-2.8 mM)
Plasma membrane disease examples
Cystic Fibrosis, familial hypercholesterolemia, and Muscular Dystrophy (Duchenne type)
What color does euchromatin stain?
Light
What color does heterochromatin stain?
Dark
Where does rRNA synthesis and ribosome subunit assembly take place?
The nucleolus
Nucleus and nucleolus disease examples
Inherited & spontaneous diseases, aneuploidy syndromes, Hutchison-Gilford progeria syndrome, Treacher Collins syndrome
Where does aerobic respiration occur in the mitochondria?
Inner membrane and cristae
What happens in the mitochondrial matrix?
Catabolic processes (TCA, fatty acid oxidation) and anabolic processes (AA synthesis, steroids). Also where the circular genome is found
Mitochondrial disease examples
MCAD, MERRF (myoclonic epilepsy with ragged-red fibers)
Note: mitochondrial diseases present with a wide range of clinical features
Lysosome
Low pH, contains acid hydrolases that degrade and recycle.
Fuse with endosomes and phagosomes. Incomplete degradation forms residual bodies (lipofuscin)
Residual bodies/lipofuscin
Protect cells from toxic effects of incomplete degradation. Accumulate in cells over times (decades).
Lipofuscin = “lipid dark” without stain
Ceroid
abnormal pathological accumulation of lipofuscin or lipofuscin-like bodies
Ceroid accumulation is a hallmark of certain lysosomal storage diseases
Lysosome disease examples
storage diseases, mucolipidoses
Functions of the smooth ER?
lipid & steroid hormone synthesis, detoxification of xenobiotics, stores Ca 2+ ions
Where are glycans added?
the rough ER (NOT the golgi… golgi just modifies)
What side do vesicles enter the golgi apparatus? What side do they exit?
Enter on the cis side, exit on the trans side
remember that the golgi is polarized!
What is it called when glucose is spontaneously, and irreversibly, added to protein?
non-enzymatic glycation
This does NOT happen in the golgi
Steps in the secretory (exocytic) pathway?
rER -> golgi -> vesicle -> plasma membrane
Where does protein “quality control” occur?
In the rER before the protein heads to the golgi. Those that are unfolded will be retained in the rER lumen or degraded
Permanent neonatal diabetes mellitus
Mutations disrupt folding in the rER, formation of disulfide bonds in the rER, and/or proteolytic removal of C peptide in secretory vessicles
Three main destinations as vesicles exit the trans Golgi network?
- Lysosome - need a specific sorting signal for this
- Regulated secretion - specific signal is needed; stored in secretory vesicle until secretion is initiated (e.g. insulin in beta cell of pancreatic islet)
- Constitutitive secretion - proteins without sorting signals follow this default pathway
I Cell Disease
Lysosomal enzymes don’t make it there, thus stuff isn’t degraded. Instead these enzymes are secreted by the cell (in the default pathway) and cause damage to cells/the matrix
Internalization pathways
- phagocytosis - phagosomes fuse with primary lysosome for degradation
- Endocytosis - extracellular molecule internalization; traffic to endosomes
- pinocytosis - extracellular fluid and dissolved substances are internalized
- Receptor-mediated endocytosis - selective endocytosis; cell surface receptors bind specific ligands
- Autophagy - degrades cell components in lysosomes; fuses with primary lysosomes; induced by starvation, damage, and stress
Endocytic pathways
Recycling
Transcytosis across a polarized cell
Delivery to a lysosome for degradation
What is the only cell pathway for degradation of large internal structures/organelles?
Autophagy
What are the two main pathways for degradation in the cell?
Autophagy & the ubiquitin proteasome system
What are the main insulin-responsive tissues in the body?
Fat, liver, and muscle
What does insulin promote in fat tissue?
Uptake of glucose and fats from blood & increases synthesis and storage of lipids
What does insulin promote in the liver?
Uptake of glucose, increase glycogen synthesis, and reduces glycogenolysis
What does insulin promote in muscles?
