Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP

The transcriptional regulator YAP orchestrates many cellular functions, including tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin-cytoskeleton-dependent and Hippo-kinase-independent mechanisms. RHO activity is necessary, but not sufficient, for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based small interfering RNA (siRNA) screens provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective extracellular matrix (ECM) remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications. Moreno-Vicente et al. report that CAV1, a key component of PM mechanosensing caveolae, mediates adaptation to ECM rigidity by modulating YAP activity through the control of actin dynamics and phosphorylation-dependent interaction of YAP with the 14-3-3-domain protein YWHAH. Cav1-dependent YAP regulation drives two pathophysiological processes: ECM remodeling and pancreatic ADM. © 2018 The Author

Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome.

BACKGROUND: The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in the setting of primary hemophagocytic lymphohistiocytosis. OBJECTIVE: We sought to investigate the pathogenic role of IFN-γ and the therapeutic efficacy of IFN-γ neutralization in an animal model of MAS. METHODS: We used an MAS model established in mice transgenic for human IL-6 (IL-6TG mice) challenged with LPS (MAS mice). Levels of IFN-γ and IFN-γ-inducible chemokines were evaluated by using real-time PCR in the liver and spleen and by means of ELISA in plasma. IFN-γ neutralization was achieved by using the anti-IFN-γ antibody XMG1.2 in vivo. RESULTS: Mice with MAS showed a significant upregulation of the IFN-γ pathway, as demonstrated by increased mRNA levels of Ifng and higher levels of phospho-signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-γ-inducible chemokines Cxcl9 and Cxcl10 in the liver and spleen, as well as in plasma. A marked increase in Il12a and Il12b expression was also found in livers and spleens of mice with MAS. In addition, mice with MAS had a significant increase in numbers of liver CD68+ macrophages. Mice with MAS treated with an anti-IFN-γ antibody showed a significant improvement in survival and body weight recovery associated with a significant amelioration of ferritin, fibrinogen, and alanine aminotransferase levels. In mice with MAS, treatment with the anti-IFN-γ antibody significantly decreased circulating levels of CXCL9, CXCL10, and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in serum levels of proinflammatory cytokines and ferritin. CONCLUSION: These results provide evidence for a pathogenic role of IFN-γ in the setting of MAS

Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease a systematic review and meta-analysis

Context: Clinical practice guidelines on the management of mineral and bone disorders due to chronic kidney disease recommend specific treatment target levels for serum phosphorus, parathyroid hormone, and calcium. Objective: To assess the quality of evidence for the association between levels of serum phosphorus, parathyroid hormone, and calcium and risks of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease. Data Sources: The databases of MEDLINE (1948 to December 2010) and EMBASE (1947 to December 2010) were searched without language restriction. Hand searches also were conducted of the reference lists of primary studies, review articles, and clinical guidelines along with full-text review of any citation that appeared relevant. Study Selection: Of 8380 citations identified in the original search, 47 cohort studies (N=327 644 patients) met the inclusion criteria. Data Extraction: The characteristics of study design, participants, exposures, and covariates together with the outcomes of all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular events at different levels of serum phosphorus, parathyroid hormone, and calcium were analyzed within studies. Data were summarized across studies (when possible) using random-effects meta-regression. Data Synthesis: The risk of death increased 18% for every 1-mg/dL increase in serum phosphorus (relative risk [RR], 1.18 [95% confidence interval {CI}, 1.12-1.25]). There was no significant association between all-cause mortality and serum level of parathyroid hormone (RR per 100-pg/mL increase, 1.01 [95% CI, 1.00-1.02]) or serum level of calcium (RR per 1-mg/dL increase, 1.08 [95% CI, 1.00-1.16]). Data for the association between serum level of phosphorus, parathyroid hormone, and calcium and cardiovascular death were each available in only 1 adequately adjusted cohort study. Lack of adjustment for confounding variables was not a major limitation of the available studies. Conclusions: The evidentiary basis for a strong, consistent, and independent association between serum levels of calcium and parathyroid hormone and the risk of death and cardiovascular events in chronic kidney disease is poor. There appears to be an association between higher serum levels of phosphorus and mortality in this population. ©2011 American Medical Association. All rights reserved

Associations between anxiety disorders and diet quality in a Swiss cohort study.

Anxiety disorders are common in the general population and can have a major impact on a person's behavior. These disorders may also affect shopping and cooking habits, which may lead to a less healthy diet. Thus, we aimed to assess whether any current anxiety disorder or current specific anxiety disorders were associated with diet quality. Data of 6392 observations of 3993 participants were retrieved from 2 data waves of a population-based prospective cohort study conducted in an urban area in Switzerland. To assess the associations of anxiety status with diet quality measured by the Alternate Healthy Eating Index (AHEI), we performed cross-sectional multilevel random-effects linear regression analyses, which accounted for potential repeated participation and a series of potential confounders. We observed an association between the presence of any current anxiety disorder and lower diet quality. For the most conclusive model, the AHEI was 1.2 points lower among those with current anxiety disorders compared to those participants with no anxiety disorder (p = 0.016). When specific anxiety disorders were included separately into the model, panic disorder was associated with lower diet quality in the fully adjusted model (p = 0.037). Our findings of reduced diet quality in people with any current anxiety disorder suggest that practical support is needed when it comes to buying and processing food. This might be systematically addressed in psychotherapy and external interdisciplinary support (e.g. occupational therapy and dietary counselling) should be involved. However, further data is needed to strengthen the findings of the present study

Epidemiology of at-risk alcohol use and associated comorbidities of interest among community-dwelling older adults: a protocol for a systematic review.

There is little epidemiological evidence and knowledge about at-risk alcohol use among community-dwelling older adults and their chronic and acute alcohol-related comorbidities of interest. This systematic review will summarise and examine relevant studies about the epidemiology of at-risk alcohol use and associated comorbidities of interest in this population. We will search the following databases, without language or date restrictions, from inception to 31 August 2019: Embase.com, Medline Ovid SP, Pubmed (NOT medline[sb]), CINAHL EBSCO, PsycINFO Ovid SP, Central-Cochrane Library Wiley and Web of Science (Core Collection). Search strategies will be developed in collaboration with a librarian. We will use predefined search terms for alcoholism, epidemiology, the elderly, living place and comorbidities of interest, as well as terms related to the identification of "measurements", "tools" or "instruments" for measuring harm from alcohol use. At-risk status will be determined by the amount of alcohol consumed and any comorbidities of interest associated with at-risk alcohol use, with the latter being documented separately or using an assessment tool for at-risk drinking. We will also examine the bibliographies of all the relevant articles found and search for unpublished studies. We will consider publications in all languages. No ethical approval is necessary. Results will be presented in national and international conferences on addiction and published in a peer-reviewed journal. CRD42018099965

CONVINCE in the context of existing evidence on haemodiafiltration

Haemodiafiltration (HDF) provides a greater removal of larger solutes and protein-bound compounds than conventional high-flux haemodialysis (HD). There are indications that the patients receiving the highest convection volumes of HDF result in improved survival compared with HD. However, the comparative efficacy of HDF versus HD remains unproven. Here we provide a comparative account of the methodology and aims of ‘the comparison of high-dose HDF with high-flux HD’ (CONVINCE) study in the context of the totality of evidence and how this study will contribute to reaching a higher level of certainty regarding the comparative efficacy of HDF versus HD in people with end-stage kidney disease

Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. This review aims to assess the benefits and harms of HIF stabilisers for the treatment of anaemia in people with CKD