Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

Adaptive Multilevel Subset Simulation with Selective Refinement

In this work we propose an adaptive multilevel version of subset simulation to estimate the probability of rare events for complex physical systems. Given a sequence of nested failure domains of increasing size, the rare event probability is expressed as a product of conditional probabilities. The proposed new estimator uses different model resolutions and varying numbers of samples across the hierarchy of nested failure sets. In order to dramatically reduce the computational cost, we construct the intermediate failure sets such that only a small number of expensive high-resolution model evaluations are needed, whilst the majority of samples can be taken from inexpensive low-resolution simulations. A key idea in our new estimator is the use of a posteriori error estimators combined with a selective mesh refinement strategy to guarantee the critical subset property that may be violated when changing model resolution from one failure set to the next. The efficiency gains and the statistical properties of the estimator are investigated both theoretically via shaking transformations, as well as numerically. On a model problem from subsurface flow, the new multilevel estimator achieves gains of more than a factor 60 over standard subset simulation for a practically relevant relative error of 25%

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV

Neutrinoless double beta decay in seesaw models

We study the general phenomenology of neutrinoless double beta decay in seesaw models. In particular, we focus on the dependence of the neutrinoless double beta decay rate on the mass of the extra states introduced to account for the Majorana masses of light neutrinos. For this purpose, we compute the nuclear matrix elements as functions of the mass of the mediating fermions and estimate the associated uncertainties. We then discuss what can be inferred on the seesaw model parameters in the different mass regimes and clarify how the contribution of the light neutrinos should always be taken into account when deriving bounds on the extra parameters. Conversely, the extra states can also have a significant impact, cancelling the Standard Model neutrino contribution for masses lighter than the nuclear scale and leading to vanishing neutrinoless double beta decay amplitudes even if neutrinos are Majorana particles. We also discuss how seesaw models could reconcile large rates of neutrinoless double beta decay with more stringent cosmological bounds on neutrino masses.Comment: 34 pages, 5 eps figures and 1 axodraw figure. Final version published in JHEP. NME results available in Appendi

Expansion of oxygen minimum zones may reduce available habitat for tropical pelagic fishes

Climate model predictions1, 2 and observations3, 4 reveal regional declines in oceanic dissolved oxygen, which are probably influenced by global warming5. Studies indicate ongoing dissolved oxygen depletion and vertical expansion of the oxygen minimum zone (OMZ) in the tropical northeast Atlantic Ocean6, 7. OMZ shoaling may restrict the usable habitat of billfishes and tunas to a narrow surface layer8, 9. We report a decrease in the upper ocean layer exceeding 3.5 ml l−1 dissolved oxygen at a rate of ≤1 m yr−1 in the tropical northeast Atlantic (0–25° N, 12–30° W), amounting to an annual habitat loss of ~5.95×1013 m3, or 15% for the period 1960–2010. Habitat compression and associated potential habitat loss was validated using electronic tagging data from 47 blue marlin. This phenomenon increases vulnerability to surface fishing gear for billfishes and tunas8, 9, and may be associated with a 10–50% worldwide decline of pelagic predator diversity10. Further expansion of the Atlantic OMZ along with overfishing may threaten the sustainability of these valuable pelagic fisheries and marine ecosystems

Plasma Levels of Middle Molecules to Estimate Residual Kidney Function in Haemodialysis without Urine Collection

© 2015 Vilar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/Licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BACKGROUND: Residual Kidney Function (RKF) is associated with survival benefits in haemodialysis (HD) but is difficult to measure without urine collection. Middle molecules such as Cystatin C and β2-microglobulin accumulate in renal disease and plasma levels have been used to estimate kidney function early in this condition. We investigated their use to estimate RKF in patients on HD. DESIGN: Cystatin C, β2-microglobulin, urea and creatinine levels were studied in patients on incremental high-flux HD or hemodiafiltration(HDF). Over sequential HD sessions, blood was sampled pre- and post-session 1 and pre-session 2, for estimation of these parameters. Urine was collected during the whole interdialytic interval, for estimation of residual GFR (GFRResidual = mean of urea and creatinine clearance). The relationships of plasma Cystatin C and β2-microglobulin levels to GFRResidual and urea clearance were determined. RESULTS: Of the 341 patients studied, 64% had urine output>100 ml/day, 32.6% were on high-flux HD and 67.4% on HDF. Parameters most closely correlated with GFRResidual were 1/β2-micoglobulin (r2 0.67) and 1/Cystatin C (r2 0.50). Both these relationships were weaker at low GFRResidual. The best regression model for GFRResidual, explaining 67% of the variation, was: GFRResidual = 160.3 · (1/β2m) - 4.2. Where β2m is the pre-dialysis β2 microglobulin concentration (mg/L). This model was validated in a separate cohort of 50 patients using Bland-Altman analysis. Areas under the curve in Receiver Operating Characteristic analysis aimed at identifying subjects with urea clearance≥2 ml/min/1.73 m2 was 0.91 for β2-microglobulin and 0.86 for Cystatin C. A plasma β2-microglobulin cut-off of ≤19.2 mg/L allowed identification of patients with urea clearance ≥2 ml/min/1.73 m2 with 90% specificity and 65% sensitivity. CONCLUSION: Plasma pre-dialysis β2-microglobulin levels can provide estimates of RKF which may have clinical utility and appear superior to cystatin C. Use of cut-off levels to identify patients with RKF may provide a simple way to individualise dialysis dose based on RKF.Peer reviewe

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Faecal immunochemical tests (FIT) can help to rule out colorectal cancer in patients presenting in primary care with lower abdominal symptoms:a systematic review conducted to inform new NICE DG30 diagnostic guidance

__Background:__ This study has attempted to assess the effectiveness of quantitative faecal immunochemical tests (FIT) for triage of people presenting with lower abdominal symptoms, where a referral to secondary care for investigation of suspected colorectal cancer (CRC) is being considered, particularly when the 2-week criteria are not met. __Methods:__ We conducted a systematic review following published guidelines for systematic reviews of diagnostic tests. Twenty-one resources were searched up until March 2016. Summary estimates were calculated using a bivariate model or a random-effects logistic regression model. __Results:__ Nine studies are included in this review. One additional study, included in our systematic review, was provided as 'academic in confidence' and cannot be described herein. When FIT was based on a single faecal sample and a cut-off of 10 μg Hb/g faeces, sensitivity estimates indicated that a negative result using either the OC-Sensor or HM-JACKarc may be adequate to rule out nearly all CRC; the summary estimate of sensitivity for the OC-Sensor was 92.1%, based on four studies, and the only study of HM-JACKarc to assess the 10 μg Hb/g faeces cut-off reported a sensitivity of 100%. The corresponding specificity estimates were 85.8% (95% CI 78.3-91.0%) and 76.6%, respectively. When the diagnostic criterion was changed to include lower grades of neoplasia, i.e. the target condition included higher risk adenoma (HRA) as well as CRC, the rule-out performance of both FIT assays was reduced. __Conclusions:__ There is evidence to suggest that triage using FIT at a cut-off around 10 μg Hb/g faeces has the potential to correctly rule out CRC and avoid colonoscopy in 75-80% of symptomatic patients. Systematic review registration: PROSPERO 4201603772