High-resolution optical spectroscopy of V838 Monocerotis in 2009

V838 Mon erupted at the beginning of 2002. In the course of the outburst the object evolved to low effective temperatures and declined as a very late M-type supergiant. Among various scenarios proposed to explain the nature of the outburst, the most promising is a stellar merger event. We aim at studying the structure and evolution of the object in the decline from the 2002 eruption. We obtained spectroscopic observations of V838 Mon in January--March 2009 with UVES/VLT. The results are analysed and compared with similar observations obtained in October 2005 with HIRES/Keck. The most striking difference between 2009 and 2005 is a complete absence of the B3V component and of the [FeII] emission lines in 2009. The present spectrum displays only the spectrum of the 2002 eruption remnant. It resembles that of an M6 giant, although the molecular bands in V838 Mon are deeper than those in standard stellar spectra of a similar spectral class. Several atomic lines, which displayed P-Cyg profiles in 2005, are now dominated by pure absorptions. Some of these lines, however, show a narrow emission component, which, as we argue, measures the radial velocity of V838 Mon. The resulting heliocentric velocity is 71 km/s, which very well agrees with the velocity obtained from SiO maser observations. The atomic lines and the molecular bands show very complex kinematics. In some atomic lines and high-excitation molecular bands we observe matter infalling in the object atmosphere. The infall components were already observed in 2005, but were less pronounced and present in fewer lines than in 2009. We argue that the most negative radial velocity components seen in the resonance atomic lines and in the low-excitation molecular bands were formed in the ejecta of the 2002 eruption. The B3V companion most probably became engulfed in an opaque dusty matter of the 2002 V838 Mon ejecta.Comment: A&A, in pres

Observations of V838 Mon in the CO rotational lines

We investigate the structure of a field around the position of V838 Mon as seen in the lowest CO rotational transitions. We also measure and analyse emission in the same lines at the position of V838 Mon.Observations have primarily been done in the CO J = 2-1 and J = 3-2 lines using the KOSMA telescope. A field of 3.4 squared degrees has been mapped in the on-the-fly mode in these transitions. Longer integration spectra in the on-off mode have been obtained to study the emission at the position of V838 Mon. Selected positions in the field have also been observed in the CO J = 1-0 transition using the Delingha telescope.In the observed field we have identified many molecular clouds. They can be divided into two groups from the point of view of their observed radial velocities. One, having V(LSR) in the range 18-32 km/s, can be identified with the Perseus Galactic arm. The other one, having V(LSR) between 44-57 km/s, probably belongs to the Norma-Cygnus arm. The radial velocity of V838 Mon is within the second range but the object does not seem to be related to any of the observed clouds. We did not find any molecular buble of a 1 degree dimension around the position of V838 Mon claimed in van Loon et al. An emission has been detected at the position of the object in the CO J = 2-1 and J = 3-2 transitions. The emission is very narrow (FWHM ~ 1.2 km/s) and at V(LSR) = 53.3 km/s. Our analysis of the data suggests that the emission is probably extended.Comment: paper accepted in A&

Harnessing the epigenome to boost immunotherapy response in non-small cell lung cancer patients

The introduction of immune checkpoint inhibitor (ICI)-based therapy for non-oncogene addicted non-small cell lung cancer (NSCLC) has significantly transformed the treatment landscape of the disease. Inhibitors of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint axis, which were initially considered as a late-line treatment option, gradually became the standard of care as first-line treatment for subgroups of NSCLC patients. However, a significant fraction of patients either fails to respond or progresses after a partial response to ICI treatment. Thus, the identification of mechanisms responsible for innate and acquired resistance to immunotherapy within a rapidly evolving tumor microenvironment (TME) is urgently required, as is the identification of reliable predictive biomarkers beyond PD-L1 expression. The deregulation of the epigenome is a key driver of cancer initiation and progression, and it has also been shown to drive therapeutic resistance. Tumor education of infiltrating myeloid cells towards an immuno-suppressive phenotype as well as induction of T-cell dysfunction in the TME is also driven by epigenome reprogramming. As it stands and, given their dynamic nature, epigenetic changes in cancer and non-cancer cells represent an attractive target to increase immunotherapy activity in NSCLC. Accordingly, clinical trials of combinatorial immuno-epigenetic drug regimens have been associated with tumor response in previously immunotherapy-resistant NSCLC patients irrespective of their PD-L1 status. Moreover, epigenetic signatures might represent valuable theragnostic biomarkers as they can be assayed easily in liquid biopsy and provide multiple layers of information. In this review, we discuss the current knowledge regarding the dysregulated epigenetic mechanisms contributing to immunotherapy resistance in NSCLC. Although the clinical data are still maturing, we highlight the attractive perspective that the synergistic model of immuno-epigenetic strategies might overcome the current limitations of immunotherapy alone and will be translated into durable clinical benefit for a broader NSCLC population

