Functional differences between the susceptibility Z−2/C−106 and protective Z+2/T−106 promoter region polymorphisms of the aldose reductase gene may account for the association with diabetic microvascular complications

AbstractStudies have shown that polymorphisms located at positions −106 and approximately −2100 base pairs (5′ALR2) in the regulatory region of the aldose reductase gene are associated with susceptibility to microvascular complications in patients with diabetes. The aim was to investigate the functional roles of these susceptibility alleles using an in vitro gene reporter assay. Susceptibility, neutral and protective 5′ALR2/−106 alleles were transfected into HepG2 cells and exposed to excess d-glucose (d-glucose at final concentrations 14 or 28 mmol/l). Transcriptional activities were determined using a dual luciferase reporter gene assay. The “susceptibility alleles” Z−2 with C−106 had the highest transcriptional activity when compared with the “protective” combination of Z+2 with C−106 alleles (58.7±9.9 vs. 10.1±0.7; P<0.0001). Those constructs with either the Z or Z−2 in combination with the C−106 allele had significantly higher transcriptional activities when compared to those with the T−106 allele (Z/C−106, 37.4±5.4 vs. Z/T−106 7.7±1.6, P<0.003; Z−2/C−106, 58.7±9.9 vs. Z−2/T−106 10.9±0.6, P<0.0001). These results demonstrate that the Z−2/C−106 haplotype is associated with elevated transcriptional activity of the aldose reductase gene. This in turn may explain the role of these polymorphisms in the susceptibility to diabetic microvascular complications

Asymmetric Induction in Intramolecular [2 + 2]-Photocycloadditions of 1,3-Disubstituted Allenes with Enones and Enoates

Irradiation of optically active allenes (89-92% ee) appended to enones and enoates affords alkylidenecyclobutane photoadducts with high levels of asymmetric induction (83-100%) derived exclusively from the allene fragment. The substrates studied include allenes tethered to enones such as 1,3-cyclohexanedionea nd 1,3-cyclopentanedione, as well as allenes tethered to functionalized coumarins. The enantiomer ratios of the photoadducts were quantified by derivatization of the products as the corresponding Mosher MTPA esters and analysis by ^1H NMR spectroscopy. The exo-methylenecyclobutanes obtained upon irradiation of allene-mumarins are isolated as single olefin diastereomers. Irradiation of a coumarin tethered at C(5) with an optically active allene affords an alkynyl-substituted oxepane with complete asymmetric induction

Gender Specific Effects of Mood on Alcohol Seeking Behaviors: Preliminary Findings using Intravenous Alcohol Self-Administration

Background Although negative mood has long been implicated in differences in alcohol seeking by men and women, little research has used precise, well-controlled laboratory experiments to examine how negative mood affects alcohol-seeking behaviors. Methods A total of 34 (19 women) community-dwelling, alcohol-using adults aged 21 to 32 (mean age = 24.86, SD = 3.40, 74.3% Caucasian; Alcohol Use Disorders Identification Test [AUDIT] = 10.1, SD = 3.4) completed 2 counterbalanced intravenous alcohol self-administration sessions: one under negative mood and one under neutral mood. Fourteen individuals (9 women; mean age = 25.00, SD = 2.77) participated in an alcohol “liking” experiment (i.e., free access [FA] drinking) and 20 individuals (10 women; mean age = 24.77, SD = 3.73) participated in an alcohol “wanting” experiment, in which gaining access to alcohol required progressively effortful work. There was no significant difference between men and women on the AUDIT, t(32) = −0.38, p = 0.71. Results Priming with negative mood induction caused a significant decrease in self-reported mood (mean change = −1.85, t(32) = −6.81, p < 0.001), as intended. In FA, negative mood was associated with a significantly increased peak breath alcohol concentration (BrAC; F = 9.41, p = 0.01), with a trend toward a greater effect in men than in women (F = 2.67, p = 0.13). Negative mood also had a significant effect on peak BrAC achieved in the progressive work paradigm (F = 5.28, p = 0.04), with a significantly stronger effect in men (F = 5.35, p = 0.03) than women; men also trended toward more consistent work for alcohol across both neutral and negative sessions. Conclusions These preliminary findings demonstrate a gender-specific response on how mood affects alcohol seeking and suggest gender-specific interventions to prevent mood-based alcohol consumption

The beta Pictoris association: Catalog of photometric rotational periods of low-mass members and candidate members

We intended to compile the most complete catalog of bona fide members and candidate members of the beta Pictoris association, and to measure their rotation periods and basic properties from our own observations, public archives, and exploring the literature. We carried out a multi-observatories campaign to get our own photometric time series and collected all archived public photometric data time series for the stars in our catalog. Each time series was analyzed with the Lomb-Scargle and CLEAN periodograms to search for the stellar rotation periods. We complemented the measured rotational properties with detailed information on multiplicity, membership, and projected rotational velocity available in the literature and discussed star by star. We measured the rotation periods of 112 out of 117 among bona fide members and candidate members of the beta Pictoris association and, whenever possible, we also measured the luminosity, radius, and inclination of the stellar rotation axis. This represents to date the largest catalog of rotation periods of any young loose stellar association. We provided an extensive catalog of rotation periods together with other relevant basic properties useful to explore a number of open issues, such as the causes of spread of rotation periods among coeval stars, evolution of angular momentum, and lithium-rotation connection.Comment: Forthcoming article, Received: 20 June 2016 / Accepted: 09 September 2016; 40 pages, 2 figures. The online figures A1-A73 are available at CD

