Large-scale multielectrode recording and stimulation of neural activity

Large circuits of neurons are employed by the brain to encode and process information. How this encoding and processing is carried out is one of the central questions in neuroscience. Since individual neurons communicate with each other through electrical signals (action potentials), the recording of neural activity with arrays of extracellular electrodes is uniquely suited for the investigation of this question. Such recordings provide the combination of the best spatial (individual neurons) and temporal (individual action-potentials) resolutions compared to other large-scale imaging methods. Electrical stimulation of neural activity in turn has two very important applications: it enhances our understanding of neural circuits by allowing active interactions with them, and it is a basis for a large variety of neural prosthetic devices. Until recently, the state-of-the-art in neural activity recording systems consisted of several dozen electrodes with inter-electrode spacing ranging from tens to hundreds of microns. Using silicon microstrip detector expertise acquired in the field of high-energy physics, we created a unique neural activity readout and stimulation framework that consists of high-density electrode arrays, multi-channel custom-designed integrated circuits, a data acquisition system, and data-processing software. Using this framework we developed a number of neural readout and stimulation systems: (1) a 512-electrode system for recording the simultaneous activity of as many as hundreds of neurons, (2) a 61-electrode system for electrical stimulation and readout of neural activity in retinas and brain-tissue slices, and (3) a system with telemetry capabilities for recording neural activity in the intact brain of awake, naturally behaving animals. We will report on these systems, their various applications to the field of neurobiology, and novel scientific results obtained with some of them. We will also outline future directions

Position Reconstruction in Drift Chambers operated with Xe, CO2 (15%)

We present measurements of position and angular resolution of drift chambers operated with a Xe,CO$_2$(15%) mixture. The results are compared to Monte Carlo simulations and important systematic effects, in particular the dispersive nature of the absorption of transition radiation and non-linearities, are discussed. The measurements were carried out with prototype drift chambers of the ALICE Transition Radiation Detector, but our findings can be generalized to other drift chambers with similar geometry, where the electron drift is perpendicular to the wire planes.Comment: 30 pages, 18 figure

Fixed-Parameter Tractable Distances to Sparse Graph Classes

We show that for various classes $\mathcal{C}$ of sparse graphs, and several measures of distance to such classes (such as edit distance and elimination distance), the problem of determining the distance of a given graph $\small{G}$ to $\mathcal{C}$ is fixed-parameter tractable. The results are based on two general techniques. The first of these, building on recent work of Grohe et al. establishes that any class of graphs that is slicewise nowhere dense and slicewise first-order definable is FPT. The second shows that determining the elimination distance of a graph $\small{G}$ to a minor-closed class $\mathcal{C}$ is FPT. We demonstrate that several prior results (of Golovach, Moser and Thilikos and Mathieson) on the fixed-parameter tractability of distance measures are special cases of our first method

A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia.

BACKGROUND The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T). METHODS/DESIGN The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase. DISCUSSION The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases. TRIAL REGISTRATION The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511)

Space charge in drift chambers operated with the Xe,CO2(15%) mixture

Using prototype modules of the ALICE Transition Radiation Detector we investigate space charge effects and the dependence of the pion rejection performance on the incident angle of the ionizing particle. The average pulse height distributions in the drift chambers operated with the Xe,CO2(15%) mixture provide quantitative information on the gas gain reduction due to space charge accumulating during the drift of the primary ionization. Our results demonstrate that the pion rejection performance of a TRD is better for tracks which are not at normal incidence to the anode wires. We present detailed simulations of detector signals, which reproduce the measurements and lend strong support to our interpretation of the measurements in terms of space charge effects.Comment: 18 pages, 10 figures, accepted for publication in Nucl.Instrum.Meth. A. Data files available at http://www-alice.gsi.de/tr

The CERES/NA45 Radial Drift Time Projection Chamber

The design, calibration, and performance of the first radial drift Time Projection Chamber (TPC) are presented. The TPC was built and installed at the CERES/NA45 experiment at the CERN SPS in the late nineties, with the objective to improve the momentum resolution of the spectrometer. The upgraded experiment took data twice, in 1999 and in 2000. After a detailed study of residual distortions a spatial resolution of 340 um in the azimuthal and 640 um in the radial direction was achieved, corresponding to a momentum resolution of Dp/p = sqrt{(1% * p/GeV)^2 + (2%)^2}.Comment: 57 pages, 59 figure

Scans for signatures of selection in Russian cattle breed genomes reveal new candidate genes for environmental adaptation and acclimation

Domestication and selective breeding has resulted in over 1000 extant cattle breeds. Many of these breeds do not excel in important traits but are adapted to local environments. These adaptations are a valuable source of genetic material for efforts to improve commercial breeds. As a step toward this goal we identified candidate regions to be under selection in genomes of nine Russian native cattle breeds adapted to survive in harsh climates. After comparing our data to other breeds of European and Asian origins we found known and novel candidate genes that could potentially be related to domestication, economically important traits and environmental adaptations in cattle. The Russian cattle breed genomes contained regions under putative selection with genes that may be related to adaptations to harsh environments (e.g., AQP5, RAD50, and RETREG1). We found genomic signatures of selective sweeps near key genes related to economically important traits, such as the milk production (e.g., DGAT1, ABCG2), growth (e.g., XKR4), and reproduction (e.g., CSF2). Our data point to candidate genes which should be included in future studies attempting to identify genes to improve the extant breeds and facilitate generation of commercial breeds that fit better into the environments of Russia and other countries with similar climates

Consumer behaviour in tourism: Concepts, influences and opportunities

Although consumer behaviour (CB) is one of the most researched areas in the field of tourism, few extensive reviews of the body of knowledge in this area exist. This review article examines what we argue are the key concepts, external influences and opportune research contexts in contemporary tourism CB research. Using a narrative review, we examine the CB literature published in three major tourism journals from 2000 to 2012. Of 519 articles identified and reviewed, 191 are included in this article. We examine the development of and scope for future research on nine key concepts, including decision-making, values, motivations, self-concept and personality, expectations, attitudes, perceptions, satisfaction, trust and loyalty. We then examine three important external influences on tourism behaviour, technology, Generation Y and the rise in concern over ethical consumption. Finally, we identify and discuss five research contexts that represent major areas for future scholarship: group and joint decision-making, under-researched segments, cross-cultural issues in emerging markets, emotions and consumer misbehaviour. Our examination of key research gaps is concluded by arguing that the hedonic and affective aspects of CB research in tourism must be brought to bear on the wider CB and marketing literature

708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects:analysis for association with psychiatric disorder and cognitive traits

A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10-5, OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies. © 2014 Macmillan Publishers Limited

Vesicle Docking to the Spindle Pole Body Is Necessary to Recruit the Exocyst During Membrane Formation in Saccharomyces cerevisiae

The meiosis II outer plaque (MOP) acts a vesicle tethering complex that is a site for de novo membrane formation. Novel mutants in a MOP protein reveal that interaction of vesicles with the MOP surface is required to recruit a second tethering complex, the exocyst, to the vesicles, suggesting a mechanism by which the MOP promotes vesicle fusion