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What was de Duve’s discovery & experiment?
Lysosomes through differential gradient centrifugation
Lysosome
50+ hydrolytic enzymes
Single membrane bound (acid phosphate marker enzyme)
pH 5
Two theories on white blood cells (example of heterophagy)
Virchow - WBC give birth to RBC (red blood cells)
Metchnikoff - Phagocytosis, WBC engulf RBC, disease prevention
Opsinization
Antibodies covering the surface of bacteria
Mysathenia Gravis
Autoimmune Disease, acetylcholine synapse
Too little Ach released OR problem with Ach receptor
Lysosomes degrade Ach more than it is synthesized
Mysathenia Gravis Drugs
Curare - Ach receptor antagonist → up MG symptoms
Eserine - inhibits Ach → Ach breakdown → up Ach down MG symptoms (Neostigmine and Predrisolone)
3H-humgarotoxin - binds to Ach receptor
Autophagy
Mitochondria & SER
LC3 mediates
Chloroquine & cisplatin (blocks DNA repair)
Environmental Lysosomal Diseases
Silicosis (silica into lyso, lyso enzymes leak, down elasticity & CO2/O2 exchange)
Chloroquine Myopathy/Retinopathy
Tay-Sachs Disease
Lacking Hex A, neurological, accumulation of ganglioside GM2
Hurler Syndrome/Mucopolysaccharidosis Type 1
Large lysosomes → gangliosides accumulate
alpha-L iduronidase defect
Hurler & normal cell experiment
Aldurazyme ERT treatment
I-Cell Disease
No MGP tag
Lysosomal enzymes & proteins don’t go to lysosomes
Excess hydrolases in ECM
Guacker Disease
Cerezyme ERT treatmentP
Pompe Disease
Acid t-glucosinase defect
Myozyme ERT treatment
Proteasomes
Only degrade proteins
Ubiquitanated
Velcade - inhibit proteasomes, cancer treatment
mitDNA
37 genes, 16,500 bases, circular, no corrections
Most mit proteins from nuclear genome
Location of mitochondria
Polarized epidermal cells, apical region, where ATP is needed
Colchicine
blocks microtubules
Why did the mitochondria lose most of its genes?
Most mitDNA proteins are hydrophobic and mitDNA proteins require local regulation
Outer mitochondrial membrane
fewer proteins, porins, voltage dependent anion channels (Ca2+)
Inner mitochondrial membrane
oxidative phosphorylation, electron transport chain, cardiolipin (glue for ETC intermediates)
Mitochondria can move on microtubules (true/false)
true
How do the mitochondria induce apoptosis?
MPTP opens from cell stress, releases cytochrome C, activates caspase 9 (death receptor), caspase 9 + procaspase 3 → caspase 3 (executioner enzyme), apoptosis
Cycloaporin A
Inhibits MPTP opening
bcl-2
B cell lymphoma, makes cancers resistant to chemo when overexpressed
Why can we not use hep G2 for drug testing and how can they be modified to be effective?
Hep G2 does not react to drugs the same way normal heptocytes do, it reacts close to how heptocytes do when combined with gal
Warburg Effect
Down O2, cancerous, ATP from glycolysis not mitochondria
Mitochondrial Myopathies
mit diseases, exercise intolerance, myoclonus epilepsy, inherited, brain or muscle issues
Glycolysis
NADH → mitochondria → ATP, uses ATP, malate-aspartate
Chemiosmotic Hypothesis Experiment
Create inside-out sub mitochondria, manipulate with DNP (down ATP, H+ gradient) and GRAM (Vm). Vm has a greater impact
ETC (electron transport chain) inhibitors
Cyanide, CO, Rotenore
Uncouplers
Inhibit protein synthesis
GRAM, Valin, DNP, Olimycin
What drug compromises the H+ gradient?
DNP, a weak lipid soluble acid, H+ ionophone
What drugs are K+ ionophones that decrease the change in Vm?
GRAM - faster, channels
Valin - slower, mobile
What happens when you treat an inside-out sub mitochondria with olimycin?
FOFl particle is removed and ATP is not produced
Joseph Priestly suggested what
The existence of photosynthesis
Engelman found
Spinogyna - ribbon chloroplasts
Isolated chloroplasts
Robert Hill and Cornelius Van Neil found
O2 comes from H2O, without light bateria move away from O2 instead of aggregating
Why are cynabacteria significant
They produce more energy than they need, are simple prokaryotes, and have been sequenced
Carotene
Carcinogen, antioxidant, failed clinical trial cause it increased the risk of cancer
Photoinhibition
plant mech to protect against too much light (PSII more sensitive, P-D1 high turnover)
Rubisco
low affinity for CO2, high abundance
most plentiful protein
C fixtation (up CO2 down O2)
Photorespiration (down CO2 up O2)
Functions of ECM
Connect and identify cells/some tissues
Receptor mediation
Filter/matrix/barrier = basal lamina
What type of media do epidermal cells require
Microporous cell culture insert with Type 1 collagen cross linked with aldehyde and soaked with FCS
What media to human embryonic stem cells (hESC) require
Special ECM, irradiated mouse fibroblasts and no feeder layer
Homophilic cell adhesion molecule
CAM that binds to an identical CAM
Experiment proving cells recognize other cells
Liver and retina cells removed and grown in culture, retina cells will not bond to liver cells
Cadherins
homophilic, Ca2+, in all substrate dependent cells
IG Superfamily
neural CAM, retinal ganglion connections, embryonic n-CAM are glycosylated (PSA → slide around)
Basal Lamina
sheet like barrier, ECM
Loose Connective Tissue
ECM, porous, hydrated, fibroblasts, collagen and elastin, longest half life
Cornea
loose connective tissue, stroma (highly ordered collagen), descemet’s membrane (basal lamina), cataracts from stroma out of alignment and death of cornea endothelial cells
Collagen
insoluble in aqueous, fibrous, glycine every 3, triple helix, resist stretching
Glycine
smallest R group, needed for a helical structure, base
Scurvy
disease, lack vit C, no collagen around arteries
Collagen synthesis requires
RER for proline hydroxylation and lysl oxidase & O2 for final step
Glycosaminoglycans
Repeating disaccharides, many neg groups, sliding surface for cells, rigid
Glycosaminoglycans Treatments
Hyaluronan - cosmetic surgery, CD44 receptors
SynVisc One - knee osteoarthritis
Protoglycans
Glycosaminoglycans + Proteins
Bind growth factors to RTK’s & Fibromycin to ECM
Syndecan 1
Fibronectin
Not present in cancer
multiadhesive, sticks cells in place
dimer, morphogenesis
Laminin
multiadhesive, in basal lamina
Encourages neuronal phenotype
trimer, self assembling
Integrin Receptors
Low affinity high abundance (changes based on stucture)
cross-talk
Mg2+
F-actin
RGD Sequence
binds integrins to ECM, fibronectin, without it cells Anoikis (apoptosis from not having a home)
LAD
leukocyte adhesion deficiency, Beta 2 integrin receptor, low extravasation (leukocytes → blood stream)
Duchenne Muscular Dystrophy
males only, skeletal muscle, laminin, dystrophin
Ehler-Danlos Syndrome
hypermobility (chronic joint pain) or classical (fragile skin), heterogeneous
Osteogenesis Imperfecta
collagen:
Type I norm structure low abundance
Type 2 no helix in collagen