The merger that led to the formation of the Milky Way's inner stellar halo and thick disk

The assembly process of our Galaxy can be retrieved using the motions and chemistry of individual stars. Chemo-dynamical studies of the nearby halo have long hinted at the presence of multiple components such as streams, clumps, duality and correlations between the stars' chemical abundances and orbital parameters. More recently, the analysis of two large stellar surveys have revealed the presence of a well-populated chemical elemental abundance sequence, of two distinct sequences in the colour-magnitude diagram, and of a prominent slightly retrograde kinematic structure all in the nearby halo, which may trace an important accretion event experienced by the Galaxy. Here report an analysis of the kinematics, chemistry, age and spatial distribution of stars in a relatively large volume around the Sun that are mainly linked to two major Galactic components, the thick disk and the stellar halo. We demonstrate that the inner halo is dominated by debris from an object which at infall was slightly more massive than the Small Magellanic Cloud, and which we refer to as Gaia-Enceladus. The stars originating in Gaia-Enceladus cover nearly the full sky, their motions reveal the presence of streams and slightly retrograde and elongated trajectories. Hundreds of RR Lyrae stars and thirteen globular clusters following a consistent age-metallicity relation can be associated to Gaia-Enceladus on the basis of their orbits. With an estimated 4:1 mass-ratio, the merger with Gaia-Enceladus must have led to the dynamical heating of the precursor of the Galactic thick disk and therefore contributed to the formation of this component approximately 10 Gyr ago. These findings are in line with simulations of galaxy formation, which predict that the inner stellar halo should be dominated by debris from just a few massive progenitors.Comment: 19 pages, 8 figures. Published in Nature in the issue of Nov. 1st, 2018. This is the authors' version before final edit

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application

The role of noise and positive feedback in the onset of autosomal dominant diseases

<p>Abstract</p> <p>Background</p> <p>Autosomal dominant (AD) diseases result when a single mutant or non-functioning gene is present on an autosomal chromosome. These diseases often do not emerge at birth. There are presently two prevailing theories explaining the expression of AD diseases. One explanation originates from the Knudson two-hit theory of hereditary cancers, where loss of heterozygosity or occurrence of somatic mutations impairs the function of the wild-type copy. While these somatic second hits may be sufficient for stable disease states, it is often difficult to determine if their occurrence necessarily marks the initiation of disease progression. A more direct consequence of a heterozygous genetic background is haploinsufficiency, referring to a lack of sufficient gene function due to reduced wild-type gene copy number; however, haploinsufficiency can involve a variety of additional mechanisms, such as noise in gene expression or protein levels, injury and second hit mutations in other genes. In this study, we explore the possible contribution to the onset of autosomal dominant diseases from intrinsic factors, such as those determined by the structure of the molecular networks governing normal cellular physiology.</p> <p>Results</p> <p>First, simple models of single gene insufficiency using the positive feedback loops that may be derived from a three-component network were studied by computer simulation using Bionet software. The network structure is shown to affect the dynamics considerably; some networks are relatively stable even when large stochastic variations in are present, while others exhibit switch-like dynamics. In the latter cases, once the network switches over to the disease state it remains in that state permanently. Model pathways for two autosomal dominant diseases, AD polycystic kidney disease and mature onset diabetes of youth (MODY) were simulated and the results are compared to known disease characteristics.</p> <p>Conclusions</p> <p>By identifying the intrinsic mechanisms involved in the onset of AD diseases, it may be possible to better assess risk factors as well as lead to potential new drug targets. To illustrate the applicability of this study of pathway dynamics, we simulated the primary pathways involved in two autosomal dominant diseases, Polycystic Kidney Disease (PKD) and mature onset diabetes of youth (MODY). Simulations demonstrate that some of the primary disease characteristics are consistent with the positive feedback - stochastic variation theory presented here. This has implications for new drug targets to control these diseases by blocking the positive feedback loop in the relevant pathways.</p

