The document discusses lipid bilayers in cell membranes and their asymmetric distribution across leaflets. It specifically focuses on four main classes of phospholipids and how they are unequally distributed between the inner and outer leaflets. One phospholipid, phosphatidylserine (PS), is almost exclusively found on the inner leaflet under normal cell circumstances. This asymmetric distribution is maintained by transporter proteins called flippases. Mutations in flippase genes can lead to diseases by disrupting this asymmetry, such as Progressive Familial Intrahepatic Cholestasis and Cerebellar Ataxia, Mental Retardation, and Disequilibrium syndrome. The author's research focuses on understanding the catalytic activity and transport
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Adopting addressbase-premium in the energy sectorJonathan Clark
This briefing document has been created to help energy suppliers who are considering adopting AddressBase Premium. It will inform stakeholders on why better address management is important, why AddressBase Premium should be considered and how other organisations implement it. Finally, it summarises the key benefits of adopting AddressBase Premium and provides guidance on what to do next.
A detailed description of programmed cell death mechanism also called Apoptosis.
It explains about the factors, mechanism and pathways involved in the apoptosis.
Phloem differentiation
sieve elements
companion cells
The ontogeny of phloem sieve element
differentiation process of sieve elements
Phloem as a hub for systemic communication within the root meristem
APOPTOSIS & CANCER
How is the initiator caspase frist activated in response to an apoptotic signal?
The role of pRB in controlling transcription of genes
The Role of p53: Guardian of the Genome
Mutations in the PI3K/Akt/mTOR Pathway Drive Cancer Cells to Grow
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Adopting addressbase-premium in the energy sectorJonathan Clark
This briefing document has been created to help energy suppliers who are considering adopting AddressBase Premium. It will inform stakeholders on why better address management is important, why AddressBase Premium should be considered and how other organisations implement it. Finally, it summarises the key benefits of adopting AddressBase Premium and provides guidance on what to do next.
A detailed description of programmed cell death mechanism also called Apoptosis.
It explains about the factors, mechanism and pathways involved in the apoptosis.
Phloem differentiation
sieve elements
companion cells
The ontogeny of phloem sieve element
differentiation process of sieve elements
Phloem as a hub for systemic communication within the root meristem
APOPTOSIS & CANCER
How is the initiator caspase frist activated in response to an apoptotic signal?
The role of pRB in controlling transcription of genes
The Role of p53: Guardian of the Genome
Mutations in the PI3K/Akt/mTOR Pathway Drive Cancer Cells to Grow
Cholestasis induces reversible accumulation of periplakin in mouse liverEnrique Moreno Gonzalez
Periplakin (PPL) is a rod-shaped cytolinker protein thought to connect cellular adhesion junctional complexes to cytoskeletal filaments. PPL serves as a structural component of the cornified envelope in the skin and interacts with various types of proteins in cultured cells; its level decreases dramatically during tumorigenic progression in human epithelial tissues. Despite these intriguing observations, the physiological roles of PPL, especially in noncutaneous tissues, are still largely unknown. Because we observed a marked fluctuation of PPL expression in mouse liver in association with the bile acid receptor farnesoid X receptor (FXR) and cholestasis, we sought to characterize the role of PPL in the liver and determine its contributions to the etiology and pathogenesis of cholestasis.
1. The cell- and organelle-delimiting fluids we call eukaryotic lipid bilayers are unequally
and heterogeneously constituted. Phospholipids are the most populous constituents and
the substrates of my research. There are four principle classes—phosphatidylserine (PS),
phosphatidylethanolamine (PE), phosphatidylcholine (PC), and sphingolipids (SL).
Eukaryotes inequitably enrich these lipids across the endoplasmic or exoplasmic leaflets.
The ‘endo’ leaflet is richest in aminophospholipids like PS and PE, whereas the ‘exo’
leaflet is enriched in the quaternary amine-possessing lipids, PC and SL.
For some of these phospholipids the asymmetry is nearly exclusive. Under basal cell
circumstances, PS is almost perfectly restricted to the ‘endo’ leaflet while the near-
entirety of SL is observed at the ‘exo’ leaflet. This nonrandom distribution implies a
mechanism preventing net movement of phospholipids “down” their concentration
gradients. One explanation is that “flippases” sort these constituents into the appropriate
leaflets by phospholipid-specific vectorial transport. P4-type ATPases are enzyme pumps
that facilitate the movement of certain amphipaths in the inward direction. ATP8a1 is one
such P4-ATPase and PS flippase.
That organellar and plasma membranes tend to asymmetry is compelling in its own right,
but this interleaflet disequilibrium is more significant for its influence on human health
and disease. Consider PS during basal cell circumstances. This GPL concentrates in the
endoplasmic leaflet and reversal of that asymmetry (above a critical threshold) is
sufficient to radically modify cell fate. As a milestone of apoptosis, tumor cells display
PS, which recruits macrophages via the PS-binding receptor (Tim-1) resulting in tumor
cell phagocytosis. After a typical 100-120 days in circulation, erythrocytes display PS
and are targeted for degradation by splenic monocytes. Exoplasmic enrichment of PS is
also implicated in the premature destruction of sickled and thalassemic red cells. For
platelets, the consequences of increased PS mole-fraction in the outer leaflet are cell
activation, cell aggregation, and stimulation of blood coagulation cascades—which
underpins the role of PS exposure in thrombotic balance and, therefore, its relevance to
pulmonary embolism, myocardial infarction, and stroke. For these reasons, PS might be
thought of as a molecular signpost and its transmembrane distribution a matter of
physiological significance.
2. Equally influential as membrane asymmetry are the membrane proteins associated with
its creation, maintenance, and reversal. P4-type ATPases are aminophospholipid
translocases that influence all levels of the secretory pathway. Several have been
implicated in disease. P4’s play a pleiotropic role in select cases of obesity and diabetes,
and ATP8a1 knockout mice show defects in delayed hippocampus-dependent learning.
Genetic studies of families with Progressive Familial Intrahepatic Cholestasis (PFIC)
identify missense mutations in a P4-type ATPase, ATP8b1. PFIC is a severe liver
syndrome of compromised bile flow; onset is juvenile and arrives with a compulsory
indication for transplantation. Cerebellar Ataxia, Mental Retardation, and Disequilibrium
(CAMRQ) syndrome is a rare, congenital, autosomal recessive disorder characterized by
dysarthria, seizures, profound intellectual disability, cerebellar hypoplasia, trunkal ataxia,
and quadrupedal gait. Genome mapping of consanguineous families predisposed to
CAMRQ syndrome pinpoints a missense mutation in ATP8a2, another P4-type ATPase.
This provides a nice survey of the significance of this field and a loose framework for
some of its long-term aspirations. But to understand how these mutations yield these
consequences, we must first understand flippase activity and the catalytic unit itself. As a
membrane-embedded molecular motor, ATP8a1 couples the favorable change in free
energy of hydrolyzing ATP's distal phosphoanhydride bond to the otherwise non-
spontaneous mechanical rearrangements required to bind one molecule of PS on the
exoplasmic leaflet and passage it through to the endoplasmic leaflet. My work focuses
on the nature of ATP8a1’s PS binding site and transport pathway.