θ13\theta_{13}, δ\delta and the neutrino mass hierarchy at a γ=350\gamma=350 double baseline Li/B β\beta-Beam

We consider a $\beta$-Beam facility where $^8$Li and $^8$B ions are accelerated at $\gamma = 350$, accumulated in a 10 Km storage ring and let decay, so as to produce intense $\bar \nu_e$ and $\nu_e$ beams. These beams illuminate two iron detectors located at $L \simeq 2000$ Km and $L \simeq 7000$ Km, respectively. The physics potential of this setup is analysed in full detail as a function of the flux. We find that, for the highest flux ($10 \times 10^{18}$ ion decays per year per baseline), the sensitivity to $\theta_{13}$ reaches $\sin^2 2 \theta_{13} \geq 2 \times10^{-4}$; the sign of the atmospheric mass difference can be identified, regardless of the true hierarchy, for $\sin^2 2 \theta_{13} \geq 4\times10^{-4}$; and, CP-violation can be discovered in 70% of the $\delta$-parameter space for $\sin^2 2 \theta_{13} \geq 10^{-3}$, having some sensitivity to CP-violation down to $\sin^2 2 \theta_{13} \geq 10^{-4}$ for $|\delta| \sim 90^\circ$.Comment: 35 pages, 20 figures. Minor changes, matches the published versio

Quantum Fields in Hyperbolic Space-Times with Finite Spatial Volume

The one-loop effective action for a massive self-interacting scalar field is investigated in $4$-dimensional ultrastatic space-time $R \times H^3/\Gamma$, $H^3/\Gamma$ being a non-compact hyperbolic manifold with finite volume. Making use of the Selberg trace formula, the $\zeta$-function related to the small disturbance operator is constructed. For an arbitrary gravitational coupling, it is found that $\zeta(s)$ has a simple pole at $s=0$. The one-loop effective action is analysed by means of proper-time regularisations and the one-loop divergences are explicitly found. It is pointed out that, in this special case, also $\zeta$-function regularisation requires a divergent counterterm, which however is not necessary in the free massless conformal invariant coupling case. Finite temperature effects are studied and the high-temperature expansion is presented. A possible application to the problem of the divergences of the entanglement entropy for a free massless scalar field in a Rindler-like space-time is briefly discussed.Comment: 13 pages, LaTex. The contribution of hyperbolic elements has been added. Other minor corrections and reference

Boundary relations and generalized resolvents of symmetric operators

The Kre\u{\i}n-Naimark formula provides a parametrization of all selfadjoint exit space extensions of a, not necessarily densely defined, symmetric operator, in terms of maximal dissipative (in \dC_+) holomorphic linear relations on the parameter space (the so-called Nevanlinna families). The new notion of a boundary relation makes it possible to interpret these parameter families as Weyl families of boundary relations and to establish a simple coupling method to construct the generalized resolvents from the given parameter family. The general version of the coupling method is introduced and the role of boundary relations and their Weyl families for the Kre\u{\i}n-Naimark formula is investigated and explained.Comment: 47 page

Uncertainty estimation for operational ocean forecast products-a multi-model ensemble for the North Sea and the Baltic Sea

Multi-model ensembles for sea surface temperature (SST), sea surface salinity (SSS), sea surface currents (SSC), and water transports have been developed for the North Sea and the Baltic Sea using outputs from several operational ocean forecasting models provided by different institutes. The individual models differ in model code, resolution, boundary conditions, atmospheric forcing, and data assimilation. The ensembles are produced on a daily basis. Daily statistics are calculated for each parameter giving information about the spread of the forecasts with standard deviation, ensemble mean and median, and coefficient of variation. High forecast uncertainty, i.e., for SSS and SSC, was found in the Skagerrak, Kattegat (Transition Area between North Sea and Baltic Sea), and the Norwegian Channel. Based on the data collected, longer-term statistical analyses have been done, such as a comparison with satellite data for SST and evaluation of the deviation between forecasts in temporal and spatial scale. Regions of high forecast uncertainty for SSS and SSC have been detected in the Transition Area and the Norwegian Channel where a large spread between the models might evolve due to differences in simulating the frontal structures and their movements. A distinct seasonal pattern could be distinguished for SST with high uncertainty between the forecasts during summer. Forecasts with relatively high deviation from the multi-model ensemble (MME) products or the other individual forecasts were detected for each region and each parameter. The comparison with satellite data showed that the error of the MME products is lowest compared to those of the ensemble members