Uptake of glucose & amino acids from blood & increased protein synthesis
Tissues
cells + extracellular matrix
Specialized functions
Specific cells + specific extracellular properties/organization
Four classic tissues
- Epithelium
- Connective tissue
- Muscle
- Nerve
What embryologic tissue does the epithelial (surface) arise from?
Primarily ectoderm and endoderm
What embryologic tissue does the CT and muscle arise from?
Primarily mesoderm
What embryologic tissue does the nerve tissue arise from?
Primarily from the neuroectoderm (CNS) and neural crest (PNS)
Where is epithelial tissue found?
All internal and external body surfaces, alimentary canal from inner lip to anal skin, line all blood & lymphatic vessels, compose all glands
Characteristics of epithelia
All cells connected to other cells, polarized (apical, basal, lateral, organelles), specializations (apical, lateral, basal), avascular, and stem cells
Note: basal lamina is the only extracellular matrix associated with epithelia
Basal lamina
“Basement membrane”
Extracellular matrix layer synthesized largely by epithelial cells, which adhere to it. The basal lamina is then adhered to connective tissue.
What do desmosomes do?
Connect intermediate filaments in one cell to those in the next cell. Located in the lateral plasma membranes
Cell-cell anchoring junctions
What do adherens junctions do?
Connect actin filament bundles in one cell with that in the next cell. Located in plasma membranes below tight junctions
Cell-cell anchoring junctions
What do tight junctions do?
Seal gaps between epithelial cells near the apical surface
Regulates diffusion between cells & prevents movement of membrane components
What do gap junctions do?
Allow the passage of small water-soluble molecules from cell to cell. Located on the lateral plasma membranes
Channel-forming junction
What do hemidesmosomes do?
Anchor intermediate filaments in a cell to extracellular matrix. Located on the basal plasma membrane
Cell-matrix anchoring junctions
What do actin-linked cell-matrix adhesions do?
Anchor actin filaments in cell to extracellular matrix
Cell-matrix anchoring junctions
What do occluding junctions do?
Seal the basal and apical compartments
Do microtubules bind junctions in epithelial cells?
No
Types of simple epithelia?
Squamous, cuboidal, and columnar
Pseudostratified epithelium
All cells adhere to basal lamina, but not all cells reach free (apical) surface
What does normal airway mucus do?
It travels up the mucociliary escalator. First, it is secreted by the goblet cells, and then it forms a layer that is propelled by cilia on the epithelial cells
Apical specializations
Microvilli, cilia, stereocilia
Function of microvili
Increase surface area, absorption
NOT motile
Function of cilia
movement/propulsion, ATP hydrolysis (by dynein motor “arms”)
Microtubule core that is motile
Stereocilia
Very long micovilli that project from the apical surface of specialized cells present in the male reproductive tract and the inner ear
Infolding
Type of basal specialization that increases surface area
Mitochondria found between infoldings in many epithelial cells
Primary Ciliary Dyskinesia
Cilia function defect, low or no motility, no or poor clearance of airway mucus
Exocrine glands
Secretory product -> duct
Endocrine glands
Secretory product -> blood
Serous gland secretion?
Watery & protein rich
Mucous gland secretion?
Thick + mucin rich
Exocrine secretory mechanisms?
Merocrine (most cells, fusion of secretory vesicles with plasma membrane)
Apocrine (specialized cells, lipid droplet secretion)
Holocrine (specialized cells - cell death and rupture)
Endocrine secretory mechanism?
Merocrine - fusion of secretory vesicles with plasma membrane
What layer of the epidermis is the transition from living to dead cells?
The stratum lucidum
Layers of the epidermis?
Come, Let’s Get Sun Burned
(All start with Stratum)
Corneum Lucidum Granulosum Spinosum Basale
What are the most numerous cells in the epidermis?
Keratinocytes
Where are keratinocyte stem cells (KSC) found?
Stratum basale
What cells do not arise from keratinocyte stem cells?
Langerhans, melanocytes, Merkel cells (function in tactile sensation)
What are prickle cells?