Circulating pre-treatment t-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy

Background: The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual. Materials and methods: We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy or in combination with chemotherapy. TCR repertoire metrics were correlated with clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression classifier by fitting all four TCR- repertoire metrics to the immune checkpoint inhibitor (ICI) CBR data. In the subsequent receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities, the best cut-off value was selected to maximise sensitivity to predict CBR to ICI. Results: We observed an association between reduced number of unique clones and CBR among patients treated with pembrolizumab monotherapy (cohort 1) [risk ratio = 2.86, 95% confidence interval (CI) 1.04-8.73, P = 0.039]. For patients treated with pembrolizumab plus chemotherapy (cohort 2), increased number of unique clones [hazard ratio (HR) = 2.96, 95% CI 1.28-6.88, P = 0.012] and Shannon diversity (HR = 2.73, 95% CI 1.08-6.87, P = 0.033), and reduced evenness (HR = 0.43, 95% CI 0.21-0.90, P = 0.025) and convergence (HR = 0.41, 95% CI 0.19-0.90, P = 0.027) were associated with improved PFS, while only an increased number of unique clones (HR = 4.62, 95% CI 1.52-14.02, P = 0.007) were associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of CBR (cohorts 1 and 2) and were strongly associated with PFS (cohort 1, HR = 0.38, 95% CI 0.19-0.78, P = 0.009) and OS (cohort 2, HR = 0.20, 95% CI 0.05-0.76, P \u3c 0.0001). Reduced TCR conversion was associated with increased frequency of irAEs needing systemic steroid treatment. Conclusion: Combined pre-treatment circulating TCR metrics might serve as a predictive biomarker for clinical outcomes among patients with advanced non-small-cell lung cancer treated with pembrolizumab alone or in combination with chemotherapy

Characterizing HR3549B using SPHERE

Aims. In this work, we characterize the low mass companion of the A0 field star HR3549. Methods. We observed HR3549AB in imaging mode with the the NIR branch (IFS and IRDIS) of SPHERE@VLT, with IFS in YJ mode and IRDIS in the H band. We also acquired a medium resolution spectrum with the IRDIS long slit spectroscopy mode. The data were reduced using the dedicated SPHERE GTO pipeline, purposely designed for this instrument. We employed algorithms such as PCA and TLOCI to reduce the speckle noise. Results. The companion was clearly visible both with IRDIS and IFS.We obtained photometry in four different bands as well as the astrometric position for the companion. Based on our astrometry, we confirm that it is a bound object and put constraints on its orbit. Although several uncertainties are still present, we estimate an age of ~100-150 Myr for this system, yielding a most probable mass for the companion of 40-50MJup and T_eff ~300-2400 K. Comparing with template spectra points to a spectral type between M9 and L0 for the companion, commensurate with its position on the color-magnitude diagram.Comment: Accepted by A&A, 13 pages, 10 Figures (Figures 9 and 10 degraded to reduce the dimension

The rotation - Lithium depletion correlation in the beta Pictoris association and LDB age determination

There is evidence in the 125-Myr Pleiades cluster, and more recently in the 5-Myr NGC 2264 cluster, that rotation plays a key role in the Lithium (Li) depletion processes among low-mass stars. Fast rotators appear to be less Li-depleted than equal-mass slow rotators. We intend to explore the existence of a Li depletion - rotation connection among the beta Pictoris members at an age of about 24 Myr, and to use such correlation either to confirm or to improve the age estimate based on the Lithium Depletion Boundary (LDB) modeling. We have photometrically monitored all the known members of the beta Pictoris association with at least one Lithium equivalent width (Li EW) measurement from the literature. We measured the rotation periods of 30 members for the first time and retrieved from the literature the rotation periods for other 36 members, building a catalogue of 66 members with measured rotation period and Li EW. We find that in the 0.3 < M < 0.8 Msun range, there is a strong correlation between rotation and Li EW. For higher mass stars, no significant correlation is found. For very low mass stars in the Li depletion onset, at about 0.1 Msun, data are too few to infer a significant correlation. The observed Li EWs are compared with those predicted by the Dartmouth stellar evolutionary models that incorporate the effects of magnetic fields. After decorrelating the Li EW from the rotation period, we find that the hot side of the LDB is fitted well by Li EW values corresponding to an age of 25±3 Myr in good agreement with independent estimates from the literature.Fil: Messina, S.. Catania Astrophysical Observatory; ItaliaFil: Lanzafame, A. C.. Catania Astrophysical Observatory; ItaliaFil: Feiden, G. A.. Uppsala University; SueciaFil: Millward, M.. York Creek Observatory; AustraliaFil: Desidera, S.. Osservatorio Astronomico Di Padova; ItaliaFil: Buccino, Andrea Paola. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Curtis, I.. Minor Planet Center; AustraliaFil: Jofre, Jorge Emiliano. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Departamento de Astrofísica Estelar; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kehusmaa, P.. Harlingten Atacama Observatory; ChileFil: Medhi, B. J.. Aryabhatta Research Institute Of Observational Sciences; IndiaFil: Monard, B.. Klein Karoo Observatory; SudáfricaFil: Petrucci, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Departamento de Astrofísica Estelar; Argentin