Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal.

This is the final published version. Available from PLoS via the DOI in this record.All relevant data are available from Figshare, under the DOI http://dx.doi. org/10.6084/m9.figshare.1292883.AIMS: Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB), and compared this to lean volunteers. MATERIALS AND METHODS: The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3 ± 2.2 kg/m(2)) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7 ± 0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity. RESULTS: Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001). Weight-loss of 29.9 ± 4 kg after surgery significantly improved GDR50 (P=0.004) but not GDR100 (P=0.3). These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001). Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA), and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA), and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively). CONCLUSIONS: Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.Diabetes Research and Wellness FoundatioMedical Research Council (MRC)Astra Zenec

Solar-Driven Reduction of Aqueous Protons Coupled to Selective Alcohol Oxidation with a Carbon Nitride-Molecular Ni Catalyst System.

Solar water-splitting represents an important strategy toward production of the storable and renewable fuel hydrogen. The water oxidation half-reaction typically proceeds with poor efficiency and produces the unprofitable and often damaging product, O2. Herein, we demonstrate an alternative approach and couple solar H2 generation with value-added organic substrate oxidation. Solar irradiation of a cyanamide surface-functionalized melon-type carbon nitride ((NCN)CNx) and a molecular nickel(II) bis(diphosphine) H2-evolution catalyst (NiP) enabled the production of H2 with concomitant selective oxidation of benzylic alcohols to aldehydes in high yield under purely aqueous conditions, at room temperature and ambient pressure. This one-pot system maintained its activity over 24 h, generating products in 1:1 stoichiometry, separated in the gas and solution phases. The (NCN)CNx-NiP system showed an activity of 763 μmol (g CNx)(-1) h(-1) toward H2 and aldehyde production, a Ni-based turnover frequency of 76 h(-1), and an external quantum efficiency of 15% (λ = 360 ± 10 nm). This precious metal-free and nontoxic photocatalytic system displays better performance than an analogous system containing platinum instead of NiP. Transient absorption spectroscopy revealed that the photoactivity of (NCN)CNx is due to efficient substrate oxidation of the material, which outweighs possible charge recombination compared to the nonfunctionalized melon-type carbon nitride. Photoexcited (NCN)CNx in the presence of an organic substrate can accumulate ultralong-lived "trapped electrons", which allow for fuel generation in the dark. The artificial photosynthetic system thereby catalyzes a closed redox cycle showing 100% atom economy and generates two value-added products, a solar chemical, and solar fuel.This work was supported by the Christian Doppler Research Association (Austrian Federal Ministry of Science, Research, and Economy and the National Foundation for Research, Technology and Development) and the OMV Group (to E.R.), an Oppenheimer PhD scholarship (to B.C.M.M.), a Marie Curie Postdoctoral Fellowship (GAN 624997 to C.A.C.), a FRQNT Postdoctoral Fellowship (to R.G.), and an ERC Starting Grant (B. V. L., Grant No. 639233).This is the final version of the article. It first appeared from American Chemical Society via http://dx.doi.org/10.1021/jacs.6b0432

The pros and cons of getting engaged in an online social community embedded within digital cognitive behavioral therapy for insomnia: survey among users

Background: Sleepio is a proven digital sleep improvement programme based on cognitive behavioural therapy (CBT) techniques. Users have the option to join an online community that includes weekly expert discussions, peer-to-peer discussion forums and personal message walls. Objective: The aims of this study were to (1) explore the reasons for deciding to engage with the Sleepio online community, (2) explore the potential benefits arising from engagement with the online community, (3) identify and describe any problematic issues related to use of the online community. Methods: In total, 100 respondents (70% female; mean age 51, range 26-82 years) completed the online survey. Most respondents had started Sleepio with chronic sleep problems (59% to to 10 years, 35% >10years), and had actively engaged with the online community (85% had made a discussion or wall post). At the time of the survey, respondents had used Sleepio for a median of 12 weeks (range from 3 weeks to 2 years). Results: Responses to the open-ended questions were analysed using thematic analysis. This analysis revealed five initial drivers for engagement including: 1) the desire to connect with people facing similar issues; 2) seeking personalised advice; 3) curiosity; 4) being invited by other members; and 5) wanting to use all available sleep improvement tools. Advantages of engagement included: access to continuous support, reduced sense of isolation, being part of a non-judgmental community, personalised advice, positive comparisons with others, encouragement to keep going, and altruism. Five potential disadvantages were: design and navigation issues, uncertain quality of user-generated content, negative comparisons with others, excessive time commitments, and data privacy concerns. Participants related their community experiences to engagement with the Sleepio programme with the many stating it had supported their efforts to achieve sleep improvement, as well as helping with adherence and commitment to the programme. Conclusions: Despite some concerns, members regarded the Sleepio community as a valuable resource. Online communities may be a useful means through which to support long-term engagement with online therapy for insomnia

Caspase-2 is upregulated after sciatic nerve transection and its inhibition protects dorsal root ganglion neurons from Apoptosis after serum withdrawal

