AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed

Higher harmonic anisotropic flow measurements of charged particles in Pb-Pb collisions at 2.76 TeV

We report on the first measurement of the triangular $v_3$, quadrangular $v_4$, and pentagonal $v_5$ charged particle flow in Pb-Pb collisions at 2.76 TeV measured with the ALICE detector at the CERN Large Hadron Collider. We show that the triangular flow can be described in terms of the initial spatial anisotropy and its fluctuations, which provides strong constraints on its origin. In the most central events, where the elliptic flow $v_2$ and $v_3$ have similar magnitude, a double peaked structure in the two-particle azimuthal correlations is observed, which is often interpreted as a Mach cone response to fast partons. We show that this structure can be naturally explained from the measured anisotropic flow Fourier coefficients.Comment: 10 pages, 4 figures, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/387

WHO global research priorities for antimicrobial resistance in human health

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR

Electroweak measurements in electron–positron collisions at w-boson-pair energies at lep

Contains fulltext : 121524.pdf (preprint version ) (Open Access

Effective lifetime measurements in the B-s(0) -> K+K-, B-0 -> K+pi(-) and B-s(0) -> pi K-+(-) decays

Measurements of the effective lifetimes in the B-s(0) -> K+K-, B-0 -> K+pi(-) and B-s(0) -> pi K-+(-) decays are presented using 1.0 fb(-1)of pp collision data collected at a centre-of-mass energy of 7 TeV by the LHCb experiment. The analysis uses a data-driven approach to correct for the decay time acceptance. The measured effective lifetimes are tau(Bs0 -> K+K-) = 1.407 +/- 0.016 (stat) +/- 0.007 (syst) ps, tau(Bs0 -> K+pi-) = 1.524 +/- 0.011 (stat) +/- 0.004 (syst) ps, tau(Bs0 ->pi+K-) = 1.60 +/- 0.06 (stat) +/- 0.01 (syst) ps. This is the most precise determination to date of the effective lifetime in the B-s(0) -> K+K- decay and provides constraints on contributions from physics beyond the Standard Model to the B-s(0) mixing phase and the width difference Delta Gamma(s). (C) 2014 The Authors. Published by Elsevier B.V

Search for the decay D-0 -> pi(+)pi(-)mu(+)mu(-)

A search for the D-0 -> pi(+)pi(-)mu(+)mu(-) decay, where the muon pair does not originate from a resonance, is performed using proton-proton collision data corresponding to an integrated luminosity of 1.0 fb(-1) recorded by the LHCb experiment at a centre-of-mass energy of 7 TeV. No signal is observed and an upper limit on the relative branching fraction with respect to the resonant decay mode D-0 -> pi(+)pi(-)phi(-> mu(+)mu(-)), under the assumption of a phase-space model, is found to be B(D-0 -> pi(+)pi(-)mu(+)mu(-))/B(D-0 -> pi(+)pi(-)phi(-> mu(+)mu(-))) pi(+)pi(-)mu(+)mu(-)) < 5.5 x 10(-7) at 90% confidence level. This is the most stringent to date

Observation of the decay B-s(0) -> (D)over-bar(0)phi

First observation of the decay B-s(0) -> (D) over bar (0)phi is reported using pp collision data, corresponding to an integrated luminosity of 1.0 fb(-1), collected by the LHCb experiment at a centre-of-mass energy of 7 TeV. The significance of the signal is 6.5 standard deviations. The branching fraction is measured relative to that of the decay B-S(0) -> (D) over bar (0)phi to be beta B-S(0) -> (D) over bar (0)phi/beta B-S(0) -> (D) over bar (0)(K) over bar*(0) = 0.069 +/- 0.013 (stat) +/- 0.007 (syst). The first measurement of the ratio of branching fractions for the decays beta B-S(0) -> (D) over bar (0)(K) over bar*(0) and beta B-S(0) -> (D) over bar (0)(K) over bar*(0) is found to be beta B-S(0) -> (D) over bar (0)(K) over bar*(0/)beta B-S(0) -> (D) over bar (0)(K) over bar*(0=7.8) +/- 0.7(stat) +/- 0.3 (syst) +/- 0.6 (f(s)/f(d)) where the last uncertainty is due to the ratio of the B(s)(0)and B-0 fragmentation fractions

Search for the rare decay D-0 -> mu(+) mu(-)

A search for the rare decay D-0 -> mu(+) mu(-) is performed using a data sample, corresponding to an integrated luminosity of 0.9 fb(-1), of pp collisions collected at a centre-of-mass energy of 7 TeV by the LHCb experiment. The observed number of events is consistent with the background expectations and corresponds to an upper limit of B(D-0 -> mu(+) mu(-)) < 6.2 (7.6) x 10(-9) at 90% (95%) confidence level. This result represents an improvement of more than a factor twenty with respect to previous measurements

Observation of B-s(0) -> chi(c1)phi decay and study of B-0 -> chi K-c1,K-2*(0) decays

The first observation of the decay B-s(0) -> chi(c1)phi and a study of B-0 -> chi K-c1,K-2*(0) decays are presented. The analysis is performed using a dataset, corresponding to an integrated luminosity of 1.0 fb(-1), collected by the LHCb experiment in pp collisions at a centre-of-mass energy of 7 TeV. The following ratios of branching fractions are measured: B(B-s(0) -> chi(c1)phi)/B(B-s(0) -> J/psi phi) = (18.9 +/- 1.8 (stat) +/- 1.3 (syst) +/- 0.8(B)) x 10(-2), B(B-0 -> chi K-c1*(0))//B(B-0 -> J/psi K*(0)) = (19.8 +/- 1.1 (stat) +/- 1.2 (syst) +/- 0.9(B)) x 10(-2), B(B-0 -> chi K-c2*(0))//B(B-0 -> chi K-c1*(0)) = (17.1 +/- 5.0 (stat) +/- 1.7 (syst) +/- 1.1(B)) x 10(-2), where the third uncertainty is due to the limited knowledge of the branching fractions of chi(c) -> J/psi gamma modes