Dissociation of accumulated genetic risk and disease severity in patients with schizophrenia

Genotype–phenotype correlations of common monogenic diseases revealed that the degree of deviation of mutant genes from wild-type structure and function often predicts disease onset and severity. In complex disorders such as schizophrenia, the overall genetic risk is still often >50% but genotype–phenotype relationships are unclear. Recent genome-wide association studies (GWAS) replicated a risk for several single-nucleotide polymorphisms (SNPs) regarding the endpoint diagnosis of schizophrenia. The biological relevance of these SNPs, however, for phenotypes or severity of schizophrenia has remained obscure. We hypothesized that the GWAS ‘top-10' should as single markers, but even more so upon their accumulation, display associations with lead features of schizophrenia, namely positive and negative symptoms, cognitive deficits and neurological signs (including catatonia), and/or with age of onset of the disease prodrome as developmental readout and predictor of disease severity. For testing this hypothesis, we took an approach complementary to GWAS, and performed a phenotype-based genetic association study (PGAS). We utilized the to our knowledge worldwide largest phenotypical database of schizophrenic patients (n>1000), the GRAS (Göttingen Research Association for Schizophrenia) Data Collection. We found that the ‘top-10' GWAS-identified risk SNPs neither as single markers nor when explored in the sense of a cumulative genetic risk, have any predictive value for disease onset or severity in the schizophrenic patients, as demonstrated across all core symptoms. We conclude that GWAS does not extract disease genes of general significance in schizophrenia, but may yield, on a hypothesis-free basis, candidate genes relevant for defining disease subgroups

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 pair-produced long-lived neutral particles decaying to jets in the ATLAS hadronic calorimeter in ppcollisions at √s=8TeV

The ATLAS detector at the Large Hadron Collider at CERN is used to search for the decay of a scalar boson to a pair of long-lived particles, neutral under the Standard Model gauge group, in 20.3fb−1of data collected in proton–proton collisions at √s=8TeV. This search is sensitive to long-lived particles that decay to Standard Model particles producing jets at the outer edge of the ATLAS electromagnetic calorimeter or inside the hadronic calorimeter. No significant excess of events is observed. Limits are reported on the product of the scalar boson production cross section times branching ratio into long-lived neutral particles as a function of the proper lifetime of the particles. Limits are reported for boson masses from 100 GeVto 900 GeV, and a long-lived neutral particle mass from 10 GeVto 150 GeV

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

Synaptic scaffold evolution generated components of vertebrate cognitive complexity

The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report, to our knowledge, the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2\u27s role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness

A randomised controlled trial of the Neuro Emotional Technique (NET) for childhood Attention Deficit Hyperactivity Disorder (ADHD): a protocol

<p>Abstract</p> <p>Background</p> <p>An abundance of literature is dedicated to research for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Most, is in the area of pharmacological therapies with less emphasis in psychotherapy and psychosocial interventions and even less in the area of complementary and alternative medicine (CAM).</p> <p>The use of CAM has increased over the years, especially for developmental and behavioral disorders, such as ADHD. 60–65% of parents with children with ADHD have used CAM. Medical evidence supports a multidisciplinary approach (i.e. pharmacological and psychosocial) for the best clinical outcomes. The Neuro Emotional Technique (NET), a branch of Chiropractic, was designed to address the biopsychosocial aspects of acute and chronic conditions including non-musculoskeletal conditions. Anecdotally, it has been suggested that ADHD may be managed effectively by NET.</p> <p>Design/methods</p> <p>A placebo controlled, double blind randomised clinical trial was designed to assess the effectiveness of NET on a cohort of children with medically diagnosed ADHD.</p> <p>Children aged 5–12 years who met the inclusion criteria were randomised to one of three groups. The control group continued on their existing medical regimen and the intervention and placebo groups had the addition of the NET and sham NET protocols added to their regimen respectively. These two groups attended a clinical facility twice a week for the first month and then once a month for six months.</p> <p>The Conners' Parent and Teacher Rating Scales (CRS) were used at the start of the study to establish baseline data and then in one month and in seven months time, at the conclusion of the study. The primary outcome measures chosen were the Conners' ADHD Index and Conners' Global Index. The secondary outcome measures chosen were the DSM-IV: Inattentive, the DSM-IV:Hyperactive-Impulsive, and the DSM-IV:Total subscales from the Conners' Rating Scales, monitoring changes in inattention, hyperactivity and impulsivity.</p> <p>Calculations for the sample size were set with a significance level of 0.05 and the power of 80%, yielding a sample size of 93.</p> <p>Discussion</p> <p>The present study should provide information as to whether the addition of NET to an existing medical regimen can improve outcomes for children with ADHD.</p> <p>Trial registration</p> <p>Australian New Zealand Clinical Trial Registration Number: ANZCTRN 012606000332527</p

