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151.
This study aimed to design novel nitrogen-rich heptazine derivatives as high energy density materials (HEDM) by exploiting
systematic structure–property relationships. Molecular structures with diverse energetic substituents at varying positions
in the basic heptazine ring were designed. Density functional techniques were used for prediction of gas phase heat of formation
by employing an isodesmic approach, while crystal density was assessed by packing calculations. The results reveal that nitro
derivatives of heptazine possess a high heat of formation and further enhancement was achieved by the substitution of nitro
heterocycles. The crystal packing density of the designed compounds varied from 1.8 to 2 g cm−3, and hence, of all the designed molecules, nitro derivatives of heptazine exhibit better energetic performance characteristics
in terms of detonation velocity and pressure. The calculated band gap of the designed molecules was analyzed to establish
sensitivity correlations, and the results reveal that, in general, amino derivatives possess better insensitivity characteristics.
The overall performance of the designed compounds was moderate, and such compounds may find potential applications in gas
generators and smoke-free pyrotechnic fuels as they are rich in nitrogen content. 相似文献
152.
Savidge TC Urvil P Oezguen N Ali K Choudhury A Acharya V Pinchuk I Torres AG English RD Wiktorowicz JE Loeffelholz M Kumar R Shi L Nie W Braun W Herman B Hausladen A Feng H Stamler JS Pothoulakis C 《Nature medicine》2011,17(9):1136-1141
The global prevalence of severe Clostridium difficile infection highlights the profound clinical significance of clostridial glucosylating toxins. Virulence is dependent on the autoactivation of a toxin cysteine protease, which is promoted by the allosteric cofactor inositol hexakisphosphate (InsP(6)). Host mechanisms that protect against such exotoxins are poorly understood. It is increasingly appreciated that the pleiotropic functions attributed to nitric oxide (NO), including host immunity, are in large part mediated by S-nitrosylation of proteins. Here we show that C. difficile toxins are S-nitrosylated by the infected host and that S-nitrosylation attenuates virulence by inhibiting toxin self-cleavage and cell entry. Notably, InsP(6)- and inositol pyrophosphate (InsP(7))-induced conformational changes in the toxin enabled host S-nitrosothiols to transnitrosylate the toxin catalytic cysteine, which forms part of a structurally conserved nitrosylation motif. Moreover, treatment with exogenous InsP(6) enhanced the therapeutic actions of oral S-nitrosothiols in mouse models of C. difficile infection. Allostery in bacterial proteins has thus been successfully exploited in the evolutionary development of nitrosothiol-based innate immunity and may provide an avenue to new therapeutic approaches. 相似文献
153.
Dihydrouridine (DHU) positions within tRNAs have long been used as sites to covalently attach fluorophores, by virtue of their unique chemical reactivity toward reduction by NaBH(4), their abundance within prokaryotic and eukaryotic tRNAs, and the biochemical functionality of the labeled tRNAs so produced. Interpretation of experiments employing labeled tRNAs can depend on knowing the distribution of dye among the DHU positions present in a labeled tRNA. Here we combine matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS) analysis of oligonucleotide fragments and thin layer chromatography to resolve and quantify sites of DHU labeling by the fluorophores Cy3, Cy5, and proflavin in Escherichia coli tRNA(Phe) and E. coli tRNA(Arg). The MALDI-MS results led us to re-examine the precise chemistry of the reactions that result in fluorophore introduction into tRNA. We demonstrate that, in contrast to an earlier suggestion that has long been unchallenged in the literature, such introduction proceeds via a substitution reaction on tetrahydrouridine, the product of NaBH(4) reduction of DHU, resulting in formation of substituted tetrahydrocytidines within tRNA. 相似文献
154.
Ledesma MC Jung-Hynes B Schmit TL Kumar R Mukhtar H Ahmad N 《Molecular medicine (Cambridge, Mass.)》2011,17(1-2):134-143
Various formulations of selenium and vitamin E, both essential human dietary components, have been shown to possess a therapeutic and preventive effect against prostate cancer. Fortuitous results of clinical trials also implied a risk-reduction effect of selenium and vitamin E supplements. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), using oral selenium and vitamin E supplementation in disease-free volunteers, was designed to test a prostate cancer chemoprevention hypothesis. SELECT was terminated early because of both safety concerns and negative data for the formulations and doses given. Here, we review and discuss the studies done before and since the inception of SELECT, as well as the parameters of the trial itself. We believe that there is a lack of appropriate in vivo preclinical studies on selenium and vitamin E despite many promising in vitro studies on these agents. It seems that the most effective doses and formulations of these agents for prostate cancer chemoprevention have yet to be tested. Also, improved understanding of selenium and vitamin E biology may facilitate the discovery of these doses and formulations. 相似文献
155.
156.
Arginine is one of the commonly used additives to enhance refolding yield of proteins, to suppress aggregation of proteins, and to increase solubility of proteins, and yet the molecular interactions that contribute to the role of arginine are unclear. Here, we present experiments, using bovine serum albumin (BSA), lysozyme (LYZ), and β-lactoglobulin (BLG) as model proteins, to show that arginine can enhance heat-induced aggregation of concentrated protein solutions, contrary to the conventional belief that arginine is a universal suppressor of aggregation. Results show that the enhancement in aggregation is caused only for BSA and BLG, but not for LYZ, indicating that arginine's preferential interactions with certain residues over others could determine the effect of the additive on aggregation. We use this previously unrecognized behavior of arginine, in combination with density functional theory calculations, to identify the molecular-level interactions of arginine with various residues that determine arginine's role as an enhancer or suppressor of aggregation of proteins. The experimental and computational results suggest that the guanidinium group of arginine promotes aggregation through the hydrogen-bond-based bridging interactions with the acidic residues of a protein, whereas the binding of the guanidinium group to aromatic residues (aggregation-prone) contributes to the stability and solubilization of the proteins. The approach, we describe here, can be used to select suitable additives to stabilize a protein solution at high concentrations based on an analysis of the amino acid content of the protein. 相似文献
157.
