Cell Control GPHR-7050-01Sp20

The Life-Preserving Advance Directive of Planned Death - Apoptosis  

Short Version:  Calcium and apoptosis are important.

Long Version:

The entrance of calcium is linked to multiple events:deleterious and beneficial to cellular regulation.

Supplementary Material on the background:

The hallmark of the phosphatidylserine flipping to the extracellular side of the membrane is a sign of apoptosis, a controlled process that costs ATP.  On the extracellular side are phosphatidylcholine and sphingomyelin.  The choline is the more abundant lipid.  When the serine flips to the extracellular side, it is time for the macrophages to arrive and vacuum the clutter.

The border  has a variety of checkpoints for drugs.  The first is the blood-brain barrier: ATP Bind Cassette.  It is comparable to the current US-Mexico border.  Under the Trump Administration “Remain in Mexico” policy, refugees who are running away from gang violence, starvation, military juntas, narco gangs, sexual assault are finding it very difficult to enter to claim desperate amnesty status.  Changes in the voltage of the neuronal membrane can get detected using the localization measurements such as the use of voltage sensitive dyes.

Organs derived from endoderm such as kidney and liver also utilize the  ATP Binding Cassette.  The liver uses the ATP for Pre systemic Drug Clearance and the kidney can excrete using the same expensive mechanism.

Calcium is a critical transport process such as VMAT (vesicular monoamine transport).  When the vesicle docks at the membrane, calcium enters.  The cell conducts an exocytosis using cellular UPS packages wrapped in claritin residues.  The ending endocytosis allows recovery of the package materials.

The hepatic presystemic clearance has destinations to the lumen of the gastrointestinal tract or to the portal vein.

Cytochrome c is located in the matrix of the mitochondria positioned between cytochrome c reduce (Complex 3) and the oxidase (Complex 4).  When the energy carrier NADH enters, protons are pumped to the intermembrane space making the space more acidic.  When the cytochrome c (cyt c ) moves to the low-calcium cytosol, it is time for apoptosis, or decluttering.

Lamin is a protein that is located on the interior side of the nuclear envelope.  When the MPF phosphorylates the lamin, it is the prometaphase in which the old nuclear skin is shedded.  Lamin is also the in vivo substrate of effector caspases.

Extrinsic Apoptosis:

When the Fas ligand or the killer lymphocyte wants to start extrinsic apoptosis, a protein sandwich known as the DISC is constructed.  Death Domain is located on Tumor Necrosis Factor Receptor.  Despite the term necrosis in the name, this is the player of extrinsic apoptosis. Fas Associated Death Domain is located on MOMP, or Adapter protein.

Bax can then folds into a donut with flowery petals  to allow the hydrophilic cyt c to pass from the matrix to the cytosol.  It is like Moses, parting the cellular debris, followed by the  musical rendition "Let my Cytochrome Go."  Following the cyt c retinue is the Apaf 1 (Apoptosome) and apoptosis inducing factor Smac/Diablo.

The use of Actinomycin can interfere with the release of the cyt c, blocking the path to intrinsic apoptosis.

The dumpsters of the eukaryotic cell are located in the lysosomes. Lysosomes maintain the V class ATPase.  The product is the proton gradient, which is necessary to activate the proenzymes.  Not just a  dumpster, lysosomes also act as a storage facility to store a variety of hydrolases.  They are inactive until the acidic environment cleaves the zymogens.  V class pumps are the converse of the F pump, which are located in plasma membranes, mitochrone, and thylakoid membranes.

Uncoupling Protein can interfere with Calcium Regulation.  Fewer ATP is produced.  ATP is needed for the excretion of calcium ions in order to maintain a low calcium environment in the cytosol.  ATP is needed for the calcium pumps in the eukaryotic plasma membranes the on the membranes of sarcoplasmic reticulum of muscle cells

Drug design must target the ATP Bind Cassette, a checkpoint that requires ATP bribing at the blood-barrier border. Compared to extrinsic apoptosis, intrinsic apoptosis was described as a more minimalist process.  No DISC sandwich required.  Then again, apoptosome can be described as the burrito of intrinsic apoptosis with ingredients like Apaf and Smac/Diablo.

Like an accredited organism, at the top of the hierarchy are the BHC-only factors like Bad and Bim.  When caspase 8 is activated for the intention of extrinsic apoptosis, caspase 8 can cleave the Asp D site of Bid.  Then, MOMP becomes activated.  Bid is considered “strongly apoptotic” and can initiate processes like reorganization of the mitochondrial cristae.  Question:  Does the surface area increase?  

The DISC burger has layers of DED, FADD, and DD.  DED is found on Pro Caspase 8.  FADD is located on the Adaptor protein.  

MPM (mitochondrial outer membrane permeabilization) drills a hole in the mitochondrial outer membrane and cleaves Bid, the initiator of apoptosis.

https://www.drawittoknowit.com/course/pathology/glossary/immunology-microbiology/adaptive-immunity-humoral-response?source=course&source-glossary=physiology

Question:  What are the lab techniques to detect organelle dilatation and ribosomal disaggregation?  These cellular hallmarks are part of the reversible phase of necrosis.  The cell can develop  pimples, known as blebbing, not to be confused with the term “blob.”  The surface area increases.  Furthermore, because of its unfortunate resemblance to the informal “blob,” blebbing may get confused as a simple process.  Further, there is  a protrusion of the membrane.  Spikes made microtubules form, compromising the asymmetry of the membrane.  Fragmentation occurs and outgoing cellular UPS packages are mailed out in apoptotic vesicles. Question: Is this process different from opsonization?