Enhancement of Both Long-Term Depression Induction and Optokinetic Response Adaptation in Mice Lacking Delphilin

In the cerebellum, Delphilin is expressed selectively in Purkinje cells (PCs) and is localized exclusively at parallel fiber (PF) synapses, where it interacts with glutamate receptor (GluR) δ2 that is essential for long-term depression (LTD), motor learning and cerebellar wiring. Delphilin ablation exerted little effect on the synaptic localization of GluRδ2. There were no detectable abnormalities in cerebellar histology, PC cytology and PC synapse formation in contrast to GluRδ2 mutant mice. However, LTD induction was facilitated at PF-PC synapses in Delphilin mutant mice. Intracellular Ca2+ required for the induction of LTD appeared to be reduced in the mutant mice, while Ca2+ influx through voltage-gated Ca2+ channels and metabotropic GluR1-mediated slow synaptic response were similar between wild-type and mutant mice. We further showed that the gain-increase adaptation of the optokinetic response (OKR) was enhanced in the mutant mice. These findings are compatible with the idea that LTD induction at PF-PC synapses is a crucial rate-limiting step in OKR gain-increase adaptation, a simple form of motor learning. As exemplified in this study, enhancing synaptic plasticity at a specific synaptic site of a neural network is a useful approach to understanding the roles of multiple plasticity mechanisms at various cerebellar synapses in motor control and learning

Neurobeachin Regulates Glutamate- and GABA-Receptor Targeting to Synapses via Distinct Pathways

Neurotransmission and synaptic strength depend on expression of post-synaptic receptors on the cell surface. Post-translational modification of receptors, trafficking to the synapse through the secretory pathway, and subsequent insertion into the synapse involves interaction of the receptor with A-kinase anchor proteins (AKAPs) and scaffolding proteins. Neurobeachin (Nbea), a brain specific AKAP, is required for synaptic surface expression of both glutamate and GABA receptors. Here, we investigated the role of Nbea-dependent targeting of postsynaptic receptors by studying Nbea interaction with synapse-associated protein 102 (SAP102/Dlg3) and protein kinase A subunit II (PKA II). A Nbea mutant lacking the PKA binding domain showed a similar distribution as wild-type Nbea in Nbea null neurons and partially restored GABA receptor surface expression. To understand the relevance of Nbea interaction with SAP102, we analysed SAP102 null mutant mice. Nbea levels were reduced by ~80 % in SAP102 null mice, but glutamatergic receptor expression was normal. A single-point mutation in the pleckstrin homology domain of Nbea (E2218R) resulted in loss of binding with SAP102. When expressed in Nbea null neurons, this mutant fully restored GABA receptor surface expression, but not glutamate receptor expression. Our results suggest that the PKA-binding domain is not essential for Nbea’s role in receptor targeting and that Nbea targets glutamate and GABA receptors to the synapse via distinct molecular pathways by interacting with specific effector proteins

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at root s = 8 TeV with the ATLAS detector (vol 75, 299, 2015)

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&gt;120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between EmissT&gt;150 GeV and EmissT&gt;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 presented