Krausemoser5133

Many studies neglect to account for variation in population served by community water systems (CWSs) when aggregating CWS-level contaminant concentrations to county level.

In an ecological epidemiologic analysis, we explored two methods-unweighted and weighted (proportion of CWS population served by county population)-to account for population served by CWS in association between arsenic and three cancers to determine the impact of population served on aggregated measures of exposure.

CWS arsenic concentration data for 19 states were obtained from Centers for Disease Control and Prevention (CDC) National Environmental Public Health Tracking Network for 2000-10, aggregated to county level, and linked to county-level cancer data for 2011-5 from National Cancer Institute and CDC State Cancer Profiles. Negative binomial regression models estimated adjusted risk ratios (aRR) and 95% confidence intervals (CI) between county-level bladder, colorectal, and kidney cancers and quartiles of aggregated cumulative county-level arsenic concentration (ppb-years).

We observed positive associations between the highest quartileof exposure, compared to the lowest, ofaggregated cumulative county-level arsenic concentration (ppb-year) for bladder [weighted aRR 1.89(1.53, 2.35)], colorectal [1.64(1.33, 2.01)], and kidney [1.69(1.37, 2.09)] cancers. We observed stronger associations utilizing the weighted exposure assessment method. However, inferences from this study are limited due to the ecologic nature of the analyses and different analytic study designs are needed to assess the utility that the weighted by CWS population served metric has for exposure assessment.

Weighting by CWS population served accounts for some potential exposure assignment error in epidemiologic analysis.

Weighting by CWS population served accounts for some potential exposure assignment error in epidemiologic analysis.γδ T cells are heterogeneous lymphocytes located in various tissues. However, a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved. In this study, we performed single-cell RNA sequencing (scRNA-seq) to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples. We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors (pre-γδ T cells). The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments. The adoptive transfer of hematopoietic progenitor Lin-Sca-1+Mac-1+ (LSM) cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma+ (IFN-γ+) but not interleukin-17a+ (IL-17a+) γδ T cells in the liver. Importantly, thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner. These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells, which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.The role of IL-17 in many inflammatory and autoimmune diseases is now well established, with three currently registered anti-IL-17-targeted therapies. This story has taken place over a period of 20 years and led to the demonstration that a T cell product could regulate, and often amplify, the inflammatory response. The first results described the contribution of IL-17 to local features in arthritis. Then, understanding was extended to its systemic effects, with a focus on cardiovascular aspects. This review provides a historical perspective of these discoveries focused on arthritis, which started in 1995, followed 10 years later by the description of Th17 cells. Today, IL-17 inhibitors for three chronic inflammatory diseases have been registered. More options are now being tested in ongoing and future clinical trials. Inhibitors of IL-17 family members and Th17 cells ranging from antibodies to small molecules are under active development. The identification of patients with IL-17-driven disease is a key target for the improved selection of patients expected to have a strongly positive response.Wearable technologies promise to redefine assessment of health behaviors, yet their clinical implementation remains a challenge. To address this gap, two of the NIH's Big Data to Knowledge Centers of Excellence organized a workshop on potential clinical applications of wearables. A workgroup comprised of 14 stakeholders from diverse backgrounds (hospital administration, clinical medicine, academia, insurance, and the commercial device industry) discussed two successful digital health interventions that involve wearables to identify common features responsible for their success. Seven features were identified including a clearly defined problem, integration into a system of healthcare delivery, technology support, personalized experience, focus on end-user experience, alignment with reimbursement models, and inclusion of clinician champions. Health providers and systems keen to establish new models of care inclusive of wearables may consider these features during program design. A better understanding of these features is necessary to guide future clinical applications of wearable technology.Chronic thromboembolic pulmonary hypertension (CTEPH) is a vascular disease characterized by the presence of organized thromboembolic material in pulmonary arteries leading to increased vascular resistance, heart failure and death. Dysfunction of endothelial cells is involved in CTEPH. The present study describes for the first time the molecular processes underlying endothelial dysfunction in the development of the CTEPH. The advanced analytical approach and the protein network analyses of patient derived CTEPH endothelial cells allowed the quantitation of 3258 proteins. The 673 differentially regulated proteins were associated with functional and disease protein network modules. The protein network analyses resulted in the characterization of dysregulated pathways associated with endothelial dysfunction, such as mitochondrial dysfunction, oxidative phosphorylation, sirtuin signaling, inflammatory response, oxidative stress and fatty acid metabolism related pathways. In addition, the quantification of advanced oxidation protein products, total protein carbonyl content, and intracellular reactive oxygen species resulted increased attesting the dysregulation of oxidative stress response. In conclusion this is the first quantitative study to highlight the involvement of endothelial dysfunction in CTEPH using patient samples and by network medicine approach.Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat psychiatric disorders with affective biases such as depression and anxiety. How SSRIs exert a beneficial action on emotions associated with life events is still unknown. Here we ask whether and how the effectiveness of the SSRI fluoxetine is underpinned by neural mechanisms in the ventral striatum. To address these issues, we studied the spiking activity of neurons in the ventral striatum of monkeys during an approach-avoidance task in which the valence assigned to sensory stimuli was manipulated. Neural responses to positive and negative events were measured before and during a 4-week treatment with fluoxetine. We conducted PET scans to confirm that fluoxetine binds within the ventral striatum at a therapeutic dose. In our monkeys, fluoxetine facilitated approach of rewards and avoidance of punishments. These beneficial effects were associated with changes in tonic and phasic activities of striatal neurons. Fluoxetine increased the spontaneous firing rate of striatal neurons and amplified the number of cells responding to rewards versus punishments, reflecting a drug-induced positive shift in the processing of emotionally valenced information. These findings reveal how SSRI treatment affects ventral striatum neurons encoding positive and negative valence and striatal signaling of emotional information. In addition to a key role in appetitive processing, our results shed light on the involvement of the ventral striatum in aversive processing. Together, the ventral striatum appears to play a central role in the action of SSRIs on emotion processing biases commonly observed in psychiatric disorders.Endotoxemia, a type of sepsis caused by gram-negative bacterial endotoxin [i.e., lipopolysaccharide (LPS)], is associated with manifestations such as cytokine storm; failure of multiple organs, including the liver; and a high mortality rate. We investigated the effect and mechanism of action of LGK974, a Wnt signaling inhibitor, in mice with LPS-induced endotoxemia, an animal model of sepsis. LGK974 significantly and dose-dependently increased the survival rate and reduced plasma cytokine levels in mice with LPS-induced endotoxemia. Transcriptome analysis of liver tissues revealed significant changes in the expression of genes associated with the Wnt pathway as well as cytokine and NF-κB signaling during endotoxemia. LGK974 treatment suppressed the activation of NF-κB signaling and cytokine expression as well as the Wnt/β-catenin pathway in the livers of endotoxemic mice. Coimmunoprecipitation of phospho-IκB and β-transducin repeat-containing protein (β-TrCP) was increased in the livers of endotoxemic mice but was reduced by LGK974 treatment.