Genome-wide screening for DNA variants associated with reading and language traits

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Publisher PDFPeer reviewe

Hydrodynamic Isotonic Fluid Delivery Ameliorates Moderate-to-Severe Ischemia-Reperfusion Injury in Rat Kidneys

Highly aerobic organs like the kidney are innately susceptible to ischemia-reperfusion (I/R) injury, which can originate from sources including myocardial infarction, renal trauma, and transplant. Therapy is mainly supportive and depends on the cause(s) of damage. In the absence of hypervolemia, intravenous fluid delivery is frequently the first course of treatment but does not reverse established AKI. Evidence suggests that disrupting leukocyte adhesion may prevent the impairment of renal microvascular perfusion and the heightened inflammatory response that exacerbate ischemic renal injury. We investigated the therapeutic potential of hydrodynamic isotonic fluid delivery (HIFD) to the left renal vein 24 hours after inducing moderate-to-severe unilateral IRI in rats. HIFD significantly increased hydrostatic pressure within the renal vein. When conducted after established AKI, 24 hours after I/R injury, HIFD produced substantial and statistically significant decreases in serum creatinine levels compared with levels in animals given an equivalent volume of saline via peripheral infusion (P<0.05). Intravital confocal microscopy performed immediately after HIFD showed improved microvascular perfusion. Notably, HIFD also resulted in immediate enhancement of parenchymal labeling with the fluorescent dye Hoechst 33342. HIFD also associated with a significant reduction in the accumulation of renal leukocytes, including proinflammatory T cells. Additionally, HIFD significantly reduced peritubular capillary erythrocyte congestion and improved histologic scores of tubular injury 4 days after IRI. Taken together, these results indicate that HIFD performed after establishment of AKI rapidly restores microvascular perfusion and small molecule accessibility, with improvement in overall renal function

Brown Carbon from Photo-Oxidation of Glyoxal and SO2 in Aqueous Aerosol

Aqueous-phase dark reactions during the co-oxidation of glyoxal and S(IV) were recently identified as a potential source of brown carbon (BrC). Here, we explore the effects of sunlight and oxidants on aqueous solutions of glyoxal and S(IV), and on aqueous aerosol exposed to glyoxal and SO2. We find that BrC is able to form in sunlit, bulk-phase, sulfite-containing solutions, albeit more slowly than in the dark. In more atmospherically relevant chamber experiments where suspended aqueous aerosol particles are exposed to gas-phase glyoxal and SO2, the formation of detectable amounts of BrC requires an OH radical source and occurs most rapidly after a cloud event. From these observations we infer that this photobrowning is caused by radical-initiated reactions as evaporation concentrates aqueous-phase reactants and aerosol viscosity increases. Positive-mode electrospray ionization mass spectrometric analysis of aerosol-phase products reveals a large number of CxHyOz oligomers that are reduced rather than oxidized (relative to glyoxal), with the degree of reduction increasing in the presence of OH radicals. This again suggests a radical-initiated redox mechanism where photolytically produced aqueous radical species trigger S(IV)–O2 auto-oxidation chain reactions, and glyoxal-S(IV) redox reactions especially if aerosol-phase O2 is depleted. This process may contribute to daytime BrC production and aqueous-phase sulfur oxidation in the atmosphere. The BrC produced, however, is about an order of magnitude less light-absorbing than wood smoke BrC at 365 nm

Kinetics, Products, and Brown Carbon Formation by Aqueous-Phase Reactions of Glycolaldehyde with Atmospheric Amines and Ammonium Sulfate

