Alterations in insulin action and contraction-mediated metabolism in myotubes derived from Roux-en-Y gastric bypass patients

Roux-en-Y gastric bypass (RYGB) surgery induces various metabolic benefits in severely obese (BMI> 40 kg/m2) individuals, including improved insulin action in peripheral tissues, most notably skeletal muscle, and remission of type 2 diabetes. Despite these improvements, the mechanism in which RYGB improves metabolism is unclear. To examine this, primary human skeletal muscle cells were isolated from muscle biopsies obtained from individuals prior to, 1-month, and 7-months following RYGB. Insulin-stimulated glycogen synthesis, an index of insulin action, improved in myotubes derived from subjects at 1-month following RYGB, which was sustained at 7-months post-surgery. The cellular mechanisms involved appear to consist of distinct acute and chronic components, with the acute response consisting of reduced muscle glycogen content and increased phosphorylation of ACC, and the chronic response associated with a physiological increase in PGC1[alpha] protein abundance. To further examine the combined role of RYGB surgery and muscle contraction on skeletal muscle metabolism, fully differentiated myotubes from RYGB patients were electrically stimulated to contract for 24-hours. Prior to surgery, myotubes were unresponsive to the benefits of muscle contraction to subsequently increase insulin action, suggesting exercise resistance in these cells. However, only 1-month following RYGB surgery, myotubes became responsive to muscle contraction, as indicated by enhanced insulin-stimulated glycogen synthesis and AS160 phosphorylation, as well as increased basal glucose oxidation. To explore whether the improvements in insulin action were due to an improved ability of cells to switch fuel preference, we examined in vitro metabolic flexibility in cells derived from RYGB patients. Utilizing several methods to examine in vitro metabolic flexibility, we were unable to detect major differences amongst the groups, suggesting that alterations in metabolic flexibility at the whole-body level following RYGB surgery are not retained in primary myotubes. The results from this study suggest RYGB surgery alters the inherent characteristics of skeletal muscle that invoke improved insulin action and exercise-responsiveness. While previous research suggest insulin action in skeletal muscle is improved once substantial weight loss is achieved, we show that, when utilizing a muscle-specific model, improvements in insulin action occur as early as 1-month following RYGB surgery. Furthermore, it appears that acute adaptations in skeletal muscle following RYGB surgery invoke a cellular environment that is more responsive to the additional benefits of muscle contraction. Collectively, the results of this study provide valuable mechanisms in which RYGB surgery and muscle contraction can improve insulin action in skeletal muscle

The Sensitivity of US Wildfire Occurrence to Pre-Season Soil Moisture Conditions Across Ecosystems

It is generally accepted that year-to-year variability in moisture conditions and drought are linked with increased wildfire occurrence. However, quantifying the sensitivity of wildfire to surface moisture state at seasonal lead-times has been challenging due to the absence of a long soil moisture record with the appropriate coverage and spatial resolution for continental-scale analysis. Here we apply model simulations of surface soil moisture that numerically assimilate observations from NASA's Gravity Recovery and Climate Experiment (GRACE) mission with the US Forest Service"TM"s historical Fire-Occurrence Database over the contiguous United States. We quantify the relationships between pre-fire-season soil moisture and subsequent-year wildfire occurrence by land-cover type and produce annual probable wildfire occurrence and burned area maps at 0.25-degree resolution. Cross-validated results generally indicate a higher occurrence of smaller fires when months preceding fire season are wet, while larger fires are more frequent when soils are dry. This result is consistent with the concept of increased fuel accumulation under wet conditions in the pre-season. These results demonstrate the fundamental strength of the relationship between soil moisture and fire activity at long lead-times and are indicative of that relationship's utility for the future development of national-scale predictive capability

Roux-en-Y Gastric Bypass Surgery Regulates Mitochondrial Dynamics Proteins in Primary Human Myotubes Derived from Severely Obese Humans

