Andresensinger2051

Three-dimensional printing (3DP) has attracted significant attention for its use in additive manufacturing techniques because it provides customizability and flexibility for fabricating structures with arbitrary shapes. Certain applications in the food and medicine industries require 3D printable materials that are both biocompatible and biodegradable. Consequently, this study reports 3D printable materials constructed from food-grade high internal phase emulsions (HIPEs). The studied HIPEs (phase ratio 85%) were stabilized by the efficient adsorption behavior of cod proteins (concentration range, 10-50 mg mL-1) at the oil-water interface. The stability of the oil-in-water HIPEs was improved by the formation of a concentration-dependent percentage of adsorbed proteins and cross-linking networks, and homogeneous and self-supporting structures were generated after 7 days of storage at 4 °C. The gel-like shear thinning rheological behavior induced by the cross-linking networks in the studied HIPEs can be tuned to obtain the desired printability and extrudability during 3DP. In the present study, the HIPEs stabilized with 50 mg mL-1 of cod proteins exhibited the highest printing resolution, gel strength, hardness, adhesiveness, and chewiness during 3DP. These food-grade HIPE inks have the potential to diversify the applications of 3DP in foods, cosmetics, drug delivery systems, and packaging materials.An intriguing challenge of drug discovery is targeting pathogenic mutant proteins that differ from their wild-type counterparts by only a single amino acid. In particular, pathogenic cysteine mutations afford promising opportunities for mutant-specific drug discovery, due to the unique reactivity of cysteine's sulfhydryl-containing side chain. Here we describe the first directed discovery effort targeting a pathogenic cysteine mutant of a protein tyrosine phosphatase (PTP), namely Y279C Src-homology-2-containing PTP 2 (SHP2), which has been causatively linked to the developmental disorder Noonan syndrome with multiple lentigines (NSML). Through a screen of commercially available compounds that contain cysteine-reactive functional groups, we have discovered a small-molecule inhibitor of Y279C SHP2 (compound 99; IC50 ≈ 6 μM) that has no appreciable effect on the phosphatase activity of wild-type SHP2 or that of other homologous PTPs (IC50 ≫ 100 μM). Compound 99 exerts its specific inhibitory effect through irreversible engagement of Y279C SHP2's pathogenic cysteine residue in a manner that is time-dependent, is substrate-independent, and persists in the context of a complex proteome. To the best of our knowledge, 99 is the first specific ligand of a disease-causing PTP mutant to be identified. This study therefore provides both a starting point for the development of NSML-directed therapeutic agents and a precedent for the identification of mutant-specific inhibitors of other pathogenic PTP mutants.Resistance to the last-line polymyxins is increasingly reported in multidrug-resistant Gram-negative pathogens, including Acinetobacter baumannii, which develops resistance via either lipid A modification (e.g., with phosphoethanolamine [pEtN]) or even lipopolysaccharide (LPS) loss in the outer membrane (OM). Considering these two different mechanisms, quantitative membrane lipidomics data were utilized to develop three OM models representing polymyxin-susceptible and -resistant A. baumannii strains. Through all-atom molecular simulations with enhanced sampling techniques, the effect of lipid A-pEtN modification and LPS loss on the action of colistin (i.e., polymyxin E) was examined for the first time, with a focus on the dynamics and energetics of colistin penetration into these OMs. Lipid A-pEtN modification improved the OM stability, impeding the penetration of colistin into the OM; this differed from the current literature that lipid A-pEtN modification confers resistance by diminishing the initial interaction with polymyxins. In contrast, the LPS deficiency significantly reduced the negative charges on the OM surface, diminishing the binding of colistin. Moreover, both lipid A-pEtN modification and LPS loss also constituted colistin resistance through disturbing the conformational transitions of the colistin molecule. Collectively, atomic-scale interactions between polymyxins and different bacterial OMs are very different and the findings may facilitate the discovery of new-generation polymyxins against Gram-negative 'superbugs'.The CblC and CblD chaperones are involved in early steps in the cobalamin trafficking pathway. Cobalamin derivatives entering the cytoplasm are converted by CblC to a common cob(II)alamin intermediate via glutathione-dependent alkyltransferase or reductive elimination activities. Cob(II)alamin is subsequently converted to one of two biologically active alkylcobalamins by downstream chaperones. The function of CblD has been elusive although it is known to form a complex with CblC under certain conditions. Here, we report that CblD provides a sulfur ligand to cob(II)alamin bound to CblC, forming an interprotein coordination complex that rapidly oxidizes to thiolato-cob(III)alamin. Cysteine scanning mutagenesis and EPR spectroscopy identified Cys-261 on CblD as the sulfur donor. The unusual interprotein Co-S bond was characterized by X-ray absorption spectroscopy and visualized in the crystal structure of the human CblD thiolato-cob(III)alamin complex. Our study provides insights into how cobalamin coordination chemistry could be utilized for cofactor translocation in the trafficking pathway.A new reactive force field based on the ReaxFF formalism is effectively parametrized against an extended training set of quantum chemistry data (containing