Multijet production in neutral current deep inelastic scattering at HERA and determination of α_{s}

Multijet production rates in neutral current deep inelastic scattering have been measured in the range of exchanged boson virtualities 10 5 GeV and –1 < η_{LAB}^{jet} < 2.5. Next-to-leading-order QCD calculations describe the data well. The value of the strong coupling constant α_{s} (M_{z}), determined from the ratio of the trijet to dijet cross sections, is α_{s} (M_{z}) = 0.1179 ± 0.0013 (stat.)_{-0.0046}^{+0.0028}(exp.)_{-0.0046}^{+0.0028}(th.)

Assessing Syndromic Surveillance of Cardiovascular Outcomes from Emergency Department Chief Complaint Data in New York City

Prospective syndromic surveillance of emergency department visits has been used for near-real time tracking of communicable diseases to detect outbreaks or other unexpected disease clusters. The utility of syndromic surveillance for tracking cardiovascular events, which may be influenced by environmental factors and influenza, has not been evaluated. We developed and evaluated a method for tracking cardiovascular events using emergency department free-text chief complaints.There were three phases to our analysis. First we applied text processing algorithms based on sensitivity, specificity, and positive predictive value to chief complaint data reported by 11 New York City emergency departments for which ICD-9 discharge diagnosis codes were available. Second, the same algorithms were applied to data reported by a larger sample of 50 New York City emergency departments for which discharge diagnosis was unavailable. From this more complete data, we evaluated the consistency of temporal variation of cardiovascular syndromic events and hospitalizations from 76 New York City hospitals. Finally, we examined associations between particulate matter ≤2.5 µm (PM(2.5)), syndromic events, and hospitalizations. Sensitivity and positive predictive value were low for syndromic events, while specificity was high. Utilizing the larger sample of emergency departments, a strong day of week pattern and weak seasonal trend were observed for syndromic events and hospitalizations. These time-series were highly correlated after removing the day-of-week, holiday, and seasonal trends. The estimated percent excess risks in the cold season (October to March) were 1.9% (95% confidence interval (CI): 0.6, 3.2), 2.1% (95% CI: 0.9, 3.3), and 1.8% (95%CI: 0.5, 3.0) per same-day 10 µg/m(3) increase in PM(2.5) for cardiac-only syndromic data, cardiovascular syndromic data, and hospitalizations, respectively.Near real-time emergency department chief complaint data may be useful for timely surveillance of cardiovascular morbidity related to ambient air pollution and other environmental events

Apparent temperature and acute myocardial infarction hospital admissions in Copenhagen, Denmark: a case-crossover study

<p>Abstract</p> <p>Background</p> <p>The influence of temperature on acute myocardial infarction (AMI) has not been investigated as extensively as the effects of broader outcomes of morbidity and mortality. Sixteen studies reported inconsistent results and two considered confounding by air pollution. We addressed some of the methodological limitations of the previous studies in this study.</p> <p>Methods</p> <p>This is the first study of the association between the daily 3-hour maximum apparent temperature (Tapp_max) and AMI hospital admissions in Copenhagen. The study period covered 1 January 1999-31 December 2006, stratified in warm (April - September) and cold (October - March) periods. A case-crossover epidemiology study design was applied. Models were adjusted for public holidays and influenza, confounding by PM₁₀, NO₂and CO was investigated, the lag and non-linear effects of Tapp_maxwas examined, effect modification by age, sex and SES was explored, and the results of the case-crossover models were compared to those of the generalised additive Poisson time-series and generalised estimating equation models.</p> <p>Results</p> <p>14 456 AMI hospital admissions (12 995 people) occurred during the study period. For an inter-quartile range (6 or 7°C) increase in the 5-day cumulative average of Tapp_max, a 4% (95% CI:-2%; 10%) and 9% (95% CI: 3%; 14%) decrease in the AMI admission rate was observed in the warm and cold periods, respectively. The 19-65 year old group, men and highest SES group seemed to be more susceptible in the cold period.</p> <p>Conclusion</p> <p>An increase in Tapp_maxis associated with a decrease in AMI admissions during the colder months.</p

