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Procedure modeling: technological innovation to regulate the danger regarding perioperative setting damage.
Familial forms of Alzheimer's disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein (APP), whose processing can result in the formation of amyloid β (Aβ). FAD can also result from mutations in the presenilin 1/2 (PSEN1/2) genes, whose protein products partially compose the γ-secretase complex that cleaves Aβ from APP fragments. Psen1-knockout (Psen1-KO) mice and knock-in (KI) mice with homozygous FAD-associated L435F mutations (Psen1LF/LF ) are embryonic and perinatally lethal, precluding a more rigorous examination of the effect of AD-causing Psen1 mutations on neurodegeneration. PD98059 order Given that the rat is a more suitable model organism with regards to surgical interventions and behavioral testing, we generated a rat KI model of the Psen1LF mutation. In this study, we focused on young Psen1LF rats to determine potential early pathogenic changes caused by this mutation. We found that, unlike Psen1LF/LF mice, Psen1LF/LF rats survive into adulthood despite the loss of γ-secretase activity. Consistent with loss of γ-secretase function, Psen1LF/LF rats exhibited low levels of Aβ38, Aβ40, and Aβ42 peptides. In contrast, levels of Aβ43, a longer and potentially more amyloidogenic Aβ form, were significantly increased in both Psen1LF/LF and Psen1LF/w rats. The longer survival of these KI rats affords the opportunity to examine the effect of homozygous Psen1 AD-associated mutations on neurodegeneration in older animals. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The the cystine/glutamate transporter system xc- consists of the light-chain subunit xCT (SLC7A11) and the heavy-chain subunit CD98 (4F2hc or SLC3A2) and exchanges extracellular cystine for intracellular glutamate at the plasma membrane. The imported cystine is reduced to cysteine and used for synthesis of glutathione, which is one of the most important antioxidants in cancer cells. Because cancer cells have increased levels of reactive oxygen species (ROS), xCT, being responsible for cystine-glutamate exchange, is overexpressed in many cancers, including glioblastoma. However, under glucose-limited conditions, xCT overexpression induces ROS accumulation and cell death. Here, we report that cell survival under glucose deprivation depends on cell density. We found that a high cell density (HD) down-regulates xCT levels and increases cell viability under glucose deprivation. We also found that growth of glioblastoma cells at HD inactivates mTOR, and that treatment with the mTOR inhibitor Torin 1 of cells grown at low density (LD) down-regulates xCT and inhibits glucose deprivation-induced cell death. The lysosome inhibitor bafilomycin A1 (BafA1) suppressed xCT down-regulation in HD-cultured glioblastoma cells and in Torin 1-treated cells grown at LD. Additionally, BafA1 exposure or ectopic xCT expression restored glucose deprivation-induced cell death at HD. These results suggest that HD inactivates mTOR and promotes lysosomal degradation of xCT, leading to improved glioblastoma cell viability under glucose-limited conditions. Our findings provide evidence that the control of xCT protein expression via lysosomal degradation is an important mechanism for metabolic adaptation in glioblastoma cells. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Myelin protein P2 is a peripheral membrane protein of the fatty acid-binding protein family that functions in the formation and maintenance of the peripheral nerve myelin sheath. Several P2 gene mutations cause human Charcot-Marie-Tooth neuropathy, but the mature myelin sheath assembly mechanism is unclear. Here, cryo-EM of myelin-like proteolipid multilayers revealed an ordered 3D lattice of P2 molecules between stacked lipid bilayers, visualizing supramolecular assembly at the myelin major dense line. The data disclosed that a single P2 layer is inserted between two bilayers in a tight intermembrane space of ~3 nm, implying direct interactions between P2 and two membrane surfaces. X-ray diffraction from P2-stacked bicelle multilayers revealed lateral protein organization, and surface mutagenesis of P2 coupled with structure-function experiments revealed a role for both the portal region of P2 and its opposite face in membrane interactions. Atomistic molecular dynamics simulations of P2 on model membrane surfaces suggested that Arg88 is critical for P2-membrane interactions, in addition to the helical lid domain. Negatively charged lipid headgroups stably anchored P2 on the myelin-like bilayer surface. Membrane binding may be accompanied by opening of the P2 β-barrel structure and ligand exchange with the apposing bilayer. Our results provide an unprecedented view into an ordered, multilayered biomolecular membrane system induced by the presence of a peripheral membrane protein from human myelin. This is an important step towards deciphering the 3D assembly of a mature myelin sheath at the molecular level. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The ovarian tumor domain (OTU) deubiquitinylating cysteine proteases OTU ubiquitin aldehyde binding 1 (OTUB1) and OTUB2 are representative members of the OTU subfamily of deubiquitinylases. Deubiquitinylation critically regulates a multitude of important cellular processes, such as apoptosis, cell signaling, and growth. Moreover, elevated OTUB expression has been observed in various cancers, including glioma, endometrial cancer, ovarian cancer, and breast cancer. Here, using molecular dynamics simulation approaches, we found that both OTUB1 and OTUB2 display a catalytic triad characteristic of proteases, but differ in their configuration and protonation states. The OTUB1 protein had a pre-arranged catalytic site, with strong electrostatic interactions between the active-site residues His-265 and Asp-267. In OTUB2, however, the arrangement of the catalytic triad was different. In the absence of ubiquitin, the neutral states of the catalytic-site residues in OTUB2 were more stable, resulting in larger distances between these residues. Only upon ubiquitin binding, did the catalytic triad in OTUB2 re-arrange and bring the active site into a catalytically feasible state. An analysis of water access channels revealed only a few diffusion trajectories for the catalytically active form of OTUB1, whereas in OTUB2 the catalytic site was solvent accessible, and a larger number of water molecules reached and left the binding pocket. Interestingly, in OTUB2, the catalytic residues His-224 and Asn-226 formed a stable hydrogen bond. We propose that the observed differences in activation kinetics, protonation states, water channels, and active-site accessibility between OTUB1 and OTUB2 may be relevant for the selective design of OTU inhibitors. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
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