Search for non-pointing photons in the diphoton and ETmiss final state in sqrt(s) = 7 TeV proton-proton collisions using the ATLAS detector

A search has been performed for photons originating in the decay of a neutral long-lived particle, exploiting the capabilities of the ATLAS electromagnetic calorimeter to make precise measurements of the flight direction of photons, as well as the calorimeter's excellent time resolution. The search has been made in the diphoton plus missing transverse energy final state, using the full data sample of 4.8 fb(-1) of 7 TeV proton-proton collisions collected in 2011 with the ATLAS detector at the LHC. No excess is observed above the background expected from Standard Model processes. The results are used to set exclusion limits in the context of gauge mediated supersymmetry breaking models, with the lightest neutralino being the next-to-lightest supersymmetric particle and decaying with a lifetime in excess of 0.25 ns into a photon and a gravitino.

Search for pair production of heavy top-like quarks decaying to a high-pT W boson and a b quark in the lepton plus jets final state at sqrts=7 TeV with the ATLAS detector

A search is presented for production of a heavy up-type quark (t') together with its antiparticle, assuming a significant branching ratio for subsequent decay into a W boson and a b quark. The search is based on 4.7 fb(-1) of pp collisions root s = 7 TeV recorded in 2011 with the ATLAS detector at the CERN Large Hadron Collider. Data are analyzed in the lepton + jets final state, characterized by a high-transverse-momentum isolated electron or muon, large missing transverse momentum and at least three jets. The analysis strategy relies on the substantial boost of the W bosons in the t'(t') over bar signal when m(t') greater than or similar to 400 GeV. No significant excess of events above the Standard Model expectation is observed and the result of the search is interpreted in the context of fourth-generation and vector-like quark models. Under the assumption of a branching ratio BR(t' -> W b) = I, a fourth-generation t' quark with mass lower than 656 GeV is excluded at 95% confidence level. In addition, in light of the recent discovery of a new boson of mass similar to 126 GeV at the LHC, upper limits are derived in the two-dimensional plane of BR(t' -> Wb) versus BR(t' -> Ht), where H is the Standard Model Higgs boson, for vector-like quarks of various masses.

ANALYTICAL MODELS OF EXOPLANETARY ATMOSPHERES. I. ATMOSPHERIC DYNAMICS VIA THE SHALLOW WATER SYSTEM

Within the context of exoplanetary atmospheres, we present a comprehensive linear analysis of forced, damped, magnetized shallow water systems, exploring the effects of dimensionality, geometry (Cartesian, pseudo-spherical, and spherical), rotation, magnetic tension, and hydrodynamic and magnetic sources of friction. Across a broad range of conditions, we find that the key governing equation for atmospheres and quantum harmonic oscillators are identical, even when forcing (stellar irradiation), sources of friction (molecular viscosity, Rayleigh drag, and magnetic drag), and magnetic tension are included. The global atmospheric structure is largely controlled by a single key parameter that involves the Rossby and Prandtl numbers. This near-universality breaks down when either molecular viscosity or magnetic drag acts non-uniformly across latitude or a poloidal magnetic field is present, suggesting that these effects will introduce qualitative changes to the familiar chevron-shaped feature witnessed in simulations of atmospheric circulation. We also find that hydrodynamic and magnetic sources of friction have dissimilar phase signatures and affect the flow in fundamentally different ways, implying that using Rayleigh drag to mimic magnetic drag is inaccurate. We exhaustively lay down the theoretical formalism (dispersion relations, governing equations, and time-dependent wave solutions) for a broad suite of models. In all situations, we derive the steady state of an atmosphere, which is relevant to interpreting infrared phase and eclipse maps of exoplanetary atmospheres. We elucidate a pinching effect that confines the atmospheric structure to be near the equator. Our suite of analytical models may be used to develop decisively physical intuition and as a reference point for three-dimensional magnetohydrodynamic simulations of atmospheric circulation.

