Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies : an exome-based case-control study

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA(A) receptors and was compared to the respective GABA(A) receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA(A) receptors in cases (odds ratio [OR] 2.40 [95% CI 1.41-4.10]; p(Nonsyn)=0.0014, adjusted p(Nonsyn)=0.019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1.46 [95% CI 1.05-2.03]; p(Nonsyn)=0.0081, adjusted p(Nonsyn)=0.016). Comparison of genes encoding GABA(A) receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA(A) receptor genes in cases compared with controls (OR 1.46 [95% CI 1.02-2.08]; p(Nonsyn)=0.013, adjusted p(Nonsyn)=0.027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABA(A) receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

A MODEST review

We present an account of the state of the art in the fields explored by the research community invested in 'Modeling and Observing DEnse STellar systems'. For this purpose, we take as a basis the activities of the MODEST-17 conference, which was held at Charles University, Prague, in September 2017. Reviewed topics include recent advances in fundamental stellar dynamics, numerical methods for the solution of the gravitational N-body problem, formation and evolution of young and old star clusters and galactic nuclei, their elusive stellar populations, planetary systems, and exotic compact objects, with timely attention to black holes of different classes of mass and their role as sources of gravitational waves. Such a breadth of topics reflects the growing role played by collisional stellar dynamics in numerous areas of modern astrophysics. Indeed, in the next decade, many revolutionary instruments will enable the derivation of positions and velocities of individual stars in the Milky Way and its satellites and will detect signals from a range of astrophysical sources in different portions of the electromagnetic and gravitational spectrum, with an unprecedented sensitivity. On the one hand, this wealth of data will allow us to address a number of long-standing open questions in star cluster studies; on the other hand, many unexpected properties of these systems will come to light, stimulating further progress of our understanding of their formation and evolution.Comment: 42 pages; accepted for publication in 'Computational Astrophysics and Cosmology'. We are much grateful to the organisers of the MODEST-17 conference (Charles University, Prague, September 2017). We acknowledge the input provided by all MODEST-17 participants, and, more generally, by the members of the MODEST communit

An experimental investigation of sand�mud suspension settling behaviour: implications for bimodal mud contents of submarine flow deposits

The settling behaviour of particulate suspensions and their deposits has been documented using a series of settling tube experiments. Suspensions comprised saline solution and noncohesive glass-ballotini sand of particle size 35·5 ?m &lt; d &lt; 250 ?m and volume fractions, ?s, up to 0·6 and cohesive kaolinite clay of particle size d &lt; 35·5 ?m and volume fractions, ?m, up to 0·15. Five texturally distinct deposits were found, associated with different settling regimes: (I) clean, graded sand beds produced by incremental deposition under unhindered or hindered settling conditions; (II) partially graded, clean sand beds with an ungraded base and a graded top, produced by incremental deposition under hindered settling conditions; (III) graded muddy sands produced by compaction with significant particle sorting by elutriation; (IV) ungraded clean sand produced by compaction and (V) ungraded muddy sand produced by compaction. A transition from particle size segregation (regime I) to suppressed size segregation (regime II or III) to virtually no size segregation (IV or V) occurred as sediment concentration was increased. In noncohesive particulate suspensions, segregation was initially suppressed at ?s ? 0·2 and entirely inhibited at ?s ? 0·6. In noncohesive and cohesive mixtures with low sand concentrations (?s &lt; 0·2), particle segregation was initially suppressed at ?m ? 0·07 and entirely suppressed at ?m ? 0·13. The experimental results have a number of implications for the depositional dynamics of submarine sediment gravity flows and other particulate flows that carry sand and mud; because the influence of moving flow is ignored in these experiments, the results will only be applicable to flows in which settling processes, in the depositional boundary, dominate over shear-flow processes, as might be the case for rapidly decelerating currents with high suspended load fallout rates. The 'abrupt' change in settling regimes between regime I and V, over a relatively small change in mud concentration (&lt;5% by volume), favours the development of either mud-poor, graded sandy deposits or mud-rich, ungraded sandy deposits. This may explain the bimodality in sediment texture (clean 'turbidite' or muddy 'debrite' sand or sandstone) found in some turbidite systems. Furthermore, it supports the notion that distal 'linked' debrites could form because of a relatively small increase in the mud concentration of turbidity currents, perhaps associated with erosion of a muddy sea floor. Ungraded, clean sand deposits were formed by noncohesive suspensions with concentrations 0·2 ? ?s ? 0·4. Hydrodynamic sorting is interpreted as being suppressed in this case by relatively high bed aggradation rates which could also occur in association with sustained, stratified turbidity currents or noncohesive debris flows with relatively high near-bed sediment concentrations.<br/