"

Opsonization 

is the coating of a particle with proteins that facilitate phagocytosis of the particle by tissue macrophages and activated follicular dendritic cells (FDCs) as well as binding by receptors on peripheral blood cells" ScienceDirect

Much of the changes that mark necrosis point toward the increase of entropy. Apoptosis is marked with terms like “fragmentation” and lowering of entropy.  The cell condenses under low entropy.  Mitochondria becomes smaller during apoptosis because of the flowery pore made by Bax.  However, the mitochondria will swell during necrosis because there are no flowery pores and Bax has no role during necrosis.

Changes that portend higher entropy such as the “rupture” of the membrane and the “dispersal” of organelles mark the reversible phase of necrosis.  There are no neatly packaged clathrin UPS packages for the cell to pick at a later time.  The lysosomes, the cellular dumpsters and storage facility of proteases powered by V class ATPase, are destroyed.  Neutrophils , the special white blood cells that are the first responders to bacterial infections, arrive.  Inflammation occurs.

Plasmolysis is described as “hydrolytic fusion of cytoplasm” which seems like a strange contradiction.  Hydrolysis occurs, which results in the removal of water molecules.  This is a breakage of bonds.  Then, there is a fusion of the dehydrated products.

The Fas ligand can bind to the CD95, the cytoplasmic tails of Fas or to the DISC burger. Uncontrolled  influx of calcium can be toxic.  It can cause irreversible cellular damage.  Luckily, the calcium detectors know to initiate apoptosis by calling the BH3 initiators.

Pharmacology Review:

The cardiovascular module was then reviewed.  Delayed after Depolarization is the pathology when the sodium calcium exchange is disrupted.  The cytosol where the caspases reside require a low calcium environment.  Therefore, excess calcium must be pumped out.  A currency exchange permits the exchange of three sodium ions from the extracellular for the excretion of one calcium ion.  Sodium is responsible for the rising phase of action potentials.  The plateau phase is the work of the calcium ions. The presence can get detected with measurements using GCAMP.  Calcium ions will bind to the calmodulin, resulting in bright fluorescence.  When the levels of calcium ions are low, the fluorescence will be dim. When the catecholamines are stimulated, there will be an excess of intracellular calcium.  The sodium calcium currency must be exchanged to prevent the Delayed after Depolarization.  Furosemide works by blocking the sodium potassium chloride cotransport in the thick ascending loop of Henle by binding to chloride transport ion channels.

Ion channels allow a wormhole for the charged particles to bypass the hydrophobic membrane.  They are not like transporters that span the entire depth of the membrane.  Digoxin covalently inhibits the primary sodium potassium transport.  This results in increase of cardiac calcium and increases the force of heart contraction. Because the intracellular calcium can get excessive, Digoxin can cause arrhythmia.  If the mass of the heart remains constant, then the acceleration must increase in order to accommodate the increase in force. Like Digoxin, spironolactone blocks the primary transport but targets the distal convoluted tubule, which is farther from the Bowman’s capsule and the Loop of Henle. Finally, Amiodarone is the rhythm control medication that can block the potassium current and its side effects include QTc prolongation, EAD, and Torsade.

To prepare for the exam, physiology was reviewed. The SGLT2 transporter is found in the kidney proximal tubule, close to the glomerulus where ninety-percent of glucose is recovered.

Physiological stimuli include hormones and growth factors, boh are signaling factors.  As Dr. M mentioned, low dihydrotestosterone (DHT) is a signal to start apoptosis.

Normoxia  will result in proteasome degradation of HIF. Under hypoxia, chromatin change will get observed (Question:  How is this change observed?  GFP?)  Lysine demtheylase are genes that assist with the pathway toward apoptosis.  Unfortunately, one of the effects of apoptosis is ROS because of the extrusion of GSH, which converts hydrogen peroxide into water.

Mitochondria plays a role in calcium regulation and synthesis of steroid hormones in organs like the adrenal cortex.  Cholesterol, however, is synthesis in the low calcium environment cytosol.

Question:  How does the hormone aldosterone cause fluid volume to increase by the mechanism of reabsorption sodium?  The movement of Calcium and Phosphate ions occur together because they are “buddies” (Khan Academy).  Is there a similar friendship between sodium and water?  Sodium is considered a highly soluble ion and will not precipitate.  It is a known spectator ion for many reactions.

Phosphatidylcholine - Wikipedia

Phosphatidylserine - Wikipedia

       

Question: Is NMR used to detect the presence of phosphatidyl serine when it flips to the external surface and crowds out the phosphatidylcholine and the sphingosine?  Choline is marked with the positively charged ammonia that is sterically hindered by three methyl groups.  The serine group can be detected if the NMR can detect the hydroxyl group.

Question:  Where do the myelin figments come from?  What is the source of those apoptotic myelin figments?

 The content for the second exam requires proficiency of pathology, histology and immunology.  All the modules are curated to potentiate previously learned knowledge. Some of the details will have to be refreshed to further potentiate.