PcTx1 affords neuroprotection in a conscious model of stroke in hypertensive rats via selective inhibition of ASIC1a

Acid-sensing ion channel la (ASIC1a) is the primary acid sensor in mammalian brain and plays a major role in neuronal injury following cerebral ischemia. Evidence that inhibition of ASIC1a might be neuroprotective following stroke was previously obtained using "PcTx1 venom" from the tarantula Psalmopeous cambridgei. We show here that the ASIC1a-selective blocker PcTx1 is present at only 0.4% abundance in this venom, leading to uncertainty as to whether the observed neuroprotective effects were due to PcTx1 blockade of ASIC1a or inhibition of other ion channels and receptors by the hundreds of peptides and small molecules present in the venom. We therefore examined whether pure PcTx1 is neuroprotective in a conscious model of stroke via direct inhibition of ASIC1a. A focal reperfusion model of stroke was induced in conscious spontaneously hypertensive rats (SHR) by administering endothelin-1 to the middle cerebral artery via a surgically implanted cannula. Two hours later, SHR were treated with a single intracerebroventricular (i.c.v.) dose of PcTx1 (1 ng/kg), an ASIC1a-inactive mutant of PcTx1 (1 ng/kg), or saline, and ledged beam and neurological tests were used to assess the severity of symptomatic changes. PcTx1 markedly reduced cortical and striatal infarct volumes measured 72 h post-stroke, which correlated with improvements in neurological score, motor function and preservation of neuronal architecture. In contrast, the inactive PcTx1 analogue had no effect on stroke outcome. This is the first demonstration that selective pharmacological inhibition of ASIC1a is neuroprotective in conscious SHRs, thus validating inhibition of ASIC1a as a potential treatment for stroke. (C) 2015 Elsevier Ltd. All rights reserved

Stress hormones, social associations and song learning in zebra finches

N.J.B. was funded by a Netherlands Organisation for Scientific Research Rubicon Fellowship during the experimental phase of this study and by a Royal Society Dorothy Hodgkin Fellowship during the write-up. K.A.S. was funded by a BBSRC David Phillips Research Fellowship during the experimental phase. C.N.T. was supported by an NERC Postdoctoral Fellowship during the experimental phase of the study. D.R.F. was funded by the Max Planck Society and received additional funding from the Deutsche Forschungsgemeinschaft (FA 1420/4-1).The use of information provided by others is a common short-cut adopted to inform decision-making. However, instead of indiscriminately copying others, animals are often selective in what, when and whom they copy. How do they decide which 'social learning strategy' to use? Previous research indicates that stress hormone exposure in early life may be important: while juvenile zebra finches copied their parents' behaviour when solving novel foraging tasks, those exposed to elevated levels of corticosterone (CORT) during development copied only unrelated adults. Here, we tested whether this switch in social learning strategy generalizes to vocal learning. In zebra finches, juvenile males often copy their father's song; would CORT-treated juveniles in free-flying aviaries switch to copying songs of other males? We found that CORT-treated juveniles copied their father's song less accurately as compared to control juveniles. We hypothesized that this could be due to having weaker social foraging associations with their fathers, and found that sons that spent less time foraging with their fathers produced less similar songs. Our findings are in line with a novel hypothesis linking early-life stress and social learning: early-life CORT exposure may affect social learning indirectly as a result of the way it shapes social affiliations. This article is part of the theme issue 'Causes and consequences of individual differences in cognitive abilities'.Publisher PDFPeer reviewe

Inflation Dynamics and Reheating

We review the theory of inflation with single and multiple fields paying particular attention to the dynamics of adiabatic and entropy/isocurvature perturbations which provide the primary means of testing inflationary models. We review the theory and phenomenology of reheating and preheating after inflation providing a unified discussion of both the gravitational and nongravitational features of multi-field inflation. In addition we cover inflation in theories with extra dimensions and models such as the curvaton scenario and modulated reheating which provide alternative ways of generating large-scale density perturbations. Finally we discuss the interesting observational implications that can result from adiabatic-isocurvature correlations and non-Gaussianity.Comment: 51 pages, latex, 16 figures, version to appear in Reviews of Modern Physic

