Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but ...few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.
Recent studies indicate that glucose metabolism is altered in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Hexokinases (HKs) catalyse the first step in glucose metabolism, and HK2 ...constitutes the principal HK inducible isoform. We hypothesise that HK2 contributes to the synovial lining hypertrophy and plays a critical role in bone and cartilage damage.
HK1 and HK2 expression were determined in RA and osteoarthritis (OA) synovial tissue by immunohistochemistry. RA FLS were transfected with either HK1 or HK2 siRNA, or infected with either adenovirus (ad)-GFP, ad-HK1 or ad-HK2. FLS migration and invasion were assessed. To study the role of HK2 in vivo, 10
particles of ad-HK2 or ad-GFP were injected into the knee of wild-type mice. K/BxN serum transfer arthritis was induced in HK2
mice harbouring Col1a1-Cre (HK2
), to delete HK2 in non-haematopoietic cells.
HK2 is particular of RA histopathology (9/9 RA; 1/8 OA) and colocalises with FLS markers. Silencing HK2 in RA FLS resulted in a less invasive and migratory phenotype. Consistently, overexpression of HK2 resulted in an increased ability to migrate and invade. It also increased extracellular lactate production. Intra-articular injection of ad-HK2 in normal knees dramatically increased synovial lining thickness, FLS activation and proliferation. HK2 was highly expressed in the synovial lining after K/BxN serum transfer arthritis. HK2
mice significantly showed decreased arthritis severity, bone and cartilage damage.
HK2 is specifically expressed in RA synovial lining and regulates FLS aggressive functions. HK2 might be an attractive selective metabolic target safer than global glycolysis for RA treatment.
We present simulations of the outer radiation belt electron flux during the March 2015 and 2013 storms using a radial diffusion model. Despite differences in disturbance short‐time intensity between ...the two storms, the response of the ultra‐relativistic electrons in the outer radiation belt was remarkably similar, both showing a sudden drop in the electron flux followed by a rapid enhancement in the outer belt flux to levels over an order of magnitude higher than those observed during the pre‐storm interval. Simulations of the ultra‐relativistic electron flux during the March 2015 storm show that outward radial diffusion can explain the flux dropout down to L*~4. However, in order to reproduce, the observed flux dropout at L* < 4 requires the addition of a loss process characterized by an electron lifetime of around 1 hr operating below L*~3.5 during the flux dropout interval. Nonetheless, during the pre‐storm and recovery phase of both storms, the radial diffusion simulation reproduces the observed flux dynamics. For the March 2013 storm, the flux dropout across all L‐shells is reproduced by outward radial diffusion activity alone. However, during the flux enhancement interval at relativistic energies, there is evidence of a growing local peak in the electron phase space density at L*~3.8, consistent with local acceleration such as by very low frequency chorus waves. Overall, the simulation results for both storms can accurately reproduce the observed electron flux only when event specific radial diffusion coefficients are used, instead of the empirical diffusion coefficients derived from ultra‐low frequency wave statistics.
Key Points
The March 2013 outer radiation belt flux dropout is consistent with fast outward ULF wave radial diffusion to a compressed magnetopause
Outward radial diffusion at high L combined with a loss process occurring on L < 3.5 is required to explain the March 2015 flux dropout
Event specific radial diffusion coefficients should be used to simulate outer belt flux dynamics especially during the storm main phase
LUX-ZEPLIN (LZ) is a next-generation dark matter direct detection experiment that will operate 4850 feet underground at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, USA. ...Using a two-phase xenon detector with an active mass of 7 tonnes, LZ will search primarily for low-energy interactions with weakly interacting massive particles (WIMPs), which are hypothesized to make up the dark matter in our galactic halo. In this paper, the projected WIMP sensitivity of LZ is presented based on the latest background estimates and simulations of the detector. For a 1000 live day run using a 5.6-tonne fiducial mass, LZ is projected to exclude at 90% confidence level spin-independent WIMP-nucleon cross sections above 1.4 × 10−48 cm2 for a 40 GeV/c2 mass WIMP. Additionally, a 5 σ discovery potential is projected, reaching cross sections below the exclusion limits of recent experiments. For spin-dependent WIMP-neutron(-proton) scattering, a sensitivity of 2.3 × 10−43 cm2 (7.1 × 10−42 cm2) for a 40 GeV/c2 mass WIMP is expected. With underground installation well underway, LZ is on track for commissioning at SURF in 2020.
Data interchange using i2b2 Klann, Jeffrey G; Abend, Aaron; Raghavan, Vijay A ...