The importance of both setting and intensity of physical activity in relation to non-clinical anxiety and depression

Physical activity is associated with good physical and mental health. Current recommendations suggest that people should achieve 30 minutes of moderate-intensity activity most days of the week to gain health benefits. This activity may be accumulated in leisure time, in active commuting, at work or in the home. Here we look at the cross-sectional relationship between physical activity and mental health as measured by the HADS anxiety and depression scores in a sample of 1,742 participants from a Scottish general population survey. The participants were men and women in three age cohorts aged around 24, 44 and 64 years who, in 1995, were interviewed face to face and also self-completed the HADS depression and anxiety scale. Respondents reported their levels of physical activity at work, in the home and in leisure time; the intensities of activity were also determined. Physical activity was related to depression scores but not to anxiety scores. There was no relationship between work physical activity and depression score. Among women, depression score increased with each additional episode of vigorous home activity. In both sexes, depression score decreased with each additional episode of vigorous leisure activity, but among men the decrease in depression score with moderate leisure activity was reversed if a lot of moderate activity was undertaken. We have found a variable relationship between depression scores and various settings for physical activity. Researchers, policymakers and practitioners who are interested in the relationship between physical activity and mental health should take into account the setting for activity as well as frequency, duration and intensity of activity

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms

Inflationary Scenarios from Branes at Angles

We describe a simple mechanism that can lead to inflation within string-based brane-world scenarios. The idea is to start from a supersymmetric configuration with two parallel static Dp-branes, and slightly break the supersymmetry conditions to produce a very flat potential for the field that parametrises the distance between the branes, i.e. the inflaton field. This breaking can be achieved in various ways: by slight relative rotations of the branes with small angles, by considering small relative velocities between the branes, etc. If the breaking parameter is sufficiently small, a large number of e-folds can be produced within the D-brane, for small changes of the configuration in the compactified directions. Such a process is local, i.e. it does not depend very strongly on the compactification space nor on the initial conditions. Moreover, the breaking induces a very small velocity and acceleration, which ensures very small slow-roll parameters and thus an almost scale invariant spectrum of metric fluctuations, responsible for the observed temperature anisotropies in the microwave background. Inflation ends as in hybrid inflation, triggered by the negative curvature of the string tachyon potential. In this paper we elaborate on one of the simplest examples: two almost parallel D4-branes in a flat compactified space.Comment: 29 pages, 9 eps figures, using JHEP3.cls, published in JHE

Special Lagrangian cones with higher genus links

For every odd natural number g=2d+1 we prove the existence of a countably infinite family of special Lagrangian cones in C^3 over a closed Riemann surface of genus g, using a geometric PDE gluing method.Comment: 48 page

Birthweight and risk markers for type 2 diabetes and cardiovascular disease in childhood: the Child Heart and Health Study in England (CHASE).

AIMS/HYPOTHESIS: Lower birthweight (a marker of fetal undernutrition) is associated with higher risks of type 2 diabetes and cardiovascular disease (CVD) and could explain ethnic differences in these diseases. We examined associations between birthweight and risk markers for diabetes and CVD in UK-resident white European, South Asian and black African-Caribbean children. METHODS: In a cross-sectional study of risk markers for diabetes and CVD in 9- to 10-year-old children of different ethnic origins, birthweight was obtained from health records and/or parental recall. Associations between birthweight and risk markers were estimated using multilevel linear regression to account for clustering in children from the same school. RESULTS: Key data were available for 3,744 (66%) singleton study participants. In analyses adjusted for age, sex and ethnicity, birthweight was inversely associated with serum urate and positively associated with systolic BP. After additional height adjustment, lower birthweight (per 100 g) was associated with higher serum urate (0.52%; 95% CI 0.38, 0.66), fasting serum insulin (0.41%; 95% CI 0.08, 0.74), HbA1c (0.04%; 95% CI 0.00, 0.08), plasma glucose (0.06%; 95% CI 0.02, 0.10) and serum triacylglycerol (0.30%; 95% CI 0.09, 0.51) but not with BP or blood cholesterol. Birthweight was lower among children of South Asian (231 g lower; 95% CI 183, 280) and black African-Caribbean origin (81 g lower; 95% CI 30, 132). However, adjustment for birthweight had no effect on ethnic differences in risk markers. CONCLUSIONS/INTERPRETATION: Birthweight was inversely associated with urate and with insulin and glycaemia after adjustment for current height. Lower birthweight does not appear to explain emerging ethnic difference in risk markers for diabetes