Observational constraints on star cluster formation theory: I. the mass-radius relation

Context. Stars form predominantly in groups usually denoted as clusters or associations. The observed stellar groups display a broad spectrum of masses, sizes, and other properties, so it is often assumed that there is no underlying structure in this diversity. Aims. Here we show that the assumption of an unstructured multitude of cluster or association types might be misleading. Current data compilations of clusters in the solar neighbourhood show correlations among cluster mass, size, age, maximum stellar mass, etc. In this first paper we take a closer look at the correlation of cluster mass and radius. Methods. We use literature data to explore relations in cluster and molecular core properties in the solar neighbourhood. Results. We show that for embedded clusters in the solar neighbourhood a clear correlation exists between cluster mass and half-mass radius of the form Mc = CRc γ with γ = 1.7 ± 0.2. This correlation holds for infrared K-band data, as well as for X-ray sources and clusters containing a hundred stars up to those consisting of a few tens of thousands of stars. The correlation is difficult to verify for clusters containing fewer than 30 stars owing to low-number statistics. Dense clumps of gas are the progenitors of the embedded clusters. We find almost the same slope for the mass-size relation of dense, massive clumps as for the embedded star clusters. This might point to a direct translation from gas to stellar mass: however, it is difficult to relate size measurements for clusters (stars) to those for gas profiles. Taking multiple paths for clump mass into cluster mass into account, we obtain an average star-formation efficiency of 18%-5.7 +9.3 for the embedded clusters in the solar neighbourhood. Conclusions. The derived mass-radius relation gives constraints for the theory of clustered star formation. Analytical models and simulations of clustered star formation have to reproduce this relation in order to be realistic. © ESO, 2016

Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors

Purpose. The purpose of our study was to develop an injectable polymeric system for the long-term localized delivery of bioactive interleukin-2 for antitumor immunotherapy. Methods. IL-2 was encapsulated into gelatin and chondroitin-6-sulfate using an aqueous-based complex coacervation. CTLL-2 cells were used to measure the bioactivity of released IL-2 and radiolabeled IL-2 was used for release studies in the rat brain and mouse liver. Antitumor efficacy studies were carried out in primary (9L gliosarcoma) and metastatic (B16-F10 melanoma) brain tumor models in rats and mice, respectively, as well as a murine liver tumor model (CT26 carcinoma). Survivors of the metastatic brain tumor challenge were rechallenged with tumor in the opposite lobe of the brain to confirm that antitumor immunologic memory had developed. Results. Bioactive IL-2 was released for over 2 weeks in vitro and in vivo IL-2 release showed significant IL-2 levels for up to 21 days. Polymeric IL-2 microspheres injected intratumorally were statistically more effective in protecting animals challenged with fatal tumor doses in the brain and the liver than placebo or autologous tumor cells genetically engineered to secrete IL-2. Immunologic memory was induced following IL-2 microsphere therapy in the B16-F10 brain tumor model that was capable of protecting 42% of animals from a subsequent intracranial tumor challenge, suggesting that tumor destruction was mediated by the immune system. Conclusions. Local IL-2 therapy using novel polymeric carriers, aimed at stimulating long-lasting antitumor immunity, may provide an improved method of treating a variety of cancers

Breaking the silence: the traumatic circle of policing

Operational police officers often work in traumatic situations. Whilst training and support is provided to officers in these areas in the UK, and some debriefing and counselling is provided, this is not fully effective in addressing the so-called ‘attitudinal’ problem of the police. We believe that one of the reasons for this is that police training does not adequately address the effects of working in traumatic conditions, and certainly does not take into account new work in the area of post-traumatic stress disorder (PTSD) which shows that trauma, and its vicarious effects, is not necessarily a mental disorder (though its symptoms may manifest as such) but is caused by physiological and emotional changes in the body. Further, studies on the social nature of trauma indicate that it is often the isolated conditions of trauma victims that can increase PTSD. Drawing on secondary data from one of the authors’ work on spirituality in the police force, we explore the connections between the physiological and emotional aspects of trauma and the conditions in which police in the UK work. We suggest that police officers’ reports of the work they do, and the way in which they learn to live with it, keeps them in an ongoing cycle of retraumatisation. We suggest that we need to take into account the physiological, social as well as psychological (or attitudinal) aspects of working in traumatic conditions if we are to provide adequate training support for police officers, so that they are not left isolated in this cycle. This has potentially far-reaching implications for the training of police officers