Mitochondrial dynamics including mitochondrial fission (e.g., Dynamin-related protein 1 (Drp1) and Fission 1 (Fis1)) and fusion (e.g., Mitofusin 2 (MFN 2)) regulates mitochondrial homeostasis. Defects in mitochondrial dynamics are suggested to contribute to skeletal muscle mitochondrial dysfunction and insulin resistance associated with severe obesity. Roux-en-Y gastric bypass (RYGB) surgery markedly improves metabolic health as indicated by enhanced substrate oxidation and insulin action in skeletal muscle. However, the underlying cellular mechanisms responsible for these are unclear and could possibly be due to the improvement of mitochondrial dynamics. PURPOSE: The purpose of this study was to determine whether RYGB surgery improves mitochondria dynamics proteins in primary human myotubes from severely obese humans. METHODS: Primary skeletal muscle cells were isolated from muscle biopsies obtained from six lean subjects (BMI = 23.4 ± 0.6 kg/m2) and six RYGB patients prior to, 1-month and 7-months after surgery (BMI = 50.2 ± 2.0, 43.2 ± 2.8 and 35.7 ± 2.2 kg/m2, respectively) and were differentiated to myotubes. On day 7 of differentiation, myotubes were harvested for further assessing the expressions of mitochondria dynamics proteins. RESULTS: Before surgery, Drp1Ser616 phosphorylation and Fis1 expression were significantly higher in myotubes derived from severely obese patients when compared to lean controls (41% and 26%, respectively, P \u3c 0.05). While there were no improvements at 1-month post-surgery, Drp1Ser616 phosphorylation and Fis1 expression were significantly decreased in myotubes from severely obese humans at 7-months post-surgery (Pre vs. 7-months post: 0.046 ± 0.004 vs. 0.035 ± 0.003; 0.023 ± 0.008 vs. 0.014 ± 0.003 AU; respectively, P \u3c 0.05), and not statistically different from lean controls. However, MFN2 expression did not change post-surgery in comparison to pre-surgery. CONCLUSION: These data suggest that RYGB surgery reduces obesity-induced rise in mitochondrial fission, but not fusion in primary human myotubes derived from severely obese humans

Mitochondria as a Target for Mitigating Sarcopenia

Sarcopenia is the loss of muscle mass, strength, and physical function that is characteristic of aging. The progression of sarcopenia is gradual but may be accelerated by periods of muscle loss during physical inactivity secondary to illness or injury. The loss of mobility and independence and increased comorbidities associated with sarcopenia represent a major healthcare challenge for older adults. Mitochondrial dysfunction and impaired proteostatic mechanisms are important contributors to the complex etiology of sarcopenia. As such, interventions that target improving mitochondrial function and proteostatic maintenance could mitigate or treat sarcopenia. Exercise is currently the only effective option to treat sarcopenia and does so, in part, by improving mitochondrial energetics and protein turnover. Exercise interventions also serve as a discovery tool to identify molecular targets for development of alternative therapies to treat sarcopenia. In summary, we review the evidence linking mitochondria and proteostatic maintenance to sarcopenia and discuss the therapeutic potential of interventions addressing these two factors to mitigate sarcopenia

Distinct Adaptations of Mitochondrial Dynamics to Electrical Pulse Stimulation in Lean and Severely Obese Primary Myotubes

BACKGROUND: Skeletal muscle from lean and obese subjects elicit differential adaptations in response to exercise/muscle contractions. In order to determine whether obesity alters the adaptations in mitochondrial dynamics in response to exercise/muscle contractions and whether any of these distinct adaptations are linked to alterations in insulin sensitivity, we compared the effects of electrical pulse stimulation (EPS) on mitochondrial network structure and regulatory proteins in mitochondrial dynamics in myotubes from lean humans and humans with severe obesity and evaluated the correlations between these regulatory proteins and insulin signaling. METHODS: Myotubes from human skeletal muscle cells obtained from lean humans (BMI 23.8 ± 1.67 kg/m(2)) and humans with severer obesity (45.5 ± 2.26 kg/m(2)) (n=8/group) were electrically stimulated for 24 hours. Four-hours after EPS, mitochondrial network structure, protein markers of insulin signaling and mitochondrial dynamics were assessed. RESULTS: EPS enhanced insulin-stimulated Akt(Ser473) phosphorylation, reduced the number of non-networked individual mitochondria and increased the mitochondrial network size in both groups (P<0.05). Mitochondrial fusion marker mitofusin 2 was significantly increased in myotubes from the lean subjects (P<0.05), but reduced in subjects with severe obesity (P<0.05). In contrast, fission marker dynamin-related protein 1 (Drp1(Ser616)) was reduced in myotubes from subjects with severe obesity (P<0.05), but remained unchanged in lean subjects. Reductions in Drp(Ser616) phosphorylation were correlated with improvements in insulin-stimulated Akt(Ser473) phosphorylation following EPS (r = −0.679, P = 0.004). CONCLUSION: Our data demonstrated that EPS induces more fused mitochondrial networks, which are associated with differential adaptations in mitochondrial dynamic processes in myotubes from lean humans and human with severe obesity. It also suggests that improved insulin signaling following muscle contractions may be linked to the reduction in Drp1 activity

