An uncommon reason for vertigo Neuromyelitis optica array disorder

Enzymatic deamidation, the conversion of glutamine (Gln) into glutamic acid (Glu) residues, mediated by tissue transglutaminase enzymes, can provoke autoimmunity by generating altered self-epitopes, a process well-known in celiac disease and more recently also described in type 1 diabetes (T1D). To identify deamidated proteins, liquid chromatography-tandem mass spectrometry is the method of choice. However, as nonenzymatic deamidations on asparagine (Asn) and to a minor extent on Gln are frequently induced in vitro during proteomics sample preparation, the accurate detection of in vivo deamidation can be hampered. Here we report on the optimization of a method to reduce in vitro generated deamidation by 70% using improved trypsin digestion conditions (90 min/pH 8). We also point to the critical importance of manual inspection of MS2 spectra, considering that only 55% of the high quality peptides with Gln deamidation were assigned correctly using an automated search algorithm. As proof of principal, using these criteria, we showed a significant increase in levels of both Asn and Gln deamidation in cytokine-exposed murine MIN6 β-cells, paralleled by an increase in tissue transglutaminase activity. These findings add evidence to the hypothesis that deamidation is occurring in stressed β-cell proteins and can be involved in the autoimmune process in T1D.Nanoparticle supercrystals (NPSCs) are of great interest as materials with emergent properties. Different types of intermolecular forces, such as van der Waals interaction and hydrogen bonding, are present in the NPSCs fabricated to date. However, the limited structural stability of such NPSCs that results from the weakness of these intermolecular forces is a challenge. Here, we report a spontaneous formation of NPSCs driven by covalent bonding interactions, a type of intramolecular force much stronger than the above-mentioned intermolecular forces. A model solution-phase anhydride reaction is used to form covalent bonds between molecules grafted on the surface of gold nanoparticles, resulting in three-dimensional NPSCs. The NPSCs are very stable in different solvents, in dried conditions, and at temperatures as high as 160 °C. In addition to this, the large library of covalent-bond-forming reactions available and the low cost of reactants make the covalent bonding approach highly versatile and economical.For the interlayer dielectric in microelectronics, light element compounds are preferably accepted due to less electronic polarization. Here, the nontrivial dielectric nature of the Sb4O6 cage-molecular crystal, known as α-antimony trioxide (α-Sb2O3), is reported. The gas-phase synthesized α-Sb2O3 nanoflakes are of high crystal quality, from which the abnormal local admittance responses were revealed by scanning microwave impedance microscopy (sMIM). The remarkably low dielectric constant (k), 2.0∼2.5, is corroborated by the analysis of the thickness-dependent sMIM-capacitance signal. In light of the theoretical calculations, the ultralow molecular density and the significantly suppressed ionic polarization are both crucial to the highly reduced k. Combining with the excellent optical band gap, thermal stability, and breakdown strength, α-Sb2O3 is a promising low k dielectric.The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.To assess the feasibility of utilizing reagent-loaded, porous polymeric nanocapsules (NCs) for chemical and biochemical sensor design, the surfaces of the NCs were decorated with 3,4-ethylenedioxythiophene (EDOT) moieties. The pores in the capsule wall allow unhindered bidirectional diffusion of molecules smaller than the programmed pore sizes, while larger molecules are either entrapped inside or blocked from entering the interior of the nanocapsules. Here, we investigate two electrochemical deposition methods to covalently attach acrylate-based porous nanocapsules with 3,4-ethylenedioxythiophene moieties on the nanocapsule surface, i.e., EDOT-decorated NCs to the surface of an existing PEDOT film (1) galvanostatic or bilayer deposition with supporting EDOT in the deposition solution and (2) potentiostatic deposition without supporting EDOT in the deposition solution. The distribution of the covalently attached NCs in the PEDOT films was studied by variable angle FTIR-ATR and XPS depth profiling. The galvanostatic deposition of EDOT-decorated NCs over an existing PEDOT (tetrakis(pentafluorophenyl)borate) [PEDOT(TPFPhB)] film resulted in a bilayer structure, with an interface between the NC-free and NC-loaded layers, that could be traced with variable angle FTIR-ATR measurements. In contrast, the FTIR-ATR and XPS analyses of the films deposited potentiostatically from a solution without EDOT and containing only the EDOT-decorated NCs showed small amounts of NCs in the entire cross section of the films.The moving boundary truncated grid (TG) method, previously developed to integrate the time-dependent Schrödinger equation and the imaginary time Schrödinger equation, is extended to the time evolution of distribution functions in phase space. A variable number of phase space grid points in the Eulerian representation are used to integrate the equation of motion for the distribution