Sciatic nerve (SN) transection-induced apoptosis of dorsal root ganglion neurons (DRGN) is one factor determining the efficacy of peripheral axonal regeneration and the return of sensation. Here, we tested the hypothesis that caspase-2(CASP2) orchestrates apoptosis of axotomised DRGN both in vivo and in vitro by disrupting the local neurotrophic supply to DRGN. We observed significantly elevated levels of cleaved CASP2 (C-CASP2), compared to cleaved caspase-3 (C-CASP3), within TUNEL+DRGN and DRG glia (satellite and Schwann cells) after SN transection. A serum withdrawal cell culture model, which induced 40% apoptotic death in DRGN and 60% in glia, was used to model DRGN loss after neurotrophic factor withdrawal. Elevated C-CASP2 and TUNEL were observed in both DRGN and DRG glia, with C-CASP2 localisation shifting from the cytosol to the nucleus, a required step for induction of direct CASP2-mediated apoptosis. Furthermore, siRNAmediated downregulation of CASP2 protected 50% of DRGN from apoptosis after serum withdrawal, while downregulation of CASP3 had no effect on DRGN or DRG glia survival. We conclude that CASP2 orchestrates the death of SN-axotomised DRGN directly and also indirectly through loss of DRG glia and their local neurotrophic factor support. Accordingly, inhibiting CASP2 expression is a potential therapy for improving both the SN regeneration response and peripheral sensory recovery

In Vitro Recombination Catalyzed by Bacterial Class 1 Integron Integrase IntI1 Involves Cooperative Binding and Specific Oligomeric Intermediates

Gene transfer via bacterial integrons is a major pathway for facilitating the spread of antibiotic resistance genes across bacteria. Recently the mechanism underlying the recombination catalyzed by class 1 integron recombinase (IntI1) between attC and attI1 was highlighted demonstrating the involvement of a single-stranded intermediary on the attC site. However, the process allowing the generation of this single-stranded substrate has not been determined, nor have the active IntI1•DNA complexes been identified. Using the in vitro strand transfer assay and a crosslink strategy we previously described we demonstrated that the single-stranded attC sequences could be generated in the absence of other bacterial proteins in addition to IntI. This suggests a possible role for this protein in stabilizing and/or generating this structure. The mechanism of folding of the active IntI•DNA complexes was further analyzed and we show here that it involves a cooperative binding of the protein to each recombination site and the emergence of different oligomeric species specific for each DNA substrate. These findings provide further insight into the recombination reaction catalyzed by IntI1

Autocalibration of accelerometer data for free-living physical activity assessment using local gravity and temperature: an evaluation on four continents.

Wearable acceleration sensors are increasingly used for the assessment of free-living physical activity. Acceleration sensor calibration is a potential source of error. This study aims to describe and evaluate an autocalibration method to minimize calibration error using segments within the free-living records (no extra experiments needed). The autocalibration method entailed the extraction of nonmovement periods in the data, for which the measured vector magnitude should ideally be the gravitational acceleration (1 g); this property was used to derive calibration correction factors using an iterative closest-point fitting process. The reduction in calibration error was evaluated in data from four cohorts: UK (n = 921), Kuwait (n = 120), Cameroon (n = 311), and Brazil (n = 200). Our method significantly reduced calibration error in all cohorts (P 0.05). Temperature correction coefficients were highest for the z-axis, e.g., 19.6-mg offset per 5°C. Further, application of the autocalibration method had a significant impact on typical metrics used for describing human physical activity, e.g., in Brazil average wrist acceleration was 0.2 to 51% lower than uncalibrated values depending on metric selection (P < 0.01). The autocalibration method as presented helps reduce the calibration error in wearable acceleration sensor data and improves comparability of physical activity measures across study locations. Temperature ultization seems essential when temperature deviates substantially from the average temperature in the record but not for multiday summary measures.This is the final version of the article. It first appeared from the American Physiological Society via http://dx.doi.org/10.1152/japplphysiol.00421.201

Delayed gastric emptying and reduced postprandial small bowel water content of equicaloric whole meal bread versus rice meals in healthy subjects: novel MRI insights

BACKGROUND/OBJECTIVES: Postprandial bloating is a common symptom in patients with functional gastrointestinal (GI) diseases. Whole meal bread (WMB) often aggravates such symptoms though the mechanisms are unclear. We used magnetic resonance imaging (MRI) to monitor the intragastric fate of a WMB meal (11% bran) compared to a rice pudding (RP) meal. SUBJECTS/METHODS: 12 healthy volunteers completed this randomised crossover study. They fasted overnight and after an initial MRI scan consumed a glass of orange juice with a 2267 kJ WMB or an equicaloric RP meal. Subjects underwent serial MRI scans every 45 min up to 270 min to assess gastric volumes and small bowel water content and completed a GI symptom questionnaire. RESULTS: The MRI intragastric appearance of the two meals was markedly different. The WMB meal formed a homogeneous dark bolus with brighter liquid signal surrounding it. The RP meal separated into an upper, liquid layer and a lower particulate layer allowing more rapid emptying of the liquid compared to solid phase (sieving). The WMB meal had longer gastric half emptying times (132±8 min) compared to the RP meal (104±7 min), P<0.008. The WMB meal was associated with markedly reduced MRI-visible small bowel free mobile water content compared to the RP meal, P<0.0001. CONCLUSIONS: WMB bread forms a homogeneous bolus in the stomach which inhibits gastric sieving and hence empties slower than the equicaloric rice meal. These properties may explain why wheat causes postprandial bloating and could be exploited to design foods which prolong satiation