Brinkwarner5393

Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by bilateral vestibular schwannomas (VS) that arise from neoplastic Schwann cells (SCs). NF2-associated VSs are often accompanied by meningioma (MN), and the majority of NF2 patients show loss of the NF2 tumor suppressor. mTORC1 and mTORC2-specific serum/glucocorticoid-regulated kinase 1 (SGK1) are constitutively activated in MN with loss of NF2. In a recent high-throughput kinome screen in NF2-null human arachnoidal and meningioma cells, we showed activation of EPH RTKs, c-KIT, and SFK members independent of mTORC1/2 activation. Subsequently, we demonstrated in vitro and in vivo efficacy of combination therapy with the dual mTORC1/2 inhibitor AZD2014 and the multi-kinase inhibitor dasatinib. eFT-508 research buy For these reasons, we investigated activated mTORC1/2 and EPH receptor-mediated signaling in sporadic and NF2-associated VS. Using primary human VS cells and a mouse allograft model of schwannoma, we evaluated the dual mTORC1/2 inhibitor AZD2014 and the tyrosine kinase inhibitor dasatinib as monotherapies and in combination. Escalating dose-response experiments on primary VS cells grown from 15 human tumors show that combination therapy with AZD2014 and dasatinib is more effective at reducing metabolic activity than either drug alone and exhibits a therapeutic effect at a physiologically reasonable concentration (~0.1 µM). In vivo, while AZD2014 and dasatinib each inhibit tumor growth alone, the effect of combination therapy exceeds that of either drug. Co-targeting the mTOR and EPH receptor pathways with these or similar compounds may constitute a novel therapeutic strategy for VS, a condition for which there is no FDA-approved pharmacotherapy.The effects of feeding an 80% plant protein diet, with and without fish protein hydrolysate (FPH) supplementation, on the growth and gut health of Atlantic salmon were investigated. Fish were fed either (A) a control diet containing 35% fishmeal, (B) an 80% plant protein diet with 15% fishmeal, (C) an 80% plant protein diet with 5% fishmeal and 10% partly hydrolysed protein, or (D) an 80% plant protein diet with 5% fishmeal and 10% soluble protein hydrolysate. Fish on the 80% plant- 15% fishmeal diet were significantly smaller than fish in the other dietary groups. However, partly-hydrolysed protein supplementation allowed fish to grow as well as fish fed the control 35% fishmeal diet. link2 Fish fed the FPH diets (diets C and D) had significantly higher levels of amino acids in their blood, including 48% and 27% more branched chain amino acids compared to fish on the 35% fishmeal diet, respectively. Plant protein significantly altered gut microbial composition, significantly decreasing α-diversity. Spirochaetes and the families Moritellaceae, Psychromonadaceae, Helicobacteraceae and Bacteroidaceae were all found at significantly lower abundances in the groups fed 80% plant protein diets compared to the control fishmeal diet.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Liquid-liquid phase separation (LLPS) explains many intracellular activities, but its role in extracellular functions has not been studied to the same extent. Here we report how LLPS mediates the extracellular function of galectin-3, the only monomeric member of the galectin family. The mechanism through which galectin-3 agglutinates (acting as a "bridge" to aggregate glycosylated molecules) is largely unknown. Our data show that its N-terminal domain (NTD) undergoes LLPS driven by interactions between its aromatic residues (two tryptophans and 10 tyrosines). Our lipopolysaccharide (LPS) micelle model shows that the NTDs form multiple weak interactions to other galectin-3 and then aggregate LPS micelles. Aggregation is reversed when interactions between the LPS and the carbohydrate recognition domains are blocked by lactose. The proposed mechanism explains many of galectin-3's functions and suggests that the aromatic residues in the NTD are interesting drug design targets.Stable inheritance of DNA methylation is critical for maintaining differentiated phenotypes in multicellular organisms. We have recently identified dual mono-ubiquitylation of histone H3 (H3Ub2) by UHRF1 as an essential mechanism to recruit DNMT1 to chromatin. Here, we show that PCNA-associated factor 15 (PAF15) undergoes UHRF1-dependent dual mono-ubiquitylation (PAF15Ub2) on chromatin in a DNA replication-coupled manner. This event will, in turn, recruit DNMT1. During early S-phase, UHRF1 preferentially ubiquitylates PAF15, whereas H3Ub2 predominates during late S-phase. H3Ub2 is enhanced under PAF15 compromised conditions, suggesting that H3Ub2 serves as a backup for PAF15Ub2. In mouse ES cells, loss of PAF15Ub2 results in DNA hypomethylation at early replicating domains. Together, our results suggest that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are prerequisite for high fidelity DNA methylation inheritance.The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity. Inhibition of Complex I, using IACS-010759, an orally bioavailable Complex I inhibitor in clinical trials, as well as succinate ubiquinone reductase (SQR) activity of Complex II, using thenoyltrifluoroacetone (TTFA) or introduction of SDHC R72C mutant, independently sensitize resistant MM to venetoclax. We demonstrate that ETC inhibition increases BCL-2 dependence and the 'primed' state via the ATF4-BIM/NOXA axis. Further, SQR activity correlates with