73 research outputs found

    A Novel PHOX/CD38/MCOLN1/TFEB Axis Important For Macrophage Activation During Bacterial Phagocytosis [preprint]

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    Macrophages are a key and heterogenous class of phagocytic cells of the innate immune system, which act as sentinels in peripheral tissues and are mobilized during infection. Macrophage activation in the presence of bacterial cells and molecules entails specific and complex programs of gene expression. How such triggers elicit the gene expression programs is incompletely understood. We previously discovered that transcription factor TFEB is a key contributor to macrophage activation during bacterial phagocytosis. However, the mechanism linking phagocytosis of bacterial cells to TFEB activation remained unknown. In this article, we describe a previously unknown pathway that links phagocytosis with the activation of TFEB and related transcription factor TFE3 in macrophages. We find that phagocytosis of bacterial cells causes an NADPH oxidase (PHOX)-dependent oxidative burst, which activates enzyme CD38 and generates NAADP in the maturing phagosome. Phago-lysosome fusion brings Ca2+ channel TRPML1/MCOLN1 in contact with NAADP, causing Ca2+ efflux from the lysosome, calcineurin activation, and TFEB nuclear import. This drives TFEB-dependent expression of important pro-inflammatory cytokines, such as IL-1α, IL-1β, and IL-6. Thus, our findings reveal that TFEB activation is a key regulatory event for the activation of macrophages. These findings have important implications for infections, cancer, obesity, and atherosclerosis

    TSO-DSO Coordination Schemes to Facilitate Distributed Resources Integration

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    The incorporation of renewable energy into power systems poses serious challenges to the transmission and distribution power system operators (TSOs and DSOs). To fully leverage these resources there is a need for a new market design with improved coordination between TSOs and DSOs. In This paper we propose two coordination schemes between TSOs and DSOs: one centralised and another decentralised that facilitate the integration of distributed based generation; minimise operational cost; relieve congestion; and promote a sustainable system. In order to achieve this, we approximate the power equations with linearised equations so that the resulting optimal power flows (OPFs) in both the TSO and DSO become convex optimisation problems. In the resulting decentralised scheme, the TSO and DSO collaborate to optimally allocate all resources in the system. In particular, we propose an iterative bi-level optimisation technique where the upper level is the TSO that solves its own OPF and determines the locational marginal prices at substations. We demonstrate numerically that the algorithm converges to a near optimal solution. We study the interaction of TSOs and DSOs and the existence of any conflicting objectives with the centralised scheme. More specifically, we approximate the Pareto front of the multi-objective optimal power flow problem where the entire system, i.e., transmission and distribution systems, is modelled. The proposed ideas are illustrated through a five bus transmission system connected with distribution systems, represented by the IEEE 33 and 69 bus feeders

    Spinach consumption and nonalcoholic fatty liver disease among adults: a case�control study

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    Background: Spinach has high antioxidants and polyphenols and showed protective effects against liver diseases in experimental studies. We aimed to assess the association between dietary intake of spinach and odds of nonalcoholic fatty liver disease (NAFLD) in a case�control study among Iranian adults. Methods: Totally 225 newly diagnosed NAFLD patients and 450 controls, aged 20�60 years, were recruited in this study. Participants� dietary intakes were collected using a valid and reliable 168-item semi-quantitative food frequency questionnaire (FFQ). The logistic regression test was used for assessing the association between total, raw, and boiled dietary spinach with the odds of NAFLD. Results: The mean (SD) age and BMI of participants (53 male) were 38.1 (8.8) years and 26.8 (4.3) kg/m2, respectively. In the final adjusted model for potential confounders, the odds (95 CI) of NAFLD in individuals in the highest tertile of daily total and raw spinach intake was 0.36 (0.19�0.71), P_trend = 0.001 and 0.47 (0.24�0.89), P_trend = 0.008, respectively compared with those in the lowest tertile. Furthermore, in the adjusted analyses, an inverse association was observed between the highest yearly intake versus no raw spinach consumption and odds of NAFLD (OR 0.41; 95% CI 0.18�0.96), P for trend = 0.013. However, there was no significant association between higher boiled spinach intake and odds of NAFLD. Conclusions: The present study found an inverse association between total and raw spinach intake with the odds of NAFLD. © 2021, The Author(s)

