Ta-doped Mo1-xTxTe2 bulk single crystals showcase a substantially heightened superconductivity, with a transition temperature as high as roughly 75 K (0 ≤ x ≤ 0.022). This improved performance is hypothesized to originate from an increased density of states at the Fermi energy. In contrast, the Td-phase Mo1-xTaxTe2 (x = 0.08) exhibits a perpendicular upper critical field of 145 Tesla, exceeding the Pauli limit, which suggests the possible occurrence of unconventional mixed singlet-triplet superconductivity, a phenomenon caused by the broken inversion symmetry. This work opens up a new avenue for exploring the intriguing phenomenon of exotic superconductivity and topological physics in transition metal dichalcogenides.
The medicinal plant, Piper betle L., renowned for its abundance of bioactive compounds, is frequently employed in diverse therapeutic contexts. Employing a multi-faceted approach, this study investigated the anti-cancer potential of compounds from P. betle petioles, comprising in silico studies, purification of 4-Allylbenzene-12-diol, and evaluation of its cytotoxicity on bone cancer metastasis. Subsequent to the SwissADME screening procedure, 4-Allylbenzene-12-diol and Alpha-terpineol were prioritized for molecular docking simulations. Accompanying this were eighteen approved drugs, targeted against fifteen significant bone cancer targets, with the inclusion of molecular dynamics investigations. 4-Allylbenzene-12-diol was found to have a multi-targeting capability, effectively interacting with all the targets analyzed, and, significantly, showing robust stability with MMP9 and MMP2 during molecular dynamics simulations and MM-GBSA analysis in Schrodinger. Following isolation and purification, cytotoxicity studies on MG63 bone cancer cell lines indicated a cytotoxic effect for the compound, reaching 75-98% cell death at a concentration of 100µg/mL. The compound 4-Allylbenzene-12-diol's matrix metalloproteinase inhibitory properties, as shown by the results, raise the possibility of its use in targeted therapies for alleviating bone cancer metastasis, given the necessary subsequent wet lab validations. Communicated by Ramaswamy H. Sarma.
FGF5's Y174H missense mutation (FGF5-H174) has been associated with trichomegaly, a condition recognized by abnormally elongated and pigmented eyelashes. Presumably holding functional significance for FGF5, the tyrosine (Tyr/Y) amino acid at position 174 is maintained across various species. The structural dynamics and binding characteristics of wild-type FGF5 (FGF5-WT) and its H174 mutant (FGF5-H174) were investigated through the application of microsecond molecular dynamics simulations, protein-protein docking, and residue interaction network analysis. Experimental findings suggest that the mutation resulted in a decrease in the protein's hydrogen bond count within its sheet secondary structure, a lessened interaction of residue 174 with surrounding residues, and a smaller count of salt bridges. On the contrary, the mutation produced an increase in the solvent-accessible surface area, an elevation in the number of hydrogen bonds between the protein and the solvent, a rise in coil secondary structure, a change in the protein C-alpha backbone root mean square deviation, fluctuations in protein residue root mean square values, and an expansion of the conformational space occupied. Utilizing protein-protein docking, in conjunction with molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) binding energy calculations, the study revealed an enhanced binding affinity of the mutated variant for fibroblast growth factor receptor 1 (FGFR1). The residue interaction network analysis indicated a profound difference in the mode of binding for the FGFR1-FGF5-H174 complex when contrasted with the FGFR1-FGF5-WT complex. In summary, the missense mutation caused increased internal instability and a more robust binding to FGFR1, featuring a significantly altered binding configuration or residue network. check details These findings potentially explain the lower pharmacological effectiveness of FGF5-H174 interacting with FGFR1, thereby impacting the process of trichomegaly. Communicated by Ramaswamy H. Sarma.