Keratinocytes in the stratum spinosum
Appearance is due to thousands of desmosomes per cell
Epidermolysis bullosa simplex (EBS)
Mutation of keratins 5 and 14 (in the basal layer)
Blisters develop soon after birth at sites subject to pressure or rubbing
Pemphigus vulgaris
Most common Pemphigus blistering disease. Autoantibodies to desmoglein 3 (desmosomes not able to attach properly)
Bullous pemphigoid
Autoimmune disease where autoantibodies cause hemidesome degradation (separates the stratum basale from the basal lamina and causes blistering on the skin)
Three types of skin stem cells
- Epidermal - stratum basale, form keratinocytes
- Sebocyte - in sebaceous gland, secrete sebum
- Bulge - in hair follicle sheath, form hair cells
Whats the most common form of skin cancer?
Basal cell carcinoma
Slow-growing, usually not metastatic, typically from follicular bulge stem cells, surgical removal common
Invasive carcinoma (epithelial proliferation)
cancer, exits epithelium and crosses the basal lamina to enter the connective tissue
Carcinoma in situ (epithelial proliferation)
Dysplasia of full thickness of the epithelium (epidermis), pre-malignant
Dysplasia (epithelial proliferation)
Abnormal epithelial cells and disordered growth; abnormal differentiation/maturation of epithelial cells
Metaplasia (epithelial proliferation)
Replacement of one epithelium for another by stress or inflammation; usually reversible
Hyperplasia (epithelial proliferation)
Normal response, increase in epithelial cell #
H and E stain
Hematoxylin - basic dye - binds acidic (basophilic) molecules like DNA
Eosin - acidic dye - binds basic (acidophilic) molecules like proteins
Erythrocyte diameter
7.8 micrometers
Location of 55S ribosome?
Mitochondria
Location of 80S ribosome?
Cytoplasm
Endothelium
simple squamous epithelium lining blood and lymphatic vessels
Mesothelium
simple squamous epithelium lining body cavities
The epidermis is composed of what?
keratinized stratified squamous epithelium
Corneocytes
Terminally differentiated, flattened dead cells
AKA keratinocytes in the stratum corneum
Tonofilaments
Intracellular keratin fibers (intermediate filaments)
Confer strength
Eccrine sweat gland
Simple coiled; almost all skin, involved in thermoregulation
Apocrine sweat gland
Simple coiled; secretes proteins, lipids, sugars, and organic compounds into hair follicles
Sweat gland ducts have what kind of epithelia?
Stratified epithelium (either squamous or cubodial)
The secretory portion of a gland has what kind of epithelia?
Glandular epithelium (not classified)
All epithelial cells secrete what?
Collagen Type IV. Secreted at the basal surface via constitutive merocrine secretion; part of basal lamina
Exocrine portion of the pancreas
Acini + ducts, glandular epithelium, merocrine secretion of zymogens
Endocrine portion of the pancreas
Islets of Langerhans, epithelioid cells (not polarized, not classified as epithelium), endocrine products like insulin, glucagon, etc
Pancreatic acinus
spherical cluster of epithelial cells that secrete products at apical plasma membranes into lumen
Parenchyma
generic term for functional cells of a tissue
Stroma
generic term for the supporting cells and matrix of a tissue
Ex: Connective tissue in many organs
What is Cellulitis?
Inflammation of the dermis and subcutaneous tissue. Etiology is a bacterial infection (endogenous or exogenous) from a break in the skin, burn, insect bite, IV, fungal infection.
Clinical signs: redness, swelling, tenderness, warmth
Connective tissue
Cells + extracellular matrix. Cells are attached to the matrix and not each other. Vascularized, can recruit immune cells.
Loose connective tissue
More cells, less ECM
Ex: lamina propria of intestinal villus
Dense connective tissue
More ECM, fewer cells
Irregular = collagen fiber orientation in many directions
Regular =collagen fiber orientation in one direction
Connective tissue cell components
Fibroblast, undifferentiated cell, plasma cell, adipocyte, macrophage, mast cell
FU PAMM (imagine Dwight from the office saying it)
Connective tissue transient (wandering) components
neutrophil, eosinophil, basophil, lymphocyte, monocyte
Immune-related!