Glycolaldehyde (GAld) is a C2 water-soluble aldehyde produced during the atmospheric oxidation of isoprene and many other species and is commonly found in cloudwater. Previous work has established that glycolaldehyde evaporates more readily from drying aerosol droplets containing ammonium sulfate (AS) than does glyoxal, methylglyoxal, or hydroxyacetone, which implies that it does not oligomerize as quickly as these other species. Here, we report NMR measurements of glycolaldehyde’s aqueous-phase reactions with AS, methylamine, and glycine. Reaction rate constants are smaller than those of respective glyoxal and methylglyoxal reactions in the pH range of 3–6. In follow-up cloud chamber experiments, deliquesced glycine and AS seed particles were found to take up glycolaldehyde and methylamine and form brown carbon. At very high relative humidity, these changes were more than 2 orders of magnitude faster than predicted by our bulk liquid NMR kinetics measurements, suggesting that reactions involving surface-active species at crowded air–water interfaces may play an important role. The high-resolution liquid chromatography–electrospray ionization–mass spectrometric analysis of filter extracts of unprocessed AS + GAld seed particles identified sugar-like C6 and C12 GAld oligomers, including proposed product 3-deoxyglucosone, with and without modification by reactions with ammonia to diimine and imidazole forms. Chamber exposure to methylamine gas, cloud processing, and simulated sunlight increased the incorporation of both ammonia and methylamine into oligomers. Many C4–C16 imidazole derivatives were detected in an extract of chamber-exposed aerosol along with a predominance of N-derivatized C6 and C12 glycolaldehyde oligomers, suggesting that GAld is capable of forming brown carbon SOA

Physics Opportunities with the 12 GeV Upgrade at Jefferson Lab

This white paper summarizes the scientific opportunities for utilization of the upgraded 12 GeV Continuous Electron Beam Accelerator Facility (CEBAF) and associated experimental equipment at Jefferson Lab. It is based on the 52 proposals recommended for approval by the Jefferson Lab Program Advisory Committee.The upgraded facility will enable a new experimental program with substantial discovery potential to address important topics in nuclear, hadronic, and electroweak physics.Comment: 64 page

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Characterisation of silent and active genes for a variable large protein of Borrelia recurrentis

BACKGROUND: We report the characterisation of the variable large protein (vlp) gene expressed by clinical isolate A1 of Borrelia recurrentis; the agent of the life-threatening disease louse-borne relapsing fever. METHODS: The major vlp protein of this isolate was characterised and a DNA probe created. Use of this together with standard molecular methods was used to determine the location of the vlp1(B. recurrentis A1) gene in both this and other isolates. RESULTS: This isolate was found to carry silent and expressed copies of the vlp1(B. recurrentis A1) gene on plasmids of 54 kbp and 24 kbp respectively, whereas a different isolate, A17, had only the silent vlp1(B. recurrentis A17) on a 54 kbp plasmid. Silent and expressed vlp1 have identical mature protein coding regions but have different 5' regions, both containing different potential lipoprotein leader sequences. Only one form of vlp1 is transcribed in the A1 isolate of B. recurrentis, yet both 5' upstream sequences of this vlp1 gene possess features of bacterial promoters. CONCLUSION: Taken together these results suggest that antigenic variation in B. recurrentis may result from recombination of variable large and small protein genes at the junction between lipoprotein leader sequence and mature protein coding region. However, this hypothetical model needs to be validated by further identification of expressed and silent variant protein genes in other B. recurrentis isolates

Decoding Brain Activity Associated with Literal and Metaphoric Sentence Comprehension Using Distributional Semantic Models

Recent years have seen a growing interest within the natural language processing (NLP)community in evaluating the ability of semantic models to capture human meaning representation in the brain. Existing research has mainly focused on applying semantic models to de-code brain activity patterns associated with the meaning of individual words, and, more recently, this approach has been extended to sentences and larger text fragments. Our work is the first to investigate metaphor process-ing in the brain in this context. We evaluate a range of semantic models (word embeddings, compositional, and visual models) in their ability to decode brain activity associated with reading of both literal and metaphoric sentences. Our results suggest that compositional models and word embeddings are able to capture differences in the processing of literal and metaphoric sentences, providing sup-port for the idea that the literal meaning is not fully accessible during familiar metaphor comprehension

A Guide for Social Science Journal Editors on Easing into Open Science

Journal editors have a large amount of power to advance open science in their respective fields by incentivising and mandating open policies and practices at their journals. The Data PASS Journal Editors Discussion Interface (JEDI, an online community for social science journal editors: www.dpjedi.org) has collated several resources on embedding open science in journal editing (www.dpjedi.org/resources). However, it can be overwhelming as an editor new to open science practices to know where to start. For this reason, we created a guide for journal editors on how to get started with open science. The guide outlines steps that editors can take to implement open policies and practices within their journal, and goes through the what, why, how, and worries of each policy and practice. This manuscript introduces and summarizes the guide (full guide: https://osf.io/hstcx).<br/