Search for CP violation in D+→ϕπ+ and D+s→K0Sπ+ decays

A search for CP violation in D + → ϕπ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fb−1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (−0.04 ± 0.14 ± 0.14)% for candidates with K − K + mass within 20 MeV/c 2 of the ϕ meson mass. A search for a CP -violating asymmetry that varies across the ϕ mass region of the D + → K − K + π + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+s→K0Sπ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%

Acute effects of fine particulate air pollution on ST segment height: A longitudinal study

Background The mechanisms for the relationship between particulate air pollution and cardiac disease are not fully understood. Air pollution-induced myocardial ischemia is one of the potentially important mechanisms. Methods We investigate the acute effects and the time course of fine particulate pollution (PM2.5) on myocardium ischemic injury as assessed by ST-segment height in a community-based sample of 106 healthy non-smokers. Twenty-four hour beat-to-beat electrocardiogram (ECG) data were obtained using a high resolution 12-lead Holter ECG system. After visually identifying and removing all the artifacts and arrhythmic beats, we calculated beat-to-beat ST-height from ten leads (inferior leads II, III, and aVF; anterior leads V3 and V4; septal leads V1 and V2; lateral leads I, V5, and V6,). Individual-level 24-hour real-time PM2.5 concentration was obtained by a continuous personal PM2.5 monitor. We then calculated, on a 30-minute basis, the corresponding time-of-the-day specific average exposure to PM2.5 for each participant. Distributed lag models under a linear mixed-effects models framework were used to assess the regression coefficients between 30-minute PM2.5 and ST-height measures from each lead; i.e., one lag indicates a 30-minute separation between the exposure and outcome. Results The mean (SD) age was 56 (7.6) years, with 41% male and 74% white. The mean (SD) PM2.5 exposure was 14 (22) μg/m3. All inferior leads (II, III, and aVF) and two out of three lateral leads (I and V6), showed a significant association between higher PM2.5 levels and higher ST-height. Most of the adverse effects occurred within two hours after PM2.5 exposure. The multivariable adjusted regression coefficients β (95% CI) of the cumulative effect due to a 10 μg/m3 increase in Lag 0-4 PM2.5 on ST-I, II, III, aVF and ST-V6 were 0.29 (0.01-0.56) μV, 0.79 (0.20-1.39) μV, 0.52 (0.01-1.05) μV, 0.65 (0.11-1.19) μV, and 0.58 (0.07-1.09) μV, respectively, with all p < 0.05. Conclusions Increased PM2.5 concentration is associated with immediate increase in ST-segment height in inferior and lateral leads, generally within two hours. Such an acute effect of PM2.5 may contribute to increased potential for regional myocardial ischemic injury among healthy individuals

Functional Conservation of the Drosophila gooseberry Gene and Its Evolutionary Alleles

The Drosophila Pax gene gooseberry (gsb) is required for development of the larval cuticle and CNS, survival to adulthood, and male fertility. These functions can be rescued in gsb mutants by two gsb evolutionary alleles, gsb-Prd and gsb-Pax3, which express the Drosophila Paired and mouse Pax3 proteins under the control of gooseberry cis-regulatory region. Therefore, both Paired and Pax3 proteins have conserved all the Gsb functions that are required for survival of embryos to fertile adults, despite the divergent primary sequences in their C-terminal halves. As gsb-Prd and gsb-Pax3 uncover a gsb function involved in male fertility, construction of evolutionary alleles may provide a powerful strategy to dissect hitherto unknown gene functions. Our results provide further evidence for the essential role of cis-regulatory regions in the functional diversification of duplicated genes during evolution