Particle production in the oscillating inflation model

We investigate the particle production of a scalar field $\chi$ coupled to an inflaton field $\phi$ ($g^2\phi^2\chi^2/2$) in the {\it oscillating inflation} model, which was recently proposed by Damour and Mukhanov. Although the fluctuation of the $\phi$ field can be effectively enhanced during a stage of the oscillating inflation, the maximum fluctuation is suppressed as the critical value $\phi_c$ which indicates the scale of the core part of the inflaton potential decreases, in taking into account the back reaction effect of created particles. As for the $\chi$ particle production, we find that larger values of the coupling constant $g$ are required to lead to an efficient parametric resonance with the decrease of $\phi_c$, because an effective mass of inflaton around the minimum of its potential becomes larger. However, it is possible to generate the superheavy $\chi$ particle whose mass is greater than $10^{14}$ GeV, which would result in an important consequence for the GUT baryogenesis.Comment: 18 pages, 14 figure

Magnetic properties of the geometrically frustrated S=1/2 antiferromagnets, La2LiMoO6 and Ba2YMoO6, with the B-site ordered double perovskite structure: Evidence for a Collective Spin Singlet Ground State

Two B-site ordered double perovskites, La2LiMoO6 and Ba2YMoO6, based on the S = 1/2 ion, Mo5+, have been investigated in the context of geometric magnetic frustration. Powder neutron diffraction, heat capacity, susceptibility, muon spin relaxation(_SR), and 89Y NMR- including MAS NMR- data have been collected. La2LiMoO6 deviates strongly from simple Curie-Weiss paramagnetic behavior below 150K and zero-field cooled/ field cooled (ZFC/FC)irreversibility occurs below 20K with a weak, broad susceptibility maximum near 5K in the ZFC data. A Curie-Weiss fit shows a reduced mu_eff=1.42\mu_B, (spin only = 1.73 muB) and a Weiss temperature, \theta_c, which depends strongly on the temperature range of the fit. Powder neutron diffraction, heat capacity and 7Li NMR show no evidence for long range magnetic order to 2K. On the other hand oscillations develop below 20K in muSR indicating at least short range magnetic correlations. Susceptibility data for Ba2YMoO6 also deviate strongly from the C-W law below 150K with a similarly reduced mu_eff = 1.72\mu_B and \theta_c = - 219(1)K. Heat capacity, neutron powder diffraction and muSR data show no evidence for long range order to 2K but a very broad maximum appears in the heat capacity. The 89Y NMR paramagnetic Knight shift shows a remarkable local spin susceptibility behavior below about 70K with two components from roughly equal sample volumes, one indicating a singlet state and the other a strongly fluctuating paramagnetic state. Further evidence for a singlet state comes from the behavior of the relaxation rate, 1/T1. These results are discussed and compared with those from other isostructural S = 1/2 materials and those based on S = 3/2 and S = 1.Comment: Accepted for publication in Phys. Rev.

High-intensity interval training in cardiac rehabilitation (HIIT or MISS UK): A multi-centre randomised controlled trial

Background: There is a lack of international consensus regarding the prescription of high-intensity interval exercise training (HIIT) for people with coronary artery disease (CAD) attending cardiac rehabilitation (CR).Aim: To assess the clinical effectiveness and safety of low-volume HIIT compared with moderate intensity steady-state (MISS) exercise training for people with CAD.Methods: We conducted a multi-centre RCT, recruiting 382 patients from 6 outpatient CR centres. Participants were randomised to twice-weekly HIIT (n = 187) or MISS (n = 195) for 8 weeks. HIIT consisted of 10 × 1-minute intervals of vigorous exercise (>85% maximum capacity) interspersed with 1-minute periods of recovery. MISS was 20-40 minutes of moderate intensity continuous exercise (60-80% maximum capacity). The primary outcome was the change in cardiorespiratory fitness (peak oxygen uptake, VO2 peak) at 8-week follow-up. Secondary outcomes included cardiovascular disease risk markers, cardiac structure and function, adverse events, and health-related quality of life.Results: At 8 weeks, VO2 peak improved more with HIIT (2.37 mL.kg-1.min-1; SD, 3.11) compared with MISS (1.32 mL.kg-1.min-1; SD, 2.66). After adjusting for age, sex and study site, the difference between arms was 1.04 mL.kg-1.min-1 (95% CI, 0.38 to 1.69; p = 0.002). Only 1 serious adverse event was possibly related to HIIT.Conclusions: In stable CAD, low-volume HIIT improved cardiorespiratory fitness more than MISS by a clinically meaningful margin. Low-volume HIIT is a safe, well tolerated, and clinically effective intervention that produces short-term improvement in cardiorespiratory fitness. It should be considered by all CR programmes as an adjunct or alternative to MISS

