The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension

Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

The Chiemgau Crater Strewn Field: Evidence of a Holocene Large Impact Event in Southeast Bavaria, Germany

The Chiemgau strewn field in the Alpine Foreland discovered in the early new millennium comprises more than 80 mostly rimmed craters in a roughly elliptically shaped area with axes of about 60 km and 30 km. The crater diameters range between a few meters and a few hundred meters. Geologically, the craters occur in Pleistocene moraine and fluvio-glacial sediments. The craters and surrounding areas so far investigated in more detail are featuring heavy deformations of the Quaternary cobbles and boulders, abundant fused rock material (impact melt rocks and various glasses), shock-metamorphic effects, and geophysical anomalies. The impact is substantiated by the abundant occurrence of metallic, glass and carbon spherules, accretionary lapilli, and of strange matter in the form of iron silicides like gupeiite and xifengite, and various carbides like, e.g., moissanite SiC. The hitherto established largest crater of the strewn field is Lake Tüttensee exhibiting an 8 m-height rim wall, a rim-to-rim diameter of about 600 m, a depth of roughly 30 m and an extensive ejecta blanket. Physical and archeological dating confine the impact event to have happened most probably between 1300 and 300 B.C. The impactor is suggested to have been a low-density disintegrated, loosely bound asteroid or a disintegrated comet in order to account for the extensive strewn field.Кратерное поле Чимгау в Альпийском предгорье обнаружено в начале нового тысячелетия; оно состоит из более чем 80 кратеров, рассеянных в области примерно эллиптической формы с осями около 30 и 60 км. Диаметр кратеров колеблется от нескольких метров до нескольких сот метров. Геологически кратеры образованы в плейстоценовых речных моренных ледниковых отложениях. Кратеры и детально исследованные прилегающие к ним районы демонстрируют признаки сильных ударных деформаций гальки и валунов четвертичного возраста, следы сильного плавления материала пород (расплав породы и различные остекленения), ударно-метаморфических эффектов и геофизических аномалий. Ударные воздействия подтверждаются обильным появлением металлических, остеклененных частиц и углерода, аккреционных лапиллий и странным материалом в форме силицидов железа, таких как gupeiite и xifengite, а также различных сплавов, например moissanite SiC. Крупнейшим образованием в кратером поле является озеро Тютензее с восьмиметровым краевым валом диаметром около 600 м, с глубиной воды около 30 м и обширными отложениями импактных выбросов. Физические и археологические свидетельства позволяют предположить наиболее вероятную датировку события между 1300 и 300 гг. до н.э. Принимая во внимание обширное поле разброса, можно предположить, что импактор был низкой плотности, возможно, рыхлосвязанный астероид или комета, подвергшиеся дефрагментации в процессе падения, учитывая обширное поле разброса

The Chiemgau Crater Strewn Field: Evidence of a Holocene Large Impact Event in Southeast Bavaria, Germany

The Chiemgau strewn field in the Alpine Foreland discovered in the early new millennium comprises more than 80 mostly rimmed craters in a roughly elliptically shaped area with axes of about 60 km and 30 km. The crater diameters range between a few meters and a few hundred meters. Geologically, the craters occur in Pleistocene moraine and fluvio-glacial sediments. The craters and surrounding areas so far investigated in more detail are featuring heavy deformations of the Quaternary cobbles and boulders, abundant fused rock material (impact melt rocks and various glasses), shock-metamorphic effects, and geophysical anomalies. The impact is substantiated by the abundant occurrence of metallic, glass and carbon spherules, accretionary lapilli, and of strange matter in the form of iron silicides like gupeiite and xifengite, and various carbides like, e.g., moissanite SiC. The hitherto established largest crater of the strewn field is Lake Tüttensee exhibiting an 8 m-height rim wall, a rim-to-rim diameter of about 600 m, a depth of roughly 30 m and an extensive ejecta blanket. Physical and archeological dating confine the impact event to have happened most probably between 1300 and 300 B.C. The impactor is suggested to have been a low-density disintegrated, loosely bound asteroid or a disintegrated comet in order to account for the extensive strewn field.Кратерное поле Чимгау в Альпийском предгорье обнаружено в начале нового тысячелетия; оно состоит из более чем 80 кратеров, рассеянных в области примерно эллиптической формы с осями около 30 и 60 км. Диаметр кратеров колеблется от нескольких метров до нескольких сот метров. Геологически кратеры образованы в плейстоценовых речных моренных ледниковых отложениях. Кратеры и детально исследованные прилегающие к ним районы демонстрируют признаки сильных ударных деформаций гальки и валунов четвертичного возраста, следы сильного плавления материала пород (расплав породы и различные остекленения), ударно-метаморфических эффектов и геофизических аномалий. Ударные воздействия подтверждаются обильным появлением металлических, остеклененных частиц и углерода, аккреционных лапиллий и странным материалом в форме силицидов железа, таких как gupeiite и xifengite, а также различных сплавов, например moissanite SiC. Крупнейшим образованием в кратером поле является озеро Тютензее с восьмиметровым краевым валом диаметром около 600 м, с глубиной воды около 30 м и обширными отложениями импактных выбросов. Физические и археологические свидетельства позволяют предположить наиболее вероятную датировку события между 1300 и 300 гг. до н.э. Принимая во внимание обширное поле разброса, можно предположить, что импактор был низкой плотности, возможно, рыхлосвязанный астероид или комета, подвергшиеся дефрагментации в процессе падения, учитывая обширное поле разброса