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A library consisting of characterized marine natural products as well as synthetic derivatives was screened for compounds capable of inhibiting the production of hydrogen sulfide ...(H2S) by cystathionine beta-synthase (CBS). Eight hits were validated and shown to inhibit CBS activity with IC50 values ranging from 83 to 187μM. The majority of hits came from a series of synthetic polyandrocarpamine derivatives. In addition, a modified fluorogenic probe for H2S detection with improved solubility in aqueous solutions is reported.
The analysis and validation of flow cytometry-based biomarkers in clinical studies are limited by the lack of standardized protocols that are reproducible across multiple centers and suitable for use ...with either unfractionated blood or cryopreserved PBMCs. Here we report the development of a platform that standardizes a set of flow cytometry panels across multiple centers, with high reproducibility in blood or PBMCs from either healthy subjects or patients 100 days after hematopoietic stem cell transplantation. Inter-center comparisons of replicate samples showed low variation, with interindividual variation exceeding inter-center variation for most populations (coefficients of variability <20% and interclass correlation coefficients >0.75). Exceptions included low-abundance populations defined by markers with indistinct expression boundaries (e.g., plasmablasts, monocyte subsets) or populations defined by markers sensitive to cryopreservation, such as CD62L and CD45RA. Automated gating pipelines were developed and validated on an independent data set, revealing high Spearman's correlations (rs >0.9) with manual analyses. This workflow, which includes pre-formatted antibody cocktails, standardized protocols for acquisition, and validated automated analysis pipelines, can be readily implemented in multicenter clinical trials. This approach facilitates the collection of robust immune phenotyping data and comparison of data from independent studies.
Reporting of United States Medical Licensing Examination Step 1 results will transition from a numerical score to a pass or fail result. We sought an objective analysis to determine changes in the ...relative importance of resident application attributes when numerical Step 1 results are replaced.
A discrete choice experiment was designed to model radiology resident selection and determine the relative weights of various application factors when paired with a numerical or pass or fail Step 1 result. Faculty involved in resident selection at 14 US radiology programs chose between hypothetical pairs of applicant profiles between August and November 2020. A conditional logistic regression model assessed the relative weights of the attributes, and odds ratios (ORs) were calculated.
There were 212 participants. When a numerical Step 1 score was provided, the most influential attributes were medical school (OR: 2.35, 95% confidence interval CI: 2.07-2.67), Black or Hispanic race or ethnicity (OR: 2.04, 95% CI: 1.79-2.38), and Step 1 score (OR: 1.8, 95% CI: 1.69-1.95). When Step 1 was reported as pass, the applicant's medical school grew in influence (OR: 2.78, 95% CI: 2.42-3.18), and there was a significant increase in influence of Step 2 scores (OR: 1.31, 95% CI: 1.23-1.40 versus OR 1.57, 95% CI: 1.46-1.69). There was little change in the relative influence of race or ethnicity, gender, class rank, or clerkship honors.
When Step 1 reporting transitions to pass or fail, medical school prestige gains outsized influence and Step 2 scores partly fill the gap left by Step 1 examination as a single metric of decisive importance in application decisions.
Autoreactive anergic B lymphocytes are considered to be dangerous because of their potential for activation and recruitment into autoimmune responses. However, they persist for days and constitute ...∼5% of the B cell pool. We assessed their functional potential in the Ars/A1 transgene model, where anergic B cells express a dual-reactive Ag receptor that binds, in addition to a self-Ag, the hapten p-azophenylarsonate (Ars). When Ars/A1 B cells were transferred into adoptive recipients that were immunized with foreign proteins covalently conjugated with Ars, endogenous IgG immune responses to both were selectively and severely diminished, and the development of T helper cells was impaired. Approximately 95% inhibition of the anti-Ars response was attained with ∼4000 transferred Ars/A1 B cells through redundant mechanisms, one of which depended on their expression of MHC class II but not upon secretion of IL-10 or IgM. This Ag-specific suppressive activity implicates the autoreactive anergic B cell as an enforcer of immunological tolerance to self-Ags.
Dissolved organic carbon (DOC) concentrations are increasing in freshwaters worldwide, with important implications for aquatic ecology, biogeochemistry, and ecosystem services. While multiple ...environmental changes may be responsible for these trends, predicting the occurrence and magnitude of “browning” and relating such trends to changes in DOC sources versus hydrologic transport remain key challenges. We analyzed long‐term trends in DOC concentration from the two dominant landscape sources (riparian soils and mire peats) and receiving streams in a boreal catchment to evaluate how browning patterns relate to land cover and hydrology. Increases in stream DOC were widespread but not universal. Browning was most pronounced in small, forested streams, where trends corresponded to twofold to threefold increases in DOC production in riparian soils and increases in annual DOC export from a forested headwater. By contrast, DOC did not change in mire peats or streams draining catchments with high lake or mire cover, nor did we observe trends in DOC export from a mire‐dominated headwater. The distinct long‐term trends in DOC sources also altered concentration‐discharge relationships, with a forested headwater shifting from transport‐limited toward chemostasis, and a mire outlet stream shifting from chemostasis to source‐limitated. Modified DOC supply to headwaters, together with altered seasonal hydrology and differences in the dominant water source along the stream network gave rise to predictable browning trends and consistent concentration‐discharge relationships. Overall, our results show that the sources of DOC to boreal aquatic ecosystems are responding to environmental change in fundamentally different ways, with important consequences for browning along boreal stream networks.