Remote Effects Modulating the Spin Equilibrium of the Resting State of Cytochrome P450cam –An Investigation Using Active Site Analogues

The crystal structure of the resting state of cytochrome P450cam (CYP101), a heme thiolate protein, shows a cluster of six water molecules in the substrate binding pocket, one of which is coordinating to iron(III) as sixth ligand. The resting state is low-spin and changes to high-spin when substrate camphor binds and H2O is removed. In contrast to the protein, previously synthesised enzyme models such as H2O[BOND]FeIII(porph)(ArS−) were shown to be purely high-spin. Iron(S−)porphyrins with different distal sites mimicking proposed remote effects have been prepared and studied by cw-EPR. The results indicate that the low-spin of the resting state of P450cam is due to the fact that the water molecule coordinating to iron has an OH−-like character because of hydrogen bonding and polarisation of the water cluster, respectively.

Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling.

Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of infection occurs within minutes, rather than the hours required to induce "emergency granulopoiesis," the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88(-/-)TICAM1(-/-) mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host.

​Indole is an essential herbivore-induced volatile priming signal in maize

Herbivore-induced volatile organic compounds prime non-attacked plant tissues to respond more strongly to subsequent attacks. However, the key volatiles that trigger this primed state remain largely unidentified. In maize, the release of the aromatic compound ​indole is herbivore-specific and occurs earlier than other induced responses. We therefore hypothesized that ​indole may be involved in airborne priming. Using ​indole-deficient mutants and synthetic indole dispensers, we show that herbivore-induced ​indole enhances the induction of defensive volatiles in neighbouring maize plants in a species-specific manner. Furthermore, the release of ​indole is essential for priming of mono- and homoterpenes in systemic leaves of attacked plants. ​Indole exposure markedly increases the herbivore-induced production of the stress hormones ​jasmonate-isoleucine conjugate and ​abscisic acid, which represents a likely mechanism for ​indole-dependent priming. These results demonstrate that ​indole functions as a rapid and potent aerial priming agent that prepares systemic tissues and neighbouring plants for incoming attacks.

State of the art: Reproduction and pregnancy in rheumatic diseases

Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their children's birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes.

Postnatal Notch1 activation induces T‑cell malignancy in conditional and inducible mouse models

The Notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of Notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEG‑IC‑Notch1 transgenic mice that have a floxed β‑geo/stop signal between a CMV promoter and intracellular domain of Notch1 (IC‑Notch1). Constitutively active IC‑Notch1 is silent until the introduction of Cre recombinase. In this study, endothelial/hematopoietic specific expression of IC‑Notch1 in double transgenic ZEG‑IC‑Notch1/Tie2‑Cre embryos induced embryonic lethality at E9.5 with defects in vascular system but not in hematopoietic system. Inducible IC‑Notch1 expression in adult mice was achieved by using tetracycline regulated Cre system. The ZEG‑IC‑Notch1/Tie2‑tTA/tet‑O‑Cre triple transgenic mice survived embryonic development when maintained on tetracycline. Post‑natal withdrawal of tetracycline induced expression of IC‑Notch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive T‑cell infiltration in multiple organs and T‑cell malignancy of lymph nodes. In addition, the protein levels of p53 and alternative reading frame (ARF) were decreased in lymphoma‑like neoplasms from the triple transgenic mice while their mRNA expression remained unchanged, suggesting that IC‑Notch1 might repress ARF‑p53 pathway by a post‑transcriptional mechanism. This study demonstrated that activation of constitutive Notch1 signaling after embryonic development alters adult hematopoiesis and induces T‑cell malignancy.

Body composition and all-cause mortality in subjects older than 65 y.

BACKGROUND A low or high body mass index (BMI) has been associated with increased mortality risk in older subjects without taking fat mass index (FMI) and fat-free mass index (FFMI) into account. This information is essential because FMI is modulated through different healthcare strategies than is FFMI. OBJECTIVE We aimed to determine the relation between body composition and mortality in older subjects. DESIGN We included all adults ≥65 y old who were living in Switzerland and had a body-composition measurement by bioelectrical impedance analysis at the Geneva University Hospitals between 1990 and 2011. FMI and FFMI were divided into sex-specific quartiles. Quartile 1 (i.e., the reference category) corresponded to the lowest FMI or FFMI quartile. Mortality data were retrieved from the hospital database, the Geneva death register, and the Swiss National Cohort until December 2012. Comorbidities were assessed by using the Cumulative Illness Rating Scale. RESULTS Of 3181 subjects included, 766 women and 1007 men died at a mean age of 82.8 and 78.5 y, respectively. Sex-specific Cox regression models, which were used to adjust for age, BMI, smoking, ambulatory or hospitalized state, and calendar time, showed that body composition did not predict mortality in women irrespective of whether comorbidities were taken into account. In men, risk of mortality was lower with FFMI in quartiles 3 and 4 [HR: 0.78 (95% CI: 0.62, 0.98) and 0.64 (95% CI: 0.49, 0.85), respectively] but was not affected by FMI. When comorbidities were adjusted for, FFMI in quartile 4 (>19.5 kg/m(2)) still predicted a lower risk of mortality (HR: 0.72; 95% CI: 0.54, 0.96). CONCLUSIONS Low FFMI is a stronger predictor of mortality than is BMI in older men but not older women. FMI had no impact on mortality. These results suggest potential benefits of preventive interventions with the aim of maintaining muscle mass in older men. This trial was registered at clinicaltrials.gov as NCT01472679.

