Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved

Assemblathon 2: evaluating de novo methods of genome assembly in three vertebrate species

Background: The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. Results: In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. Conclusions: Many current genome assemblers produced useful assemblies, containing a significant representation of their genes and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Development of structural and functional connectivity in the thalamocortical somatosensory pathway in the wallaby

Neuronal activity is implicated as a driving force in the development of sensory systems. In order for it to play a developmental role, however, the pathways involved must be capable of transmitting this activity. The relationship between afferent arrival, synapse formation and the onset of chemical neurotransmission has been examined using the advantageous model of a marsupial mammal, the wallaby (Macropus eugenii), to determine at what stage activity has the capacity to influence cortical development. It is known that thalamocortical afferents arrive in the somatosensory cortex on postnatal day (P)15 and that their growth cones reach to the base of the compact cell zone of the cortical plate. However, electronmicroscopy showed that thalamocortical synapses were absent at this stage. Glutamatergic responses were recorded in the cortex following stimulation of the thalamus in slices at this time but only in magnesium-free conditions. The responses were mediated entirely by N-methyl-d-aspartate (NMDA) receptors. From P28, responses could be recorded in normal magnesium and comprised a dominant NMDA-mediated component and a non-NMDA mediated component. At this time thalamocortical synapses were first identified and they were in the cortical plate. By P63 the non-NMDA-mediated component had increased relative to the NMDA-mediated component, and by P70 layer IV began to emerge and contained thalamocortical synapses. By P76 a fast non-NMDA-mediated peak dominated the response. This coincides with the appearance of cortical whisker-related patches and the onset in vivo of responses to peripheral stimulation of the whiskers

Retinocollicular synaptogenesis and synaptic transmission during formation of the visual map in the superior colliculus of the wallaby (Macropus eugenii)

Spontaneous retinal activity has been implicated in the development of the topographic map in the superior colliculus (SC) but a direct demonstration that it reaches the colliculus is lacking. Here we investigate when the retinocollicular projection is capable of transmitting information from the retina in a marsupial mammal, the wallaby (Macropus eugenii). The projection develops postnatally, allowing in vivo analysis throughout development. Quantification of retinocollicular synaptogenesis has been combined with electrophysiology of the development and characteristics of retinocollicular transmission, including in vivo and in vitro recording in the same animals. Prior to postnatal day (P) 12-14 in vitro recording detected only presynaptic activity in retinal axons in the colliculus, in response to stimulation of the optic nerve. Postsynaptic responses, comprising both N-methyl-d-aspartate (NMDA) and non-NMDA responses, were first detected in vitro at P12-14 and retinal synapses were identified. In contrast, postsynaptic responses to optic nerve stimulation could not be detected in vivo until P39, around the time that retinal axons begin arborizing. Around this age density and numbers of total synapses began increasing in the retinorecipient layers of the colliculus. By P55-64, the numbers of retinal synapses had increased significantly and density and numbers of retinal and total synapses continued to increase up to P94-99. During this time the map is undergoing refinement and degenerating axons and synapses were present. The discrepancy between in vitro and in vivo onset of functional connections raises the question of when retinal activity reaches collicular cells in the intact, unanaesthetized animal and this will require investigation

Surface initiated actin polymerization from top-down manufactured nanopatterns

Protocols to fabricate high aspect-ratio biologically-based nanostructures using a top-down fabricated polymer platform and surface-initiated actin polymerization were developed