Connective tissue ECM components
protein fibers (collagen and reticular elastic), ground substance (proteoglycans, glycosaminoglycans), basal/external lamina, tissue fluid
Fibroblasts
Most abundant and widely distributed CT cell
Synthesize ECM (fibers and ground substance)
Fibers = collagen and elastic
Ground substance = proteins and polysaccaharides
“All purpose cell”
Adipocyte
White fat = unilocular, one large lipid droplet
Brown fat = multilocular, many small lipid droplets
Lipid droplet is primarily triacylglycerols
Do connective tissue cells synthesize a basal or external lamina?
No. Basal lamina is for epithelia
Primary function of ECM?
Managing extracellular stress (tension, torsion, compression, shear)
What is the most abundant protein in the body?
Collagen
Collagen Type I
Fibril, fiber, bundle
Bone, skin, tendons, ligaments, cornea
Synthesized by fibroblast, tendinocyte, osteoblast
Collagen Type II
Fibril, Fiber
Cartilage
Synthesized by chondroblast, chondrocyte
Collagen Type III
Fibril, thin fiber (branched networks
Reticular fibers (lymph nodes, spleen, liver, blood vessels, skin)
Synthesized by reticular cell, fibroblast, smooth muscle cell
Collagen Type IV
Sheet or plaque
Basal lamina, external lamina (bind to ECM molecules like laminin)
Synthesized by adipocyte, epithelial cell, muscle cell, Schwann cell
Collagen Type VII
Fibril
Anchoring fibrils (skin, eye, uterus, esophagus). Function to connect basal/external lamina to CT
Synthesized by fibroblast
Order of Collagen Type 1 organization
Tropocollagen triple helix, fibril (68nm is the banding pattern; critical feature of strength is covalent crosslinks here), fiber, bundle
Collagen synthesis steps
- Pro-alpha chain synthesis
- Hydroxylation & Glycosylation
- Self-assembly of three pro-alpha chains
- Procollagen triple-helix formation and secretion through merocrine function
- Extra-cellular: self polymerization to make fibril with 68nm banding pattern & covalent cross-linking
Examples of collagen diseases
- Osteogenesis imperfecta (OI): brittle bone disease (multiple fractures), caused by defects in type 1 collagen
- Ehlers-Danlos Syndrome: joint hyper mobility, tissue fragility, and skin extensibility
Blue sclera sign
Sclera is rich in dense, irregular CT (type I collagen). An issue with type I like OI or EDS will cause bilateral blue sclera
Elastic fibers
Composed of elastin core (crosslinked monomers like collagen) and microfibrils (fibrillin)
Ex: desmosine. Measure of this in the urine is a clinical measure of tissue damage
Marfan syndrome is caused by what?
A defect in the fibrillin 1 gene (not elastin!)
Ground substance
Space filling molecules, fluid-filled. Found between CT fibers, resists pushing (compressive stress)
Examples: glycosaminoglycans (GAGs), proteoglycans (PGs)
Hyaluronic Acid
Very long GAG; repeating disaccharide; function is to organize water, shock absorption, lubrication in synovial joints
Proteoglycans
core protein + GAGs
Multi-adhesive proteins (MAGs?)
Link ground substance molecules in the ECM to each other and cells
Ex: fibronectin
What cells exit the blood, enter connective tissue, differentiate, and remain in CT?