Search for nonpointing and delayed photons in the diphoton and missing transverse momentum final state in 8 TeV pp collisions at the LHC using the ATLAS detector

A search has been performed, using the full 20.3  fb −1 data sample of 8 TeV proton-proton collisions collected in 2012 with the ATLAS detector at the LHC, for photons originating from a displaced vertex due to the decay of a neutral long-lived particle into a photon and an invisible particle. The analysis investigates the diphoton plus missing transverse momentum final state, and is therefore most sensitive to pair production of long-lived particles. The analysis technique exploits the capabilities of the ATLAS electromagnetic calorimeter to make precise measurements of the flight direction, as well as the time of flight, of photons. No excess is observed over the Standard Model predictions for background. Exclusion limits are set within the context of gauge mediated supersymmetry breaking models, with the lightest neutralino being the next-to-lightest supersymmetric particle and decaying into a photon and gravitino with a lifetime in the range from 250 ps to about 100 ns.

Self-assembly into nanoparticles is essential for receptor mediated uptake of therapeutic antisense oligonucleotides

Antisense oligonucleotides (ASOs) have the potential of revolutionizing medicine due to their ability to manipulate gene function for therapeutic purposes. ASOs are chemically modified and/or incorporated with nanoparticles to enhance their stability and cellular uptake; however, one of the biggest challenges is the poor understanding of their uptake mechanism, which is needed for designing better ASOs with high activity and low toxicity. Here, we study the uptake mechanism of three therapeutically relevant ASOs (peptide-conjugated phosphorodiamidate morpholino (P-PMO), 2?Omethyl phosphorothioate (2?OMe) and phosphorothioated tricyclo DNA (tcDNA) that have been optimized to induce exon skipping in models of Deuchenne muscular dystrophy (DMD). We show that P-PMO and tcDNA have high propensity to spontaneously self-assemble into nanoparticles. P-PMO forms micelles of defined size and their net charge (zeta potential) is dependent on the medium and concentration. In biomimetic conditions and at low concentrations P-PMO obtains net negative charge and its uptake is mediated by class A scavenger receptor subtypes (SCARAs) as shown by competitive inhibition and RNAi silencing experiments in-vitro. In-vivo, the activity of P-PMO was significantly decreased in SCARA1 knock-out mice compared to wild-type animals. Additionally, we show that SCARA1 is involved in the uptake of tcDNA and 2?OMe as shown by competitive inhibition and co-localization experiments. Surface plasmon resonance binding analysis to SCARA1 demonstrated that P-PMO and tcDNA have higher binding profiles to the receptor compared to 2?OMe. These results demonstrate receptor-mediated uptake for a range of ASO chemistries, a mechanism that is dependent on their self-assembly into nanoparticles.

The new final Clinical Skills examination in human medicine in Switzerland: Essential steps of exam development, implementation and evaluation, and central insights from the perspective of the national Working Group

