Introduction Deux polymorphismes identifiés par des études GWAS affectent le niveau de proinsuline à jeun (rs11603334) et la sécrétion d’insuline induite par le glucose (rs1552224). Ils sont ...localisés dans la région 5’non traduite (5-UTR) du gène ARAP1 . Un autre gène situé à proximité pourrait également être impliqué, STARD10 . Pour déterminer les mécanismes moléculaires impliqués, nous avons étudié les effets sur la sécrétion d’insuline de la modification de l’expression d’ Arap1 et StarD10 dans la cellule beta ainsi que l’effet des SNP sur l’expression. Matériels et méthodes L’expression d’ ARAP1 ou STARD10 a été inhibée par siRNA et les protéines surexprimées grâce à un plasmide. La sécrétion d’insuline a été mesurée par radioimmunodosage. La 5-UTR du transcrit court d’ ARAP1 a été clonée en amont de la séquence codant pour la luciférase. Les SNP ont été modifié par mutagenèse dirigée pour générer les constructions portant les variants à risque ou protecteurs. Résultats La surexpression de STARD10 dans les cellules MIN6 diminue la sécrétion d’insuline induite par le glucose (30 mM versus 3 mM) ou KCl (30 mM). La surexpression d’ ARAP1 n’a pas d’effet significatif sur la sécrétion d’insuline induite par le glucose ou KCl bien qu’on observe une tendance à la baisse. L’inhibition par siRNA n’a eu aucun effet sur la sécrétion d’insuline. Les variants protecteurs ont induit une baisse d’activité de la luciferase en comparaison avec les variants à risque après expression dans les cellules bêta humaines (EndoC-βH1) et murines (INS1 (832/13). L’analyse séparée des SNP montre que cet effet est observé seulement avec le SNP rs11603334. Conclusion Ces données suggèrent que STARD10 , impliqué dans le transfert de phospholipides entre les organelles intracellulaires, pourrait agir en aval de la métabolisation du glucose, au niveau du trafic et/ou de l’exocytose des granules d’insuline. Le SNP rs11603334 régulerait l’expression d’ ARAP1 (et potentiellement de STARD10 ), qui pourrait également jouer un rôle dans la sécrétion d’insuline.
► Animals tolerated a pCO2 up to 145Pa, their health status deteriorated at 284Pa. ► Exposure to elevated pCO2 reduced somatic and reproductive growth. ► N excretion increased, feeding rate decreased ...leading to a shift in energy budgets. ► First report of extracellular pH compensation by HCO3-accumulation in echinoderms. ► At high pCO2 71% of animals ceased feeding and revealed a strong metabolic acidosis.
Anthropogenic CO2 emission will lead to an increase in seawater pCO2 of up to 80–100Pa (800–1000μatm) within this century and to an acidification of the oceans. Green sea urchins (Strongylocentrotus droebachiensis) occurring in Kattegat experience seasonal hypercapnic and hypoxic conditions already today. Thus, anthropogenic CO2 emissions will add up to existing values and will lead to even higher pCO2 values >200Pa (>2000μatm). To estimate the green sea urchins’ potential to acclimate to acidified seawater, we calculated an energy budget and determined the extracellular acid base status of adult S. droebachiensis exposed to moderately (102–145Pa, 1007–1431μatm) and highly (284–385Pa, 2800–3800μatm) elevated seawater pCO2 for 10 and 45 days.
A 45-day exposure to elevated pCO2 resulted in a shift in energy budgets, leading to reduced somatic and reproductive growth. Metabolic rates were not significantly affected, but ammonium excretion increased in response to elevated pCO2. This led to decreased O:N ratios. These findings suggest that protein metabolism is possibly enhanced under elevated pCO2 in order to support ion homeostasis by increasing net acid extrusion. The perivisceral coelomic fluid acid–base status revealed that S. droebachiensis is able to fully (intermediate pCO2) or partially (high pCO2) compensate extracellular pH (pHe) changes by accumulation of bicarbonate (maximum increases 2.5mM), albeit at a slower rate than typically observed in other taxa (10-day duration for full pHe compensation). At intermediate pCO2, sea urchins were able to maintain fully compensated pHe for 45 days. Sea urchins from the higher pCO2 treatment could be divided into two groups following medium-term acclimation: one group of experimental animals (29%) contained remnants of food in their digestive system and maintained partially compensated pHe (+2.3mM HCO3−), while the other group (71%) exhibited an empty digestive system and a severe metabolic acidosis (−0.5 pH units, −2.4mM HCO3−). There was no difference in mortality between the three pCO2 treatments.
The results of this study suggest that S. droebachiensis occurring in the Kattegat might be pre-adapted to hypercapnia due to natural variability in pCO2 in its habitat. We show for the first time that some echinoderm species can actively compensate extracellular pH. Seawater pCO2 values of >200Pa, which will occur in the Kattegat within this century during seasonal hypoxic events, can possibly only be endured for a short time period of a few weeks. Increases in anthropogenic CO2 emissions and leakages from potential sub-seabed CO2 storage (CCS) sites thus impose a threat to the ecologically and economically important species S. droebachiensis.
Abaloparatide is a 34–amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal ...osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE.
Proportions of patients experiencing BMD gains from baseline of >0%, >3%, and >6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites.
At months 6, 12, and 18, there were significantly more >3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P < 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the >0% and >6% responder thresholds.
In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.
