An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially ...initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.
Coral reefs are declining worldwide. The abundance of corals has decreased alongside a rise of filter feeders, turf, and algae in response to intensifying human pressures. This shift in prevalence of ...functional groups alters the biogeochemical processes in tropical water ecosystems, thereby influencing reef functioning. An urgent challenge is to understand the functional consequences of these shifts to develop suitable management strategies that aim at preserving the biological functions of reefs. Here, we quantify biogeochemical processes supporting key reef functions (i.e. net community calcification (NCC) and production (NCP) and nutrient recycling) in situ for five different benthic assemblages currently dominating shallow degraded Caribbean reef habitats. To this end, a transparent custom-made enclosure was placed over communities dominated by either one of five functional groups – coral, turf and macroalgae, bioeroding sponges, cyanobacterial mats, or sand – to determine chemical fluxes between these communities and the overlying water, during both day and night. To account for the simultaneous influence that distinct biogeochemical processes have on measured variables, the rates were then derived by solving a model consisting of differential equations describing the contribution of each process to the measured chemical fluxes. Inferred rates were low compared to those known for reef flats worldwide. Reduced accretion potential was recorded, with negative or very modest net community calcification rates for all communities. Net production during the day was also low, suggesting limited accumulation of biomass through photosynthesis and remineralisation of organic matter at night was relatively high in comparison, resulting in net heterotrophy over the survey period for most communities. Estimated recycling processes (i.e. nitrification and denitrification) were high but did not fully counterbalance nutrient release from aerobic mineralisation, rendering all substrates sources of nitrogen. Results suggest similar directions and magnitudes of key biogeochemical processes of distinct communities on this shallow Curaçaoan reef. We infer that the amount and type of organic matter released by abundant algal turfs and cyanobacterial mats on this reef likely enhances heterotroph activity and stimulates the proliferation of less diverse copiotrophic microbial populations, rendering the studied reef net heterotrophic and drawing the biogeochemical “behaviour” of distinct communities closer to each other.
Treatment of dysplastic Barrett's oesophagus prevents progression to adenocarcinoma; however, the optimal diagnostic strategy for Barrett's oesophagus is unclear. The Cytosponge-trefoil factor 3 ...(TFF3) is a non-endoscopic test for Barrett's oesophagus. The aim of this study was to investigate whether offering this test to patients on medication for gastro-oesophageal reflux would increase the detection of Barrett's oesophagus compared with standard management.
This multicentre, pragmatic, randomised controlled trial was done in 109 socio-demographically diverse general practice clinics in England. Randomisation was done both at the general practice clinic level (cluster randomisation) and at the individual patient level, and the results for each type of randomisation were analysed separately before being combined. Patients were eligible if they were aged 50 years or older, had been taking acid-suppressants for symptoms of gastro-oesophageal reflux for more than 6 months, and had not undergone an endoscopy procedure within the past 5 years. General practice clinics were selected by the local clinical research network and invited to participate in the trial. For cluster randomisation, clinics were randomly assigned (1:1) by the trial statistician using a computer-generated randomisation sequence; for individual patient-level randomisation, patients were randomly assigned (1:1) by the general practice clinics using a centrally prepared computer-generated randomisation sequence. After randomisation, participants received either standard management of gastro-oesophageal reflux (usual care group), in which participants only received an endoscopy if required by their general practitioner, or usual care plus an offer of the Cytosponge-TFF3 procedure, with a subsequent endoscopy if the procedure identified TFF3-positive cells (intervention group). The primary outcome was the diagnosis of Barrett's oesophagus at 12 months after enrolment, expressed as a rate per 1000 person-years, in all participants in the intervention group (regardless of whether they had accepted the offer of the Cytosponge-TFF3 procedure) compared with all participants in the usual care group. Analyses were intention-to-treat. The trial is registered with the ISRCTN registry, ISRCTN68382401, and is completed.