Key Points
DOC concentrations increased dramatically over 15 years in riparian forest soils and streams but not mire peats and wetland outlet streams
Relative contribution of land cover in the catchment shapes heterogeneity in browning among streams in the network
Changes in the depth profile of riparian soil DOC have altered C‐Q relationships throughout the broader stream network
Recent success in the use of immunotherapy for a broad range of cancers has propelled the field of cancer immunology to the forefront of cancer research. As more and more young investigators join the ...community of cancer immunologists, the Arthur L. Irving Family Foundation Cancer Immunology Symposium provided a platform to bring this expanding and vibrant community together and support the development of the future leaders in the field. This commentary outlines the lessons that emerged from the inaugural symposium highlighting the areas of scientific and career development that are essential for professional growth in the field of cancer immunology and beyond. Leading scientists and clinicians in the field provided their experience on the topics of scientific trajectory, career trajectory, publishing, fundraising, leadership, mentoring, and collaboration. Herein, we provide a conceptual and practical framework for career development to the broader scientific community.
Introduction: Compared to other direct oral anticoagulants, betrixaban has a longer half-life, smaller peak-trough variance, minimal renal clearance, and minimal hepatic Cytochrome P (CYP) ...metabolism. The Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial evaluated the efficacy and safety of extended duration betrixaban compared to standard duration enoxaparin in acutely ill hospitalized patients.
Areas covered: This article describes the role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely ill medical patients. This article provides a consolidated summary of the primary APEX study findings as well as prespecified and exploratory substudies. This article also provides a review of the results of studies in which other direct factor Xa inhibitors have been evaluated in an extended duration regimen in this patient population.
Expert commentary: While previous agents have demonstrated that extended duration VTE prophylaxis can be efficacious, betrixaban is the first agent to demonstrate efficacy without an increase in major bleeding. The totality of the data from the APEX trial supports extended duration betrixaban for VTE prophylaxis in the acute medically ill patient population. As such, betrixaban has been approved in the USA for extended VTE prophylaxis in at-risk acute medically ill patients.
RhoA plays a fundamental role in regulation of the actin cytoskeleton, intercellular attachment, and cell proliferation. During amelogenesis, ameloblasts (which produce the enamel proteins) undergo ...dramatic cytoskeletal changes and the RhoA protein level is up‐regulated. Transgenic mice were generated that express a dominant‐negative RhoA transgene in ameloblasts using amelogenin gene‐regulatory sequences. Transgenic and wild‐type (WT) molar tooth germs were incubated with sodium fluoride (NaF) or sodium chloride (NaCl) in organ culture. Filamentous actin (F‐actin) stained with phalloidin was elevated significantly in WT ameloblasts treated with NaF compared with WT ameloblasts treated with NaCl or with transgenic ameloblasts treated with NaF, thereby confirming a block in the RhoA/Rho‐associated protein kinase (ROCK) pathway in the transgenic mice. Little difference in quantitative fluorescence (an estimation of fluorosis) was observed between WT and transgenic incisors from mice provided with drinking water containing NaF. We subsequently found reduced transgene expression in incisors compared with molars. Transgenic molar teeth had reduced amelogenin, E‐cadherin, and Ki67 compared with WT molar teeth. Hypoplastic enamel in transgenic mice correlates with reduced expression of the enamel protein, amelogenin, and E‐cadherin and cell proliferation are regulated by RhoA in other tissues. Together these findings reveal deficits in molar ameloblast function when RhoA activity is inhibited.
In this study, we developed and psychometrically evaluated the Online Sexual Objectification Experiences Scale (OSOES). We collected data from 816 emerging adult college women across two samples. ...Exploratory and confirmatory factor analyses revealed three factors: Unwanted Sexual Advances (example item: “How often have you received unwanted messages online asking about your sexual experience?”), Negative Appearance Commentary (example item : “How often has another person insulted you by calling you unattractive online?”), and Indirect Sexual Objectification (example item: “How often have you read a sexual comment posted to a photo of another woman's body online?”). OSOES scores were internally consistent and were strongly correlated with scores of self-objectification, body surveillance, and body shame. OSOES subscale scores also provided evidence of incremental validity in predicting self-objectification and objectified body consciousness above and beyond offline interpersonal sexual objectification. We hope that findings from the present study and the OSOES can be used by researchers, clinicians, and educators to understand the frequency of online sexual objectification experiences among women and as a result, work to mitigate harmful outcomes. Additional online materials for this article are available on PWQ's website at http://journals.sagepub.com/doi/suppl/DOI: 10.1177/03616843241250295
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