KELT-6b: A P~7.9 d Hot Saturn Transiting a Metal-Poor Star with a Long-Period Companion

We report the discovery of KELT-6b, a mildly-inflated Saturn-mass planet transiting a metal-poor host. The initial transit signal was identified in KELT-North survey data, and the planetary nature of the occulter was established using a combination of follow-up photometry, high-resolution imaging, high-resolution spectroscopy, and precise radial velocity measurements. The fiducial model from a global analysis including constraints from isochrones indicates that the V=10.38 host star (BD+31 2447) is a mildly evolved, late-F star with T_eff=6102 \pm 43 K, log(g_*)=4.07_{-0.07}^{+0.04} and [Fe/H]=-0.28 \pm 0.04, with an inferred mass M_*=1.09 \pm 0.04 M_sun and radius R_star=1.58_{-0.09}^{+0.16} R_sun. The planetary companion has mass M_P=0.43 \pm 0.05 M_J, radius R_P=1.19_{-0.08}^{+0.13} R_J, surface gravity log(g_P)=2.86_{-0.08}^{+0.06}, and density rho_P=0.31_{-0.08}^{+0.07} g~cm^{-3}. The planet is on an orbit with semimajor axis a=0.079 \pm 0.001 AU and eccentricity e=0.22_{-0.10}^{+0.12}, which is roughly consistent with circular, and has ephemeris of T_c(BJD_TDB)=2456347.79679 \pm 0.00036 and P=7.845631 \pm 0.000046 d. Equally plausible fits that employ empirical constraints on the host star parameters rather than isochrones yield a larger planet mass and radius by ~4-7%. KELT-6b has surface gravity and incident flux similar to HD209458b, but orbits a host that is more metal poor than HD209458 by ~0.3 dex. Thus, the KELT-6 system offers an opportunity to perform a comparative measurement of two similar planets in similar environments around stars of very different metallicities. The precise radial velocity data also reveal an acceleration indicative of a longer-period third body in the system, although the companion is not detected in Keck adaptive optics images.Comment: Published in AJ, 17 pages, 15 figures, 6 table

Effect of weekend admission on in-hospital mortality and functional outcomes for patients with acute subarachnoid haemorrhage (SAH)

BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is an acute cerebrovascular event with high socioeconomic impact as it tends to affect younger patients. The recent NCEPOD study looking into management of aSAH has recommended that neurovascular units in the United Kingdom should aim to secure cerebral aneurysms within 48 h and that delays because of weekend admissions can increase the mortality and morbidity attributed to aSAH. METHOD: We used data from a prospective audit of aSAH patients admitted between January 2009 and December 2011. The baseline demographic and clinical features of the weekend and weekday groups were compared using the chi-squared test and T-test. Cox proportional hazards models (Proc Phreg in SAS) were used to calculate the adjusted overall hazard of in-hospital death associated with admission on weekend, adjusting for age, sex, baseline WFNS grade, type of treatment received and time from scan to treatment. Sliding dichotomy analysis was used to estimate the difference in outcomes after SAH at 3 months in weekend and weekday admissions. RESULTS: Those admitted on weekends had a significantly higher scan to treatment time (83.05 ± 83.4 h vs 40.4 ± 53.4 h, P < 0.0001) and admission to treatment (71.59 ± 79.8 h vs 27.5 ± 44.3 h, P < 0.0001) time. After adjustments for adjusted for relevant covariates weekend admission was statistically significantly associated with excess in-hospital mortality (HR = 2.1, CL [1.13–4.0], P = 0.01). After adjustments for all the baseline covariates, the sliding dichotomy analysis did not show effects of weekend admission on long-term outcomes on the good, intermediate and worst prognostic bands. CONCLUSIONS: This study provides important data showing excess in-hospital mortality of patients with SAH on weekend admissions served by the United Kingdom’s National Health Service.; However, there were no effects of weekend admission on long-term outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00701-016-2746-z) contains supplementary material, which is available to authorized users