Between March 20, 2017, and March 21, 2019, 113 general practice clinics were enrolled, but four clinics dropped out shortly after randomisation. Using an automated search of the electronic prescribing records of the remaining 109 clinics, we identified 13 657 eligible patients who were sent an introductory letter with 14 days to opt out. 13 514 of these patients were randomly assigned (per practice or at the individual patient level) to the usual care group (n=6531) or the intervention group (n=6983). Following randomisation, 149 (2%) of 6983 participants in the intervention group and 143 (2%) of 6531 participants in the usual care group, on further scrutiny, did not meet all eligibility criteria or withdrew from the study. Of the remaining 6834 participants in the intervention group, 2679 (39%) expressed an interest in undergoing the Cytosponge-TFF3 procedure. Of these, 1750 (65%) met all of the eligibility criteria on telephone screening and underwent the procedure. Most of these participants (1654 95%; median age 69 years) swallowed the Cytosponge successfully and produced a sample. 231 (3%) of 6834 participants had a positive Cytosponge-TFF3 result and were referred for an endoscopy. Patients who declined the offer of the Cytosponge-TFF3 procedure and all participants in the usual care group only had an endoscopy if deemed necessary by their general practitioner. During an average of 12 months of follow-up, 140 (2%) of 6834 participants in the intervention group and 13 (<1%) of 6388 participants in the usual care group were diagnosed with Barrett's oesophagus (absolute difference 18·3 per 1000 person-years 95% CI 14·8–21·8; rate ratio adjusted for cluster randomisation 10·6 95% CI 6·0–18·8, p<0·0001). Nine (<1%) of 6834 participants were diagnosed with dysplastic Barrett's oesophagus (n=4) or stage I oesophago-gastric cancer (n=5) in the intervention group, whereas no participants were diagnosed with dysplastic Barrett's oesophagus or stage I gastro-oesophageal junction cancer in the usual care group. Among 1654 participants in the intervention group who swallowed the Cytosponge device successfully, 221 (13%) underwent endoscopy after testing positive for TFF3 and 131 (8%, corresponding to 59% of those having an endoscopy) were diagnosed with Barrett's oesophagus or cancer. One patient had a detachment of the Cytosponge from the thread requiring endoscopic removal, and the most common side-effect was a sore throat in 63 (4%) of 1654 participants.
In patients with gastro-oesophageal reflux, the offer of Cytosponge-TFF3 testing results in improved detection of Barrett's oesophagus. Cytosponge-TFF3 testing could also lead to the diagnosis of treatable dysplasia and early cancer. This strategy will lead to additional endoscopies with some false positive results.
Cancer Research UK, National Institute for Health Research, the UK National Health Service, Medtronic, and the Medical Research Council.
Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether ...genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3), was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8). Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8), as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype 6.4 × 10(-17), OR 2.3 (1.9, 2.9). By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.
The impact of anthropogenic ocean acidification (OA) on marine ecosystems is a vital concern facing marine scientists and managers of ocean resources. Euthecosomatous pteropods (holoplanktonic ...gastropods) represent an excellent sentinel for indicating exposure to anthropogenic OA because of the sensitivity of their aragonite shells to the OA conditions less favorable for calcification. However, an integration of observations, experiments and modelling efforts is needed to make accurate predictions of how these organisms will respond to future changes to their environment. Our understanding of the underlying organismal biology and life history is far from complete and must be improved if we are to comprehend fully the responses of these organisms to the multitude of stressors in their environment beyond OA. This review considers the present state of research and understanding of euthecosomatous pteropod biology and ecology of these organisms and considers promising new laboratory methods, advances in instrumentation (such as molecular, trace elements, stable isotopes, palaeobiology alongside autonomous sampling platforms, CT scanning and high-quality video recording) and novel field-based approaches (i.e. studies of upwelling and CO2 vent regions) that may allow us to improve our predictive capacity of their vulnerability and/or resilience. In addition to playing a critical ecological and biogeochemical role, pteropods can offer a significant value as an early-indicator of anthropogenic OA. This role as a sentinel species should be developed further to consolidate their potential use within marine environmental management policy making.
The 5-HT6 receptor (5-HT6R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT6R antagonists to improve off-target selectivity ...compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N′-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1–49) displaying high 5-HT6R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT6R antagonist showing good human in vitro metabolic stability. Rat pharmacokinetic data were sufficiently good to enable further in vivo profiling.