A minimum estimate for the incidence of gastric cancer in Eastern Kenya

We documented available information concerning incident cases of gastric cancer in part of Kenya's Eastern Province between 1991 and 1993. By reviewing the records of all major health facilities in the area, 200 cases of gastric carcinoma were found giving an annual average crude incidence rate of 7.01 per 100 000 males and 3.7 for females (world age-standardised rates, 14.3 for males and 7.1 for females). There is likely to be underascertainment of cases especially among those aged over 65 years. Previous incidence estimates for the same area of Kenya were reviewed and a 10-fold increase in the recorded indirectly standardised incidence rate between the periods 1965–70 and 1991–93 was noted but this may be due to improved diagnostic facilities. The recent rates in this part of Kenya are comparable to Eastern European rates and similar to those recorded in other highland regions of Africa. © 2001 Cancer Research Campaig

Resonant particle production with non-minimally coupled scalar fields in preheating after inflation

We investigate a resonant particle production of a scalar field $\chi$ coupled non-minimally to a spacetime curvature $R$ ($\xi R \chi^2$) as well as to an inflaton field $\phi$ ($g^2\phi^2\chi^2$). In the case of $g < 3 \times 10^{-4}$, $\xi$ effect assists $g$-resonance in certain parameter regimes. However, for $g > 3 \times 10^{-4}$, $g$-resonance is not enhanced by $\xi$ effect because of $\xi$ suppression effect as well as a back reaction effect. If $\xi \approx -4$, the maximal fluctuation of produced $\chi$-particle is $\sqrt{}_{max} \approx 2 \times 10^{17}$ GeV for $g < 1 \times 10^{-5}$, which is larger than the minimally coupled case with $g \approx 1 \times 10^{-3}$.Comment: 33pages, 12figures. to appear in Physical Review

MultiPhen: Joint Model of Multiple Phenotypes Can Increase Discovery in GWAS

The genome-wide association study (GWAS) approach has discovered hundreds of genetic variants associated with diseases and quantitative traits. However, despite clinical overlap and statistical correlation between many phenotypes, GWAS are generally performed one-phenotype-at-a-time. Here we compare the performance of modelling multiple phenotypes jointly with that of the standard univariate approach. We introduce a new method and software, MultiPhen, that models multiple phenotypes simultaneously in a fast and interpretable way. By performing ordinal regression, MultiPhen tests the linear combination of phenotypes most associated with the genotypes at each SNP, and thus potentially captures effects hidden to single phenotype GWAS. We demonstrate via simulation that this approach provides a dramatic increase in power in many scenarios. There is a boost in power for variants that affect multiple phenotypes and for those that affect only one phenotype. While other multivariate methods have similar power gains, we describe several benefits of MultiPhen over these. In particular, we demonstrate that other multivariate methods that assume the genotypes are normally distributed, such as canonical correlation analysis (CCA) and MANOVA, can have highly inflated type-1 error rates when testing case-control or non-normal continuous phenotypes, while MultiPhen produces no such inflation. To test the performance of MultiPhen on real data we applied it to lipid traits in the Northern Finland Birth Cohort 1966 (NFBC1966). In these data MultiPhen discovers 21% more independent SNPs with known associations than the standard univariate GWAS approach, while applying MultiPhen in addition to the standard approach provides 37% increased discovery. The most associated linear combinations of the lipids estimated by MultiPhen at the leading SNPs accurately reflect the Friedewald Formula, suggesting that MultiPhen could be used to refine the definition of existing phenotypes or uncover novel heritable phenotypes