Hormonal Signal Amplification Mediates Environmental Conditions during Development and Controls an Irreversible Commitment to Adulthood

Many animals can choose between different developmental fates to maximize fitness. Despite the complexity of environmental cues and life history, different developmental fates are executed in a robust fashion. The nematode Caenorhabditis elegans serves as a powerful model to examine this phenomenon because it can adopt one of two developmental fates (adulthood or diapause) depending on environmental conditions. The steroid hormone dafachronic acid (DA) directs development to adulthood by regulating the transcriptional activity of the nuclear hormone receptor DAF-12. The known role of DA suggests that it may be the molecular mediator of environmental condition effects on the developmental fate decision, although the mechanism is yet unknown. We used a combination of physiological and molecular biology techniques to demonstrate that commitment to reproductive adult development occurs when DA levels, produced in the neuroendocrine XXX cells, exceed a threshold. Furthermore, imaging and cell ablation experiments demonstrate that the XXX cells act as a source of DA, which, upon commitment to adult development, is amplified and propagated in the epidermis in a DAF-12 dependent manner. This positive feedback loop increases DA levels and drives adult programs in the gonad and epidermis, thus conferring the irreversibility of the decision. We show that the positive feedback loop canalizes development by ensuring that sufficient amounts of DA are dispersed throughout the body and serves as a robust fate-locking mechanism to enforce an organism-wide binary decision, despite noisy and complex environmental cues. These mechanisms are not only relevant to C. elegans but may be extended to other hormonal-based decision-making mechanisms in insects and mammals

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features

Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi–like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi–like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi–like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers’ relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi–like features.Amélie Bonnefond, Anne Raimondo, Fanny Stutzmann, Maya Ghoussaini, Shwetha Ramachandrappa, David C. Bersten, Emmanuelle Durand, Vincent Vatin, Beverley Balkau, Olivier Lantieri, Violeta Raverdy, François Pattou, Wim Van Hul, Luc Van Gaal, Daniel J. Peet, Jacques Weill, Jennifer L. Miller, Fritz Horber, Anthony P. Goldstone, Daniel J. Driscoll, John B. Bruning, David Meyre, Murray L. Whitelaw and Philippe Frogue

Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.Shwetha Ramachandrappa, Anne Raimondo, Anna M.G. Cali, Julia M. Keough, Elana Henning, Sadia Saeed, Amanda Thompson, Sumedha Garg, Elena G. Bochukova, Soren Brage, Victoria Trowse, Eleanor Wheeler, Adrienne E. Sullivan, Mehul Dattani, Peter E. Clayton, Vippan Datta, John B. Bruning, Nick J. Wareham, Stephen O'Rahilly, Daniel J. Peet, Ines Barroso, Murray L. Whielaw and I. Sadaf Farooq

CMS distributed computing workflow experience

The vast majority of the CMS Computing capacity, which is organized in a tiered hierarchy, is located away from CERN. The 7 Tier-1 sites archive the LHC proton-proton collision data that is initially processed at CERN. These sites provide access to all recorded and simulated data for the Tier-2 sites, via wide-area network (WAN) transfers. All central data processing workflows are executed at the Tier-1 level, which contain re-reconstruction and skimming workflows of collision data as well as reprocessing of simulated data to adapt to changing detector conditions. This paper describes the operation of the CMS processing infrastructure at the Tier-1 level. The Tier-1 workflows are described in detail. The operational optimization of resource usage is described. In particular, the variation of different workflows during the data taking period of 2010, their efficiencies and latencies as well as their impact on the delivery of physics results is discussed and lessons are drawn from this experience. The simulation of proton-proton collisions for the CMS experiment is primarily carried out at the second tier of the CMS computing infrastructure. Half of the Tier-2 sites of CMS are reserved for central Monte Carlo (MC) production while the other half is available for user analysis. This paper summarizes the large throughput of the MC production operation during the data taking period of 2010 and discusses the latencies and efficiencies of the various types of MC production workflows. We present the operational procedures to optimize the usage of available resources and we the operational model of CMS for including opportunistic resources, such as the larger Tier-3 sites, into the central production operation