    Transcription factor TFEB cell-autonomously modulates susceptibility to intestinal epithelial cell injury in vivo

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    Understanding the transcription factors that modulate epithelial resistance to injury is necessary for understanding intestinal homeostasis and injury repair processes. Recently, transcription factor EB (TFEB) was implicated in expression of autophagy and host defense genes in nematodes and mammalian cells. However, the in vivo roles of TFEB in the mammalian intestinal epithelium were not known. Here, we used mice with a conditional deletion of Tfeb in the intestinal epithelium (Tfeb ΔIEC) to examine its importance in defense against injury. Unperturbed Tfeb ΔIEC mice exhibited grossly normal intestinal epithelia, except for a defect in Paneth cell granules. Tfeb ΔIEC mice exhibited lower levels of lipoprotein ApoA1 expression, which is downregulated in Crohn’s disease patients and causally linked to colitis susceptibility. Upon environmental epithelial injury using dextran sodium sulfate (DSS), Tfeb ΔIEC mice exhibited exaggerated colitis. Thus, our study reveals that TFEB is critical for resistance to intestinal epithelial cell injury, potentially mediated by APOA1

    TFEB regulates murine liver cell fate during development and regeneration

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    It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer

    Intestinal Epithelial Wnt Signaling Mediates Acetylcholine-Triggered Host Defense against Infection

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    Regulated antimicrobial peptide expression in the intestinal epithelium is key to defense against infection and to microbiota homeostasis. Understanding the mechanisms that regulate such expression is necessary for understanding immune homeostasis and inflammatory disease and for developing safe and effective therapies. We used Caenorhabditis elegans in a preclinical approach to discover mechanisms of antimicrobial gene expression control in the intestinal epithelium. We found an unexpected role for the cholinergic nervous system. Infection-induced acetylcholine release from neurons stimulated muscarinic signaling in the epithelium, driving downstream induction of Wnt expression in the same tissue. Wnt induction activated the epithelial canonical Wnt pathway, resulting in the expression of C-type lectin and lysozyme genes that enhanced host defense. Furthermore, the muscarinic and Wnt pathways are linked by conserved transcription factors. These results reveal a tight connection between the nervous system and the intestinal epithelium, with important implications for host defense, immune homeostasis, and cancer

    Gas Injection for Enhancement of Condensate Recovery in a Gas Condensate Reservoir

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    Gas condensate reservoirs suffer losses in well productivity due to near wellbore condensate dropout when the flowing bottom-hole pressure declines below the dew point pressure. Pressure maintenance and gas cycling are the common practices used in the oil and gas field to alleviate this problem and develop gas condensate reservoirs. The injection of dry gas into a retrograde gas condensate reservoir helps in vaporizing the condensate and increases its dew point. This article investigates the situation of one of the reservoirs located in southern Iran in Zagros area. First, based on the reservoir composition, the phase diagram has been plotted. Peng-Robinson equation of state for the equilibrium calculations and Lee-Kesler characterization of heavy fractions are used in this software. After that the effect of nitrogen, pure methane, a composition of ethane and methane, and carbon dioxide injections on reservoir recovery has been investigated and compared to a natural depletion scheme. The full system, including two separators and a stock tank, are simulated simultaneously and the effect of each type of injection on the liquid and gas production is investigated. Full mixing has been assumed in all of the injections studied. By comparing between the results it is concluded that in an injection process, required injection rate to maintain reservoir pressure above dew point pressure and avoid liquid formation in the reservoir for pure methane, a composition of ethane and methane, pure nitrogen and carbon dioxide, and liquid recovery in all cases are investigated. According to the results, with increasing ethane mole percent in the injecting gas a lower injecting rate for the same liquid recovery is needed. Because with increasing heavy components mole percent in injecting gas, average molecular weight of injecting gas, and reservoir gas becomes closer and there will be a better mixing between them and, therefore, liquid recovery will be improved. Thus, a composition of ethane and methane with more ethane mole percent is better than others. © 2015 Taylor and Francis Group, LLC
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