venetoclax sensitivity in patient samples irrespective of t(11;14) status. Use of SQR activity in a functional-biomarker informed manner may better select for MM patients responsive to venetoclax therapy.Large-scale photochemical synthesis of high value chemicals under mild conditions is an ideal method of green chemical production. However, a scalable photocatalytic process has been barely reported due to the costly preparation, low stability of photosensitizers and critical reaction conditions required for classical photocatalysts. Here, we report the merging of flow chemistry with heterogeneous photoredox catalysis for the facile production of high value compounds in a continuous flow reactor with visible light at room temperature in air. In the flow reactor system, polymeric carbon nitrides, which are cheap, sustainable and stable heterogeneous photocatalysts, are immobilized onto glass beads and fibers, demonstrating a highly flexible construction possibility for devices of the photocatalytic materials. As an example of the production of high value chemicals, important chemical structures such as cyclobutanes, which are basic building blocks for many pharmaceutical compounds, like magnosalin, are synthesized in flow with high catalytic efficiency and stability.Expression of the matricellular protein CCN1 (CYR61) is associated with inflammation and is required for successful wound repair. Here, we show that CCN1 binds bacterial pathogen-associated molecular patterns including peptidoglycans of Gram-positive bacteria and lipopolysaccharides of Gram-negative bacteria. CCN1 opsonizes methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa and accelerates their removal by phagocytosis and increased production of bactericidal reactive oxygen species in macrophages through the engagement of integrin αvβ3. Mice with myeloid-specific Ccn1 deletion and knock-in mice expressing CCN1 unable to bind αvβ3 are more susceptible to infection by S. aureus or P. aeruginosa, resulting in increased mortality and organ colonization. Furthermore, CCN1 binds directly to TLR2 and TLR4 to activate MyD88-dependent signaling, cytokine expression and neutrophil mobilization. CCN1 is therefore a pattern recognition receptor that opsonizes bacteria for clearance and functions as a damage-associated molecular pattern to activate inflammatory responses, activities that contribute to wound healing and tissue repair.The development of new high dielectric materials is essential for advancement in modern electronics. Oxides are generally regarded as the most promising class of high dielectric materials for industrial applications as they possess both high dielectric constants and large band gaps. Most previous researches on high dielectrics were limited to already known materials. In this study, we conducted an extensive search for high dielectrics over a set of ternary oxides by combining crystal structure prediction and density functional perturbation theory calculations. link3 From this search, we adopted multiple stage screening to identify 441 new low-energy high dielectric materials. Among these materials, 33 were identified as potential high dielectrics favorable for modern device applications. Our research has opened an avenue to explore novel high dielectric materials by combining crystal structure prediction and high throughput screening.Ferroptosis is a newly characterized form of regulated cell death mediated by iron-dependent accumulation of lipid reactive oxygen species and holds great potential for cancer therapy. However, the molecular mechanisms underlying ferroptosis remain largely elusive. In this study, we define an integrative role of DJ-1 in ferroptosis. Inhibition of DJ-1 potently enhances the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo. Metabolic analysis and metabolite rescue assay reveal that DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity. Consequently, more ferroptosis is induced when homocysteine generation is decreased, which might be the only source of glutathione biosynthesis when cystine uptake is blocked. Thus, our findings show that DJ-1 determines the response of cancer cells to ferroptosis, and highlight a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy.Integrative research on water resources requires a wide range of socio-environmental datasets to better understand human-water interactions and inform decision-making. However, in transboundary watersheds, integrating cross-disciplinary and multinational datasets is a daunting task due to the disparity of data sources and the inconsistencies in data format, content, resolution, and language. This paper introduces a socio-environmental geodatabase that transcends political and disciplinary boundaries in the Rio Grande/Río Bravo basin (RGB). The geodatabase aggregates 145 GIS data layers on five main themes (i) Water & Land Governance, (ii) Hydrology, (iii) Water Use & Hydraulic Infrastructures, (iv) Socio-Economics, and (v) Biophysical Environment. Datasets were primarily collected from public open-access data sources, processed with ArcGIS, and documented through the FGCD metadata standard. By synthesizing a broad array of datasets and mapping public and private water governance, we expect to advance interdisciplinary research in the RGB, provide a replicable approach to dataset compilation for transboundary watersheds, and ultimately foster transboundary collaboration for sustainable resource management.