First Light LBT AO Images of HR 8799 bcde at 1.65 and 3.3 Microns: New Discrepancies between Young Planets and Old Brown Dwarfs

As the only directly imaged multiple planet system, HR 8799 provides a unique opportunity to study the physical properties of several planets in parallel. In this paper, we image all four of the HR 8799 planets at H-band and 3.3 microns with the new LBT adaptive optics system, PISCES, and LBTI/LMIRCam. Our images offer an unprecedented view of the system, allowing us to obtain H and 3.3$ micron photometry of the innermost planet (for the first time) and put strong upper-limits on the presence of a hypothetical fifth companion. We find that all four planets are unexpectedly bright at 3.3 microns compared to the equilibrium chemistry models used for field brown dwarfs, which predict that planets should be faint at 3.3 microns due to CH4 opacity. We attempt to model the planets with thick-cloudy, non-equilibrium chemistry atmospheres, but find that removing CH4 to fit the 3.3 micron photometry increases the predicted L' (3.8 microns) flux enough that it is inconsistent with observations. In an effort to fit the SED of the HR 8799 planets, we construct mixtures of cloudy atmospheres, which are intended to represent planets covered by clouds of varying opacity. In this scenario, regions with low opacity look hot and bright, while regions with high opacity look faint, similar to the patchy cloud structures on Jupiter and L/T transition brown-dwarfs. Our mixed cloud models reproduce all of the available data, but self-consistent models are still necessary to demonstrate their viability.Comment: Accepted to Ap

Impact of exposure measurement error in air pollution epidemiology: effect of error type in time-series studies

<p>Abstract</p> <p>Background</p> <p>Two distinctly different types of measurement error are Berkson and classical. Impacts of measurement error in epidemiologic studies of ambient air pollution are expected to depend on error type. We characterize measurement error due to instrument imprecision and spatial variability as multiplicative (i.e. additive on the log scale) and model it over a range of error types to assess impacts on risk ratio estimates both on a per measurement unit basis and on a per interquartile range (IQR) basis in a time-series study in Atlanta.</p> <p>Methods</p> <p>Daily measures of twelve ambient air pollutants were analyzed: NO₂, NO_x, O₃, SO₂, CO, PM₁₀mass, PM_2.5mass, and PM_2.5components sulfate, nitrate, ammonium, elemental carbon and organic carbon. Semivariogram analysis was applied to assess spatial variability. Error due to this spatial variability was added to a reference pollutant time-series on the log scale using Monte Carlo simulations. Each of these time-series was exponentiated and introduced to a Poisson generalized linear model of cardiovascular disease emergency department visits.</p> <p>Results</p> <p>Measurement error resulted in reduced statistical significance for the risk ratio estimates for all amounts (corresponding to different pollutants) and types of error. When modelled as classical-type error, risk ratios were attenuated, particularly for primary air pollutants, with average attenuation in risk ratios on a per unit of measurement basis ranging from 18% to 92% and on an IQR basis ranging from 18% to 86%. When modelled as Berkson-type error, risk ratios per unit of measurement were biased away from the null hypothesis by 2% to 31%, whereas risk ratios per IQR were attenuated (i.e. biased toward the null) by 5% to 34%. For CO modelled error amount, a range of error types were simulated and effects on risk ratio bias and significance were observed.</p> <p>Conclusions</p> <p>For multiplicative error, both the amount and type of measurement error impact health effect estimates in air pollution epidemiology. By modelling instrument imprecision and spatial variability as different error types, we estimate direction and magnitude of the effects of error over a range of error types.</p