Resident fixed cells: macrophage, mast cell, plasma cell
Extravasation
process of exiting blood at post-capillary venules (after mast cell and macrophage stimulation)
Simplified inflammatory response
- Mast cells and macrophages in CT release primary inflammatory mediators that cause vessels to dilates and “leak”
- Extravasation of leukocytes into CT (neutrophils, basophils, and eosinophils)
- Macrophages phagocytose microbes, dead cells & debris
Scleroderma
Excess healing by fibroblasts; chronic inflammation. Fibroblasts produce excess collagen and skin becomes thickened and hardened
Epidermolysis Bullosa
a group of rare inherited skin diseases that are characterized by the development of blisters following minimal pressure to the skin
Treatment for epidermolysis bullosa?
preventing and treating wounds and infection
Four major types of epidermolysis bullosa?
- Simplex (EBS)
- Junctional (JEB)
- Dermolytic or Dystrophic (DEB)
- Mixed (Kindler syndrome)
EB Simplex
Intraepidermal cleavage due to defects in keratins 5 and 14
autosomal dominant
Junctional EB
intra-lamina lucida split, autosomal recessive, least common type, lethal by age 2
Dystrophic EB
subepidermal cleaveage due to deficient or defective collagen 7 fibrils
Research in EB?
Protein replacement therapy: replace or boost missing or defective protein
Cell-based therapy: stem cells, fibroblasts, or gene-corrected cells. Bone marrow transplants
Gene therapy: corrected gene transfer via retrovirus or stem cell therapy
Where are large amounts of glycogen stored?
Liver and muscle cells
Glycolipid
sphingosine + monosaccharide or oligosaccharide
Where is the C chain of insulin removed during the synthesis & secretion pathway?
Within the secretory vessicle
Types of autophagy
macro, micro, and chaperone-mediated
Does H&E stain glycogen?
Nope. Glycogen isn’t charged so no stain.
PAS does stain it red-pink
Forms of specialized connective tissue?
Adipose, blood, bone, cartilage, hemopoietic, lymphatic
Two types of endocrine glands
- Secretory portion is classified epithelial cells (e.g. thyroid follicle)
- Secretory portion is not classified; epithelioid-like (“glandular epithelium”
What do all epithelial cells secrete at the basal surface?
Type 4 Collagen; it’s a constitutive merocrine secretion that makes up part of the basal lamina
Three types of cartilage
- hyaline
- elastic
- fibrocartilage
HEF
Hyaline cartilage
mechanical support, covers articulating surfaces of bones, model for skeletal bone formation
predominantly type 2 collagen
found in growth plates, trachea, costal cartilages, larynx, tip of nose
surrounded by perichondrium EXCEPT for articular cartilage
Elastic cartilage
found where resilience and springiness are needed (ear and epiglottis)
contains type 2 collagen + increased amount of elastic fibers
surrounded by perichondrium
Fibrocartilage
very limited; transitional form
combo of dense regular CT & hyaline cartilage - mostly type 1 collagen with some type 2
plays a role in fracture repair
found in intervertebral disks, pubic symphysis, menisci, and where tendons insert into bones
NO perichondrium
Cartilage
Specialized CT that is composed of chondrocytes (95%) and ECM
Avascular and aneural
Chondrocytes
occur singularly or in nests; synthesize the extracellular matrix; housed in lacunae (small cavities in ECM)
Perichondrium
dense, irregular CT capsule that surrounds hyaline (sans articular part) + elastic cartilages. Source of nutrients and oxygen for avascular cartilage
Two types of cartilage growth
- Appositional growth - new cartilage forms at surface of existing cartilage. Deposition on the outside surface of cartilage
- Interstitial growth - new cartilage forms within existing cartilage. This is what chondrocytes do. They divide and create cell nests - get space between them as they divide (note: they are NOT stem cells)
What type(s) of cartilage are capable of repair?
Fibrocartilage. During bone repair it is formed around the broken bone & then undergoes calcification
Hyaline and elastic cartilage are not capable of repair (avascular!). Hyaline undergoes calcification & gets replace by bone
Fibrous outer layer of the bone?
Periosteum
Covers the outer surface except at epiphyses
Multilayered
The innercellular layer contains osteoblasts, osteoclasts, osteoprogenitor cells, and bone lining cells
Inner layer of the bone?