Journal of the American Medical Informatics Association,
09/2016, Letnik:
23, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Objective Reinventing data extraction from electronic health records (EHRs) to meet new analytical needs is slow and expensive. However, each new data research network that wishes to support its own ...analytics tends to develop its own data model. Joining these different networks without new data extraction, transform, and load (ETL) processes can reduce the time and expense needed to participate. The Informatics for Integrating Biology and the Bedside (i2b2) project supports data network interoperability through an ontology-driven approach. We use i2b2 as a hub, to rapidly reconfigure data to meet new analytical requirements without new ETL programming.
Materials and Methods Our 12-site National Patient-Centered Clinical Research Network (PCORnet) Clinical Data Research Network (CDRN) uses i2b2 to query data. We developed a process to generate a PCORnet Common Data Model (CDM) physical database directly from existing i2b2 systems, thereby supporting PCORnet analytic queries without new ETL programming. This involved: a formalized process for representing i2b2 information models (the specification of data types and formats); an information model that represents CDM Version 1.0; and a program that generates CDM tables, driven by this information model. This approach is generalizable to any logical information model.
Results Eight PCORnet CDRN sites have implemented this approach and generated a CDM database without a new ETL process from the EHR. This enables federated querying within the CDRN and compatibility with the national PCORnet Distributed Research Network.
Discussion We have established a way to adapt i2b2 to new information models without requiring changes to the underlying data. Eight Scalable Collaborative Infrastructure for a Learning Health System sites vetted this methodology, resulting in a network that, at present, supports research on 10 million patients’ data.
Conclusion New analytical requirements can be quickly and cost-effectively supported by i2b2 without creating new data extraction processes from the EHR.
ABSTRACT
We present the results of a systematic search of the Transiting Exoplanet Survey Satellite (TESS) 2-min cadence data for new rapidly oscillating Ap (roAp) stars observed during the Cycle 2 ...phase of its mission. We find seven new roAp stars previously unreported as such and present the analysis of a further 25 roAp stars that are already known. Three of the new stars show multiperiodic pulsations, while all new members are rotationally variable stars, leading to almost 70 per cent (22) of the roAp stars presented being α2 CVn-type variable stars. We show that targeted observations of known chemically peculiar stars are likely to overlook many new roAp stars, and demonstrate that multiepoch observations are necessary to see pulsational behaviour changes. We find a lack of roAp stars close to the blue edge of the theoretical roAp instability strip, and reaffirm that mode instability is observed more frequently with precise, space-based observations. In addition to the Cycle 2 observations, we analyse TESS data for all-known roAp stars. This amounts to 18 further roAp stars observed by TESS. Finally, we list six known roAp stars that TESS is yet to observe. We deduce that the incidence of roAp stars amongst the Ap star population is just 5.5 per cent, raising fundamental questions about the conditions required to excite pulsations in Ap stars. This work, coupled with our previous work on roAp stars in Cycle 1 observations, presents the most comprehensive, homogeneous study of the roAp stars in the TESS nominal mission, with a collection of 112 confirmed roAp stars in total.
Weakly interacting massive particles (WIMPs) are a leading candidate for dark matter and are expected to produce nuclear recoil (NR) events within liquid xenon time-projection chambers. We present a ...measurement of the scintillation timing characteristics of liquid xenon in the LUX dark matter detector and develop a pulse shape discriminant to be used for particle identification. To accurately measure the timing characteristics, we develop a template-fitting method to reconstruct the detection times of photons. Analyzing calibration data collected during the 2013–2016 LUX WIMP search, we provide a new measurement of the singlet-to-triplet scintillation ratio for electron recoils (ER) below 46 keV, and we make, to our knowledge, a first-ever measurement of the NR singlet-to-triplet ratio at recoil energies below 74 keV. We exploit the difference of the photon time spectra for NR and ER events by using a prompt fraction discrimination parameter, which is optimized using calibration data to have the least number of ER events that occur in a 50% NR acceptance region. We then demonstrate how this discriminant can be used in conjunction with the charge-to-light discrimination to possibly improve the signal-to-noise ratio for nuclear recoils.
The monetary incentive delay task breaks down reward processing into discrete stages for fMRI analysis. Here we look at anticipation of monetary gain and loss contrasted with neutral anticipation. We ...meta-analysed data from 15 original whole-brain group maps (
n
= 346) and report extensive areas of relative activation and deactivation throughout the whole brain. For both anticipation of gain and loss we report robust activation of the striatum, activation of key nodes of the putative salience network, including anterior cingulate and anterior insula, and more complex patterns of activation and deactivation in the central executive and default networks. On between-group comparison, we found significantly greater relative deactivation in the left inferior frontal gyrus associated with incentive valence. This meta-analysis provides a robust whole-brain map of a reward anticipation network in the healthy human brain.
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