•Significantly more abaloparatide patients were all-site BMD responders versus placebo or teriparatide•At each individual anatomic site, there were significantly more abaloparatide BMD responders versus placebo•For TH, there were significantly more abaloparatide BMD responders for each threshold and timepoint versus teriparatide•For FN, at all timepoints, significantly more abaloparatide patients were >3% and >6% responders versus teriparatide•Results are consistent with the early nonvertebral fracture risk reduction with abaloparatide observed in ACTIVE
Two sets of V and Rc light curves of V789 Her and one complete set of BVRcIc light curves of V1007 Cas were observed and presented. By analyzing all these light curves together with the Sloan g′i′ ...light curves observed by Kjurkchieva et al., we determined that both systems are W-subtype contact binaries and that V789 Her is a medium contact system, while V1007 Cas is a shallow contact system. Because the two binaries show totally eclipsing primary minima, the photometric results are reliable. In addition, the light curves of the two systems are asymmetric, requiring a dark spot on the primary or the secondary component in the modeling. By compiling all available times of minimum light including literatures, SuperWASP archive and ours, we analyzed the orbital period variations. We derived that the O − C diagram of V789 Her displays a periodic oscillation whose period and amplitude are 29.2 years and 0.0179 days and the period of V1007 Cas exhibits a continuous decrease at dP/dt = −1.78( 0.09) × 10−7 days yr−1. The cyclic period modulation of V789 Her is probably attributed to the light travel time effect via a tertiary companion with very small mass. The continuous period decrease of V1007 Cas may result from the mass transfer between the two components. However, we cannot rule out the possibility of angular momentum loss because V1007 Cas shows strong magnetic activity. By analyzing the evolutionary status of the components of the two systems, we determined that they exhibit typical characteristics of other W-subtype contact binaries.
The statistical significance of a candidate gravitational-wave (GW) event is crucial to the prospects for a confirmed detection, or for its selection as a candidate for follow-up electromagnetic ...observation. To determine the significance of a GW candidate, a ranking statistic is evaluated and compared to an empirically-estimated background distribution, yielding a false alarm probability or p-value. The reliability of this background estimate is limited by the number of background samples and by the fact that GW detectors cannot be shielded from signals, making it impossible to identify a pure background data set. Different strategies have been proposed: in one method, all samples, including potential signals, are included in the background estimation, whereas in another method, coincidence removal is performed in order to exclude possible signals from the estimated background. Here we report on a mock data challenge, performed prior to the first detections of GW signals by Advanced LIGO, to compare these two methods. The all-samples method is found to be self-consistent in terms of the rate of false positive detection claims, but its p-value estimates are systematically conservative and subject to higher variance. Conversely, the coincidence-removal method yields a mean-unbiased estimate of the p-value but sacrifices self-consistency. We provide a simple formula for the uncertainty in estimate significance and compare it to mock data results. Finally, we discuss the use of different methods in claiming the detection of GW signals.
Lung cancer is the most common cancer in China. Previous studies have indicated that lung cancer incidence exhibits remarkable spatial heterogeneity, and lung cancer is related to outdoor air ...pollution. However, the non-linear spatial association between outdoor air pollution and lung cancer incidence in China remains unclear.
In this study, the relationships between the lung cancer incidence of males and females from 207 counties in China in 2013 with annual concentrations of PM2.5, PM10, SO
, NO
, CO and O
were analysed. GeoDetector q statistic was used for examining the non-linear spatial association between outdoor air pollution and incidence of lung cancer.
An apparent spatial and population gender heterogeneity was found in the spatial association between outdoor air pollution and lung cancer incidence. Among the six selected pollutants, SO
has the greatest influence on lung cancer (q = 0.154 in females) in north China. In the south, each selected pollutant has a significant impact on males or females, and the mean q value in the south is 0.181, which is bigger than that in the north (q = 0.154). In addition, the pollutants have evident non-linear interaction effects on lung cancer. In north China, the interaction between SO
and PM2.5 is the dominant interaction, with q values of 0.207 in males and 0.334 in females. In the south, the dominant interactive factors are between SO
and O
in males and between SO
and CO in females, with q values of 0.45, 0.232 respectively. Smoking is a substantial contributor to lung cancer among men, either in South or North China, with q value of 0.143 and 0.129 respectively, and the interaction between smoking and air pollutants increases this risk.
This study implies that the influence of SO
and PM2.5 on lung cancer should be focused on in north China, and in the south, the impact of O
and CO as well as their interaction with SO
need to be paid more attention. Smoking, particularly in men, remains a significant risk factor for lung cancer in both North and South China.
Abstract Objective To compare a shear bond strength test for resin composite cements developed in order to better consider the shrinkage stress (here termed “Swiss shear test”) with the shear test ...design according to ISO 29022. Method Four restorative materials (VITA Enamic (VE), VITA Suprinity (VS), Vitablocs Mark II (VM) and VITA YZ T (YZ)) served as substrate. VE, VS and VM were polished or etched. YZ was polished, sandblasted or etched. Specimens were either bonded according to the Swiss or the ISO shear test. RelyX Unicem 2 Automix, Maxcem Elite and PermaFlo DC were used as cements. Shear bond strength (SBS) was measured. Failure modes (adhesive, cohesive or mixed) were evaluated by means of SEM. Results Mean SBS values obtained with the Swiss shear test were significantly lower than those obtained with the ISO shear test. VE and VM exhibited similar SBS, values of VS were significantly higher. On etched surfaces VM and VE exhibited primarily cohesive failures, VS primarily adhesive failures. On polished substrates significantly lower bond strength values and exclusively adhesive failures were observed. YZ exhibited solely adhesive failures. Compared to polished YZ, SBS significantly increased after sandblasting and even more after etching. Only for adhesively failed specimens mean SBS values of Swiss and ISO shear test were strongly correlated. Significance Both test designs showed the same ranking of test results. When adhesive failure occurred test results were strongly correlated. When cohesive failure was involved, both test designs did not provide reliable results.
PDF