function, and the boundaries of the TG are adaptively determined as the distribution function evolves in time. Appropriate grid points are activated and deactivated for propagation of the distribution function, and no advance information concerning the dynamics in phase space is required. The TG method is used to integrate the equations of motion for phase space distribution functions, including the Klein-Kramers, Wigner-Moyal, and modified Caldeira-Leggett equations. this website Even though the initial distribution function is nonnegative, the solutions to the Wigner-Moyal and modified Caldeira-Leggett equations may develop negative basins in phase space originating from interference effects. Trajectory-based methods for propagation of the distribution function do not permit the formation of negative regions. However, the TG method can correctly capture the negative basins. Comparisons between the computational results obtained from the full grid and TG calculations demonstrate that the TG method not only significantly reduces the computational effort but also permits accurate propagation of various distribution functions in phase space.Many studies have associated the consumption of (poly)phenol-rich diets with health benefits. However, accurate high-throughput quantitative methods for estimating exposure covering a broad spectrum of (poly)phenols are lacking. We have developed and validated a high-throughput method for the simultaneous quantification of 119 (poly)phenol metabolites in plasma and urine using ultra high-performance liquid chromatography coupled with triple quadrupole mass spectrometry, with a very fast sample treatment and a single run time of 16 min. This method is highly sensitive, precise, accurate, and shows good linearity for all compounds (R2 > 0.992). This novel method will allow a quantitative assessment of habitual (poly)phenol intake in large epidemiological studies as well as clinical studies investigating the health benefits of dietary (poly)phenols.Linking two fragments binding in nearby subpockets together has become an important technique in fragment-based drug discovery to optimize the binding potency of fragment hits. Despite the expected favorable translational and orientational entropic contribution to the binding free energy of the linked molecule, brute force enumeration of chemical linker for linking fragments is rarely successful, and the vast majority of linked molecules do not exhibit the expected gains of binding potency. In this paper, we examine the physical factors that contribute to the change of binding free energy from fragment linking and develop a method to rigorously calculate these different physical contributions. We find from these analyses that multiple confounding factors make successful fragment linking strategies rare, including (1) possible change of the binding mode of the fragments in the linked state compared to separate binding of the fragments, (2) unfavorable intramolecular strain energy of the bioactive conformation ion of the fragments in the binding pocket of the proteins is found to be, in our analysis, the dominant reason why most fragment linking strategies do not exhibit the expected gains of binding potency. These findings have further provided rich physical insights, which we expect should facilitate more successful fragment linking strategies to be formulated in the future.Theanine (thea) is one of the most important plant-derived characteristic secondary metabolites and a major healthcare product because of its beneficial biological activities, such as being an antianxiety agent, promoting memory, and lowering blood pressure. Thea mostly accumulates in Camellia plants and is especially rich in Camellia sinensis (tea plant). Although some functional genes (e.g., TS, GOGAT, and GS) attributed to thea accumulation have been separately well explored in tea plants, the evolution of a regulatory module (highly interacting gene group) related to thea metabolism remains to be elaborated. Herein, a thea-associated regulatory module (TARM) was mined by using a comprehensive analysis of a weighted gene coexpression network in Camellia and non-Camellia species. Comparative genomic analysis of 84 green plant species revealed that TARM originated from the ancestor of green plants (algae) and that TARM genes were recruited from different evolutionary nodes with the most gene duplication events at the early stage. Among the TARM genes, two core transcription factors of NAC080 and LBD38 were deduced, which may play a crucial role in regulating the biosynthesis of thea. Our findings provide the first insights into the origin and evolution of TARM and indicate a promising paradigm for identifying vital regulatory genes involved in thea metabolism.We report characterization of the biosynthetic pathway of the potent immunosuppressant (-)-FR901483 (1) through heterologous expression and enzymatic assays. The biosynthetic logic to form the azatricyclic alkaloid is consistent with those proposed in biomimetic syntheses and involves aza-spiro annulation of dityrosyl-piperazine to form a ketoaldehyde intermediate, followed by regioselective aldol condensation, stereoselective ketoreduction, and phosphorylation. A possible target of 1 is proposed based on the biosynthetic studies.