Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans

Solute carrier (SLC) transporters mediate the uptake of biologically active compounds in the intestine. Reduced oxygenation (hypoxia) is an important factor influencing intestinal homeostasis. The aim of this study was to investigate the pathophysiological consequences of hypoxia on the expression and function of SLCs in human intestine. Hypoxia was induced in human intestinal epithelial cells (IECs) in vitro (0.2; 1% O2 or CoCl2). For human in vivo studies, duodenal biopsies and serum samples were obtained from individuals (n = 16) acutely exposed to 4,554 meters above sea levels. Expression of relevant targets was analyzed by quantitative PCR, Western blotting, or immunofluorescence. Serum levels of inflammatory mediators and nucleosides were determined by ELISA and LC/MS-MS, respectively. In the duodenum of volunteers exposed to high altitude we observed decreased mRNA levels of apical sodium-dependent bile acid transporter (ASBT), concentrative nucleoside transporters 1/2 (CNT1/2), organic anion transporting polypeptide 2B1 (OATP2B1), organic cation transporter 2 (OCTN2), peptide transporter 1 (PEPT1), serotonin transporter (SERT), and higher levels of IFN-γ, IL-6, and IL-17A. Serum levels of IL-10, IFN-γ, matrix metalloproteinase-2 (MMP-2), and serotonin were elevated, whereas the levels of uridine decreased upon exposure to hypoxia. Hypoxic IECs showed reduced levels of equilibrative nucleoside transporter 2 (ENT2), OCTN2, and SERT mRNAs in vitro, which was confirmed on the protein level and was accompanied by activation of ERK1/2, increase of hypoxia-inducible factor (HIF) proteins, and production of IL-8 mRNA. Costimulation with IFN-γ and IL-6 during hypoxia further decreased the expression of SERT, ENT2, and CNT2 in vitro. Reduced oxygen supply affects the expression pattern of duodenal SLCs that is accompanied by changes in serum levels of proinflammatory cytokines and biologically active compounds demonstrating that intestinal transport is affected during systemic exposure to hypoxia in humans

Your evidence or mine? : Systematic evaluation of reviews of marine protected area effectiveness

Marine protected areas (MPAs) are a key strategy for mitigating the impacts of fisheries, but their designation can be controversial, and there is uncertainty surrounding when and where MPAs are most effective. Evidence synthesis that collates primary research on MPA effectiveness can provide a crucial bridge between research, policy and practice. However, reviews vary in scope and rigour, meaning decision-makers face the challenge of identifying appropriate reviews. Documenting differences amongst reviews can therefore support nonspecialists in locating the most relevant and rigorous reviews and can also assist researchers in targeting evidence gaps. We addressed these priorities by systematically searching for reviews examining effectiveness of MPAs for biodiversity, critically appraising methods used and categorizing review scope. The 27 reviews assessed overlapped in scope (suggesting some redundancy) and differed substantially in reliability. Key strengths related to the effects of MPAs on fish abundance and the influence of MPA size and age on effectiveness. However, several gaps were noted, with some questions not addressed and others lacking highly reliable syntheses – importantly, the latter may create the perception that particular questions have been adequately addressed, potentially deterring new syntheses. Our findings indicate key aspects of review conduct that could be improved (e.g. documenting critical appraisal of primary research, evaluating potential publication bias) and can facilitate evidence-based policy by guiding nonspecialists to the most reliable and relevant reviews. Lastly, we suggest that future reviews with broader taxonomic coverage and considering the influence of a wider range of MPA characteristics on effectiveness would be beneficial

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

The complexity of interacting nutritional drivers behind food selection, a review of northern cervids

The research literature on food selection by large herbivores is extensive. Still, we are generally lacking in our knowledge of the influence of potentially interacting chemical contents of the food. We made a qualitative review of a systematic literature search of studies that empirically link chemical contents of food to the food selection by northern cervids (genera Alces, Capreolus, Cervus, Dama, Odocoileus, Rangifer). We found that although the majority of the 98 relevant studies measuring any given food constituent (energy, protein, fiber, minerals, plant secondary metabolites) provided support for it acting as a driver of food selection (in either a negative or positive way), there was little support for the traditional hypotheses of maximization or limitation of any single constituent. Rather, because of the animals’ need to acquire an appropriate intake of several constituents at the same time, our review highlights how new empirical stud- ies need to focus on several food constituents in synchrony: (1) Study designs should capture sufficient variation in the content of food constituents in order to tease apart their many co-variations; and (2) insights about nutritional drivers may be lost if one uses only composite currencies such as crude energy, crude fiber, ash, or tannins, which may mask contrasting selection patterns of the lumped constituents. Season had an apparent influence on the selection of some food constituents, particularly various fiber frac- tions. In contrast, our review revealed a lack of evidence that cervids more strongly select for protein in summer than they do in winter. Our overall conclusion of the review is that interacting chemical contents of food make the nutritional value of a given food type into a varying entity. To better elucidate this varia- tion, we need new technologies that non-invasively capture nutrient intake of free-ranging animals, across seasons.The complexity of interacting nutritional drivers behind food selection, a review of northern cervidspublishedVersio