Thachamvally Riyesh Vinayagamurthy Balamurugan Arnab Sen Veerakyathappa Bhanuprakash Gnanavel Venkatesan Vinita Yadav Raj Kumar Singh 《中国病毒学》2011,26(5):324-337
In this study, thermo-adapted (Ta) PPR vaccines were assessed for their stability at 25, 37, 40, 42 and 45°C in lyophilized
form using two extrinsic stabilizers {lactalbumin hydrolysate-sucrose (LS) and stabilizer E} and in reconstituted form with
the diluents (1 mol/L MgSO4 or 0.85% NaCl). The lyophilized vaccines showed an expiry period of 24–26 days at 25°C, 7–8 days at 37°C and 3–4 days at
40°C. LS stabilizer was superior at 42°C with a shelf-life of 44 h, whereas in stabilizer E, a 40 h shelf-life with a comparable
half-life was observed. At 45°C, the half-life in stabilizer E was better than LS and lasted for 1 day. Furthermore, the reconstituted
vaccine maintained the titre for 48 h both at 4°C and 25°C and for 24–30 h at 37°C. As both the stabilizers performed equally
well with regard to shelf-life and half-life, the present study suggests LS as stabilizer as a choice for lyophilization with
0.85% NaCl diluent, because it has better performance at higher temperature. These Ta vaccines can be used as alternatives
to existing vaccines for the control of the disease in tropical countries as they are effective in avoiding vaccination failure
due to the breakdown in cold-chain maintenance, as this vaccine is considerably more stable at ambient temperatures. 相似文献
158.
HIV-1 Nef modulates disease progression through interactions with over 30 host proteins. Individual chains fold into membrane-interacting N-terminal and C-terminal core (Nefcore) domains respectively. Nef exists as small oligomers near membranes and associates into higher oligomers such as tetramers or hexadecamers in the cytoplasm. Earlier structures of the Nefcore in apo and complexed forms with the Fyn-kinase SH3 domain revealed dimeric association details and the role of the conserved PXXP recognition motif (residues 72–78) of Nef in SH3-domain interactions. The crystal structure of the tetrameric Nef reported here corresponds to the elusive cytoplasmic stage. Comparative analyses show that subunits of Nefcore dimers (open conformation) swing out with a relative displacement of ∼22 Å and rotation of ∼174° to form the ‘closed’ tetrameric structure. The changes to the association are around Asp125, a conserved residue important for viral replication and the important XR motif (residues 107–108). The tetramer associates through C4 symmetry instead of the 222 symmetry expected when two dimers associate together. This novel dimer-tetramer transition agrees with earlier solution studies including small angle X-ray scattering, analytical ultracentrifugation, dynamic laser light scattering and our glutaraldehyde cross-linking experiments. Comparisons with the Nefcore—Fyn-SH3 domain complexes reveal that the PXXP motif that interacts with the SH3-domain in the dimeric form is sterically occluded in the tetramer. However the 151–180 loop that is distal to the PXXP motif and contains several protein interaction motifs remains accessible. The results suggest how changes to the oligomeric state of Nef can help it distinguish between protein partners. 相似文献
159.
Identifying emerging viral pathogens and characterizing their transmission is essential to developing effective public health measures in response to an epidemic. Phylogenetics, though currently the most popular tool used to characterize the likely host of a virus, can be ambiguous when studying species very distant to known species and when there is very little reliable sequence information available in the early stages of the outbreak of disease. Motivated by an existing framework for representing biological sequence information, we learn sparse, tree-structured models, built from decision rules based on subsequences, to predict viral hosts from protein sequence data using popular discriminative machine learning tools. Furthermore, the predictive motifs robustly selected by the learning algorithm are found to show strong host-specificity and occur in highly conserved regions of the viral proteome. 相似文献
160.
Marginal zone B cells (MZB) mount a rapid antibody response, potently activate naïve T cells, and are enriched in autoreactive B cells. MZBs express high levels of CD1d, the restriction element for invariant natural killer T cells (iNKT). Here, we examined the effect of iNKT cells on MZB cell activation and numbers in vitro and in vivo in normal and autoimmune mice. Results show that iNKT cells activate MZBs, but restrict their numbers in vitro and in vivo in normal BALB/c and C57/BL6 mice. iNKT cells do so by increasing the activation-induced cell death and curtailing proliferation of MZB cells, whereas they promote the proliferation of follicular B cells. Sorted iNKT cells can directly execute this function, without help from other immune cells. Such MZB regulation by iNKTs is mediated, at least in part, via CD1d on B cells in a contact-dependent manner, whereas iNKT-induced proliferation of follicular B cells occurs in a contact- and CD1d-independent manner. Finally, we show that iNKT cells reduce ‘autoreactive’ MZB cells in an anti-DNA transgenic model, and limit MZB cell numbers in autoimmune-prone (NZB×NZW)F1 and non-obese diabetic mice, suggesting a potentially new mechanism whereby iNKT cells might regulate pathologic autoimmunity. Differential regulation of follicular B cells versus potentially autoreactive MZBs by iNKT cells has important implications for autoimmune diseases as well as for conditions that require a rapid innate B cell response. 相似文献