more than 120 different structures) to describe accurately silver and silver-thiolate systems. The results obtained with this novel representation demonstrate that the novel ReaxFF paradigm is a powerful methodology to reproduce more appropriately average geometric and energetic properties of metal clusters and slabs when compared to the earlier ReaxFF parametrizations dealing with silver and gold. ReaxFF cannot describe adequately specific geometrical features such as the observed shorter distances between the under-coordinated atoms at the cluster edges. Geometric and energetic properties of thiolates adsorbed on a silver Ag20 pyramid are correctly represented by the new ReaxFF and compared with results for gold. The simulation of self-assembled monolayers of thiolates on a silver (111) surface does not indicate the formation of staples in contrast to the results for gold-thiolate systems.Zircon (ZrSiO4, I41/amd) can accommodate actinides, such as thorium, uranium, and plutonium. The zircon structure has been determined for several of the end-member compositions of other actinides, such as plutonium and neptunium. However, the thermodynamic properties of these actinide zircon structure types are largely unknown due to the difficulties in synthesizing these materials and handling transuranium actinides. Thus, we have completed a thermodynamic study of cerium orthosilicate, stetindite (CeSiO4), a surrogate of PuSiO4. For the first time, the standard enthalpy of formation of CeSiO4 was obtained by high temperature oxide melt solution calorimetry to be -1971.9 ± 3.6 kJ/mol. Stetindite is energetically metastable with respect to CeO2 and SiO2 by 27.5 ± 3.1 kJ/mol. The metastability explains the rarity of the natural occurrence of stetindite and the difficulty of its synthesis. Applying the obtained enthalpy of formation of CeSiO4 from this work, along with those previously reported for USiO4 and ThSiO4, we developed an empirical energetic relation for actinide orthosilicates. The predicted enthalpies of formation of AnSiO4 are then determined with a discussion of future strategies for efficiently immobilizing Pu or minor actinides in the zircon structure.The Viral Protein 35 (VP35), a crucial protein of the Zaire Ebolavirus (EBOV), interacts with a plethora of human proteins to cripple the human immune system. Despite its importance, the entire structure of the tetrameric assembly of EBOV VP35 and the means by which it antagonizes the autophosphorylation of the kinase domain of human protein kinase R (PKRK) is still elusive. We consult existing structural information to model a tetrameric assembly of the VP35 protein where 93% of the protein is modeled using crystal structure templates. We analyze our modeled tetrameric structure to identify interchain bonding networks and use molecular dynamics simulations and normal-mode analysis to unravel the flexibility and deformability of the different regions of the VP35 protein. We establish that the C-terminal of VP35 (VP35C) directly interacts with PKRK to prevent it from autophosphorylation. Further, we identify three plausible VP35C-PKRK complexes with better affinity than the PKRK dimer formed during autophosphorylation and use protein design to establish a new stretch in VP35C that interacts with PKRK. The proposed tetrameric assembly will aid in better understanding of the VP35 protein, and the reported VP35C-PKRK complexes along with their interacting sites will help in the shortlisting of small molecule inhibitors.The aim of the current study was to investigate whether degradation of rapeseed meal (RSM) by a swine gut microbiota consortium was improved by modifying RSM by treatment with cellulase (CELL), two pectinases (PECT), or alkaline (ALK) compared to untreated RSM and to assess whether microbiota composition and activity changed. The predicted relative abundances of carbohydrate digestion and absorption, glycolysis, pentose phosphate pathway, and pyruvate metabolism were significantly increased upon CELL and ALK feeding, and CELL and ALK also exhibited increased total short-chain fatty acid (SCFA) production compared to CON. Megasphaera, Prevotella, and Desulfovibrio were significantly positively correlated with SCFA production. Findings were validated in ileal cannulated pigs, which showed that CELL and ALK increased fiber degradation of RSM. In conclusion, CELL and ALK rather than PECT1 or PECT2 increased fiber degradation in RSM, and this information could guide feed additive strategies to improve efficiency and productivity in the swine industry.Heterostructures of inorganic halide perovskites with mixed-dimensional inorganic nanomaterials have shown great potential not only in the field of optoelectronic energy devices and photocatalysis but also for improving our fundamental understanding of the charge transfer across the heterostructure interface. Herein, we present for the first time the heterostructure integration of the CsPbBr3 nanocrystal with an N-doped carbon dot. We explore the photoluminescence (PL) and photoconductivity of the heterostructure of CsPbBr3 nanocrystals and N-doped carbon dots. PL quenching of CsPbBr3 nanocrystals with the addition of N-doped carbon dots was observed. https://www.selleckchem.com/products/gcn2-in-1.html The photoexcited electrons from the conduction band of CsPbBr3 are trapped in the N-acceptor state of N-doped carbon dots, and the charge transfer occurs via quasi type II-like electronic band alignment. The charge transfer in the halide perovskite-based heterostructure should motivate further research into the new heterostructure synthesis with perovskites and the fundamental understanding of the mechanism of charge/energy transfer across the heterostructure interface.