On coral reefs, some of the most aggressive calcium carbonate eroders are dinoflagellate-hosting sponges of the genus
Cliona
. Like in other marine taxa, the influence of these symbiotic ...microorganisms on the metabolism of the host sponge, and thereby on erosion of the surrounding ecosystem, is increasingly acknowledged. Despite elevating pH (and hence carbonate saturation state), dinoflagellate photosynthesis promotes bioerosion by their hosts. This paradox might be solved by a spatial isolation of photosynthesis from carbonate dissolution, but it remains unknown which mechanism connects the dinoflagellates’ photosynthesis with the sponge’s bioerosion. Here, we simulate the outcomes of photosynthesis in two separate ways, namely as production of carbon-rich compounds (in this case glycerol) and as an increase in oxygen content. This allows testing their potential to enhance bioerosion rates of sponge holobionts that were preconditioned under variable photosynthetic regimes. We find that glycerol, a commonly shared photosynthate in marine symbioses, stimulates chemical bioerosion rates in the dark of photosynthetically impaired sponges. Chemical bioerosion was all the more limited by availability of sufficient oxygen, while the combination of added glycerol and oxygen boosted chemical bioerosion rates. We argue that under normal physiological conditions, bioerosion is promoted by both organic carbon and oxygen production, and we provide evidence for the storage of photosynthates for night-time use. We further discuss our findings in the context of the current knowledge of the bioerosion mechanism, which we expand by integrating the effects of carbon-rich compounds and oxygen as drivers for bioerosion by
Cliona
.
Stress is a potent modulator of brain function and particularly mnemonic processes. While chronic stress is associated with long-term deficits in memory, the effects of acute stress on mnemonic ...functions are less clear as previous reports have been inconsistent. Some studies suggest that cortisol, a stress hormone that modulates biological changes in response to stress, may enhance memory consolidation and impair memory retrieval. However, other studies report no effect of cortisol on either memory consolidation or retrieval. These discrepancies could be due to differences in the timing and sequencing of the experimental procedures or individual differences in participants' stress response. In the present study, we examined the effect of increased cortisol levels due to acute stress, induced by the Trier Social Stress Test (TSST), on a pattern separation memory task while differentiating the distinct stages of memory processing and controlling for the effects of diurnal variation. Sixty-nine young adults completed a 2-d study in which subjects either underwent the TSST immediately following the encoding part of the memory task, targeting memory consolidation, or immediately prior to the recognition part of the memory task on the second day, targeting memory retrieval. Control subjects completed the same study procedures but underwent a control version of the TSST that did not induce a stress response. Mnemonic discrimination of highly similar stimuli was enhanced by stress induced during consolidation with better discrimination showing a significant correlation with increased cortisol responses. Stress induced during memory retrieval showed no significant effect on memory performance. These findings suggest that stress induced changes in cortisol differentially affect the consolidation and retrieval stages of memory function.
High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics ...of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
Anthropogenic pressures threaten the health of coral reefs globally. Some of these pressures directly affect coral functioning, while others are indirect, for example by promoting the capacity of ...bioeroders to dissolve coral aragonite. To assess the coral reef status, it is necessary to validate community-scale measurements of metabolic and geochemical processes in the field, by determining fluxes from enclosed coral reef patches. Here, we investigate diurnal trends of carbonate chemistry, dissolved organic carbon, oxygen, and nutrients on a 20 m deep coral reef patch offshore from the island of Saba, Dutch Caribbean by means of tent incubations. The obtained trends are related to benthic carbon fluxes by quantifying net community calcification (NCC) and net community production (NCP). The relatively strong currents and swell-induced near-bottom surge at this location caused minor seawater exchange between the incubated reef and ambient water. Employing a compensating interpretive model, the exchange is used to our advantage as it maintains reasonably ventilated conditions, which conceivably prevents metabolic arrest during incubation periods of multiple hours. No diurnal trends in carbonate chemistry were detected and all net diurnal rates of production were strongly skewed towards respiration suggesting net heterotrophy in all incubations. The NCC inferred from our incubations ranges from -0.2 to 1.4 mmol CaCO
m
h
(-0.2 to 1.2 kg CaCO
m
year
) and NCP varies from -9 to -21.7 mmol m
h
(net respiration). When comparing to the consensus-based
approach, the estimated NCC rate for the incubated full planar area (0.36 kg CaCO
m
year
) was lower, but still within range of the different NCC inferred from our incubations. Field trials indicate that the tent-based incubation as presented here, coupled with an appropriate interpretive model, is an effective tool to investigate, in situ, the state of coral reef patches even when located in a relatively hydrodynamic environment.
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