Objective: Since 2011, the new national final examination in human medicine has been implemented in Switzerland, with a structured clinical-practical part in the OSCE format. From the perspective of the national Working Group, the current article describes the essential steps in the development, implementation and evaluation of the Federal Licensing Examination Clinical Skills (FLE CS) as well as the applied quality assurance measures. Finally, central insights gained from the last years are presented. Methods: Based on the principles of action research, the FLE CS is in a constant state of further development. On the foundation of systematically documented experiences from previous years, in the Working Group, unresolved questions are discussed and resulting solution approaches are substantiated (planning), implemented in the examination (implementation) and subsequently evaluated (reflection). The presented results are the product of this iterative procedure. Results: The FLE CS is created by experts from all faculties and subject areas in a multistage process. The examination is administered in German and French on a decentralised basis and consists of twelve interdisciplinary stations per candidate. As important quality assurance measures, the national Review Board (content validation) and the meetings of the standardised patient trainers (standardisation) have proven worthwhile. The statistical analyses show good measurement reliability and support the construct validity of the examination. Among the central insights of the past years, it has been established that the consistent implementation of the principles of action research contributes to the successful further development of the examination. Conclusion: The centrally coordinated, collaborative-iterative process, incorporating experts from all faculties, makes a fundamental contribution to the quality of the FLE CS. The processes and insights presented here can be useful for others planning a similar undertaking. Keywords: national final examination, licensing examination, summative assessment, OSCE, action research

Choosing the path of austerity: how parties and policy coalitions influence welfare state retrenchment in periods of fiscal consolidation

What are the conditions under which some austerity programmes rely on substantial cuts to social spending? More specifically, do the partisan complexion and the type of government condition the extent to which austerity policies imply welfare state retrenchment? This article demonstrates that large budget consolidations tend to be associated with welfare state retrenchment. The findings support a partisan and a politico-institutionalist argument: (i) in periods of fiscal consolidation, welfare state retrenchment tends to be more pronounced under left-wing governments; (ii) since welfare state retrenchment is electorally and politically risky, it also tends to be more pronounced when pursued by a broad pro-reform coalition government. Therefore, the article shows that during budget consolidations implemented by left-wing broad coalition governments, welfare state retrenchment is greatest. Using long-run multipliers from autoregressive distributed lag models on 17 OECD countries during the 1982–2009 period, substantial support is found for these expectations.

Replications of fundamental research models in ultra high dilutions 1994 and 2015 - update on a bibliometric study

INTRODUCTION This paper focuses exclusively on experimental models with ultra high dilutions (i.e. beyond 10(-23)) that have been submitted to replication scrutiny. It updates previous surveys, considers suggestions made by the research community and compares the state of replication in 1994 with that in 2015. METHODS Following literature research, biochemical, immunological, botanical, cell biological and zoological studies on ultra high dilutions (potencies) were included. Reports were grouped into initial studies, laboratory-internal, multicentre and external replications. Repetition could yield either comparable, or zero, or opposite results. The null-hypothesis was that test and control groups would not be distinguishable (zero effect). RESULTS A total of 126 studies were found. From these, 28 were initial studies. When all 98 replicative studies were considered, 70.4% (i.e. 69) reported a result comparable to that of the initial study, 20.4% (20) zero effect and 9.2% (9) an opposite result. Both for the studies until 1994 and the studies 1995-2015 the null-hypothesis (dominance of zero results) should be rejected. Furthermore, the odds of finding a comparable result are generally higher than of finding an opposite result. Although this is true for all three types of replication studies, the fraction of comparable studies diminishes from laboratory-internal (total 82.9%) to multicentre (total 75%) to external (total 48.3%), while the fraction of opposite results was 4.9%, 10.7% and 13.8%. Furthermore, it became obvious that the probability of an external replication producing comparable results is bigger for models that had already been further scrutinized by the initial researchers. CONCLUSIONS We found 28 experimental models which underwent replication. In total, 24 models were replicated with comparable results, 12 models with zero effect, and 6 models with opposite results. Five models were externally reproduced with comparable results. We encourage further replications of studies in order to learn more about the model systems used.

Global Optimization with Sparse and Local Gaussian Process Models

We present a novel surrogate model-based global optimization framework allowing a large number of function evaluations. The method, called SpLEGO, is based on a multi-scale expected improvement (EI) framework relying on both sparse and local Gaussian process (GP) models. First, a bi-objective approach relying on a global sparse GP model is used to determine potential next sampling regions. Local GP models are then constructed within each selected region. The method subsequently employs the standard expected improvement criterion to deal with the exploration-exploitation trade-off within selected local models, leading to a decision on where to perform the next function evaluation(s). The potential of our approach is demonstrated using the so-called Sparse Pseudo-input GP as a global model. The algorithm is tested on four benchmark problems, whose number of starting points ranges from 102 to 104. Our results show that SpLEGO is effective and capable of solving problems with large number of starting points, and it even provides significant advantages when compared with state-of-the-art EI algorithms.