Central and west African tropical rainforests serve as the primary source of the zoonotic monkeypox virus, which occasionally spreads to other areas. Considering the lack of a cure, administering an antiviral drug developed for smallpox in the treatment of monkeypox is currently considered a permissible action. We primarily investigated the potential of existing medications or compounds as new therapeutics for monkeypox. It is a successful method for discovering or developing new medicinal compounds intended for unique pharmacological and therapeutic uses. Using homology modeling, this study established the structure of Monkeypox VarTMPK (IMNR). Based on the superior docking pose of standard ticovirimat, the pharmacophore model, specific to the ligand, was determined. Compound binding energies, assessed via molecular docking, positioned tetrahydroxycurcumin, procyanidin, rutin, vicenin-2, and kaempferol 3-(6''-malonylglucoside) as the top five strongest binders to VarTMPK (1MNR). We additionally employed 100-nanosecond molecular dynamics simulations for the six compounds, including a reference, leveraging insights from binding energies and intermolecular interactions. The results of molecular dynamics (MD) studies, corroborated by docking and simulation analyses, showed a shared interaction pattern for ticovirimat and the five other compounds at the active site, targeting the specific amino acids Lys17, Ser18, and Arg45. In the analysis of all the compounds, ZINC4649679 (Tetrahydroxycurcumin) presented the highest binding energy of -97 kcal/mol and showed a stable protein-ligand complex through molecular dynamics simulations. Safety was evident in the ADMET profile estimation for the docked phytochemicals. To measure the compounds' efficacy and safety, further biological evaluation in a wet lab setting is required.
In various diseases, including cancer, Alzheimer's disease, and arthritis, Matrix Metalloproteinase-9 (MMP-9) plays a critical role. The activation of MMP-9 zymogen (pro-MMP-9) was successfully inhibited by the JNJ0966 compound, contributing to its desired selectivity. Up to this point, no further small molecules have been identified since the discovery of JNJ0966. Computational investigations were extensively employed to strengthen the prospect of identifying promising candidates. This research aims to pinpoint potential hits from the ChEMBL database, leveraging molecular docking and dynamic simulations. The protein, identified by PDB ID 5UE4, featuring a unique inhibitor strategically positioned within MMP-9's allosteric binding pocket, was selected for investigation. check details By way of structure-based virtual screening and MMGBSA binding affinity estimations, five potential drug candidates were identified. Using ADMET analysis and molecular dynamics (MD) simulations, a detailed exploration of the high-scoring molecules was undertaken. Concerning docking assessment, ADMET analysis, and molecular dynamics simulation, all five hits displayed improved performance compared to JNJ0966. check details Based on our research conclusions, these effects merit investigation within both in vitro and in vivo settings to evaluate their impact on proMMP9, with a view to their possible application as anticancer pharmaceuticals. The outcome of our research, as communicated by Ramaswamy H. Sarma, could contribute to hastening the identification of drugs that impede proMMP-9 activity.
A novel pathogenic variant in the TRPV4 gene was identified in this study, where it contributes to familial nonsyndromic craniosynostosis (CS) with consistent penetrance and variable expressivity.
Whole-exome sequencing was applied to germline DNA from a family exhibiting nonsyndromic CS, achieving a mean depth of coverage of 300 per sample, ensuring at least 25-fold coverage for over 98% of the target region. The four affected family members were uniquely found to possess the novel TRPV4 variant, c.469C>A, in this investigation. A model of the variant was created, leveraging the structural information of the TRPV4 protein of Xenopus tropicalis. In order to assess the effect of the TRPV4 p.Leu166Met mutation on channel activity and downstream MAPK signaling, in vitro assays were performed on HEK293 cells that had been engineered to overexpress either wild-type TRPV4 or the mutated protein.
A novel, highly penetrant heterozygous variant in TRPV4 (NM 0216254c.469C>A) was discovered by the authors. A mother and all three of her offspring developed nonsyndromic CS. This particular variant induces a modification of an amino acid (p.Leu166Met) within the intracellular ankyrin repeat domain, which is remote from the Ca2+-dependent membrane channel domain. Unlike other TRPV4 mutations within channelopathies, this variant does not hinder channel activity as assessed by in silico modelling and in vitro overexpression experiments in HEK293 cells.
The authors' analysis of these findings supports the hypothesis that this new variant impacts CS by adjusting the interaction of allosteric regulatory factors with TRPV4, in contrast to direct changes in the channel's activity. This study's impact on the comprehension of TRPV4 channelopathies, both genetically and functionally, is substantial, especially for the genetic counseling of patients presenting with CS.
These findings, the authors argued, supported the hypothesis that the novel variant acts on CS by changing how allosteric regulatory factors interact with TRPV4, not by altering the channel's function itself. The study contributes to a greater comprehension of TRPV4 channelopathies' genetic and functional characteristics, and specifically underscores its relevance to genetic counseling for patients experiencing congenital skin syndromes (CS).
Detailed investigation of epidural hematomas (EDH) in infants remains relatively uncommon. This study sought to determine the results of patients, under 18 months of age, who had a diagnosis of EDH.
In a retrospective single-center study by the authors, 48 infants, under 18 months of age, who had undergone supratentorial EDH surgery in the past ten years were examined.