Endosteum
Covers internal bone surfaces (marrow cavity, Haversian canal)
Single cellular layer (osteoblasts, osteoclasts, osteoprogenitor cells, and bone lining cells)
Two kinds of bone?
- Compact
2. Spongy (aka trabecular)
Composition of bone?
35% cells (osteo- -blasts, -clasts, and -cytes) + ECM of ground substance + 90% collagen 1
65% mineral crystals (primarily calcium phosphate in the form of hydroxyapatite crystals)
osteoprogenitor cell
Derived from mesenchyme; differentiate into osteoblasts
Osteoblasts
synthesizes organic components of ECM; found adjacent to bone matrix they have synthesized
Osteocyte
mature bone cell residing in a lacuna; synthesizes organic components of ECM
completely surrounded by its own matrix
numerous processes allow cell-to-cell communication with osteoblasts and osteocytes
How are nutrients and waste transported in bone?
Small channels radiate from each lacuna through the mineralized matrix
Act as passage routes from nutrients/waste
** gap junctions are essential
How does bone tissue grow?
By appositional growth, NOT interstitial
Bone deposition occurs by osteoblasts and osteocytes
Requires vitamin C and oxygen
How does bone, the organ, grow?
- Intramembranous ossification - differentiation of mesenchymal cells into osteoprogenitor cells
- Endochondral ossification - involves the erosin of hyaline (or fibrocartilage) cartilage by osteoclasts and deposition of bone by osteoblasts and osteocytes
Intramembranous Ossification
Mesenchymal cells differentiate into osteoblasts. Osteoblasts deposit osteoid that then becomes mineralized bone.
Bone formation occurs at numerous sites simultaneously in form of spicules which “grow together” as they expand to form trabeculae of bone
Occurs in flat bones of the cranium, face, mandible and maxilla
Endochondral Ossification
Requires interstitial and appositional growth of cartilage, erosion of that cartilage, vascularization, and bone deposition by osteoblasts and osteocytes
Process associated with bone growth/development. Weight-bearing bones of axial skeleton and bones of the extremities
How does bone grow in width?
By appositional growth
How does bone grow in length?
By interstitial growth of cartilage and appositional growth of bone
What promotes vascular invasion in bone growth?
Hypertrophying chondrocytes secreting VEGF (Vascular Endothelial Growth Factor)
What type of collagen forms a “scaffold” around hypertrophying chondrocytes in bone growth?
Collagen X
A point mutation in the gene for this causes a form of dwarfism (chondrodysplasia)
Regulation of endochondral ossification
Nutritional (vitamin C, calcium, oxygen)
Hormonal (IGF-I is produced in the liver in response to growth hormone secretion. Stimulates chondrocyte proliferation and bone growth. FGF is a negative regulator of bone growth by inhibiting chondrocyte proliferation)
Bone remodeling
Relies on osteoclasts to break down old matrix and osteoblasts to lay down new matrix
(advancing cutting cone & closing cone)
What causes an osteoclast precursor to mature?
Binding of RANKL to RANK
osteoprotegerin secreted by osteoblasts inhibits RANKL
What increases osteoclast numbers?
Parathyroid hormone (PTH) increases numbers to resorb bone and increase blood calcium
What inhibits osteoclast numbers?
Calcitonin inhibits activity and decreases blood calcium
Osteopetrosis
Thick dense bones, treatment is bone marrow transplant
Osteoporosis
Decrease in bone mass and increase in bone fragility. Treatment is diet, hormone replacement therapy or anti-RANKL antibodies
Paget’s Disease
Abnormal bone architecture, enlarged and misshapen bones. Treatment is calcitonin and bisphosphonates
Steps in bone repair
- Granulation tissue from fibroblasts and periosteal cells
- Soft callus of dense CT and fibrocartilage forms to help stabilize the bone. At the same time osteoprogenitor cells divide and differentiate into osteoblasts
- Hard callus of mixed spicules of calcified fibrocartilage and bone forms. At the same time, endochondral ossification is ongoing
- Bone remodeling occurs and Haversian systems are rebuilt
