Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder.

BackgroundAutism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution and mechanisms driving the male bias are less understood. Here, we aimed to identify familial and sex-differential risk loci in the largest available, uniformly ascertained, densely genotyped sample of multiplex ASD families from the Autism Genetics Resource Exchange (AGRE), and to compare results with earlier findings from AGRE.MethodsFrom a total sample of 1,008 multiplex families, we performed genome-wide, non-parametric linkage analysis in a discovery sample of 847 families, and separately on subsets of families with only male, affected children (male-only, MO) or with at least one female, affected child (female-containing, FC). Loci showing evidence for suggestive linkage (logarithm of odds ≥2.2) in this discovery sample, or in previous AGRE samples, were re-evaluated in an extension study utilizing all 1,008 available families. For regions with genome-wide significant linkage signal in the discovery stage, those families not included in the corresponding discovery sample were then evaluated for independent replication of linkage. Association testing of common single nucleotide polymorphisms (SNPs) was also performed within suggestive linkage regions.ResultsWe observed an independent replication of previously observed linkage at chromosome 20p13 (P < 0.01), while loci at 6q27 and 8q13.2 showed suggestive linkage in our extended sample. Suggestive sex-differential linkage was observed at 1p31.3 (MO), 8p21.2 (FC), and 8p12 (FC) in our discovery sample, and the MO signal at 1p31.3 was supported in our expanded sample. No sex-differential signals met replication criteria, and no common SNPs were significantly associated with ASD within any identified linkage regions.ConclusionsWith few exceptions, analyses of subsets of families from the AGRE cohort identify different risk loci, consistent with extreme locus heterogeneity in ASD. Large samples appear to yield more consistent results, and sex-stratified analyses facilitate the identification of sex-differential risk loci, suggesting that linkage analyses in large cohorts are useful for identifying heritable risk loci. Additional work, such as targeted re-sequencing, is needed to identify the specific variants within these loci that are responsible for increasing ASD risk

Schizophrenia: Genome, Interrupted

Structural chromosomal variation is increasingly recognized as an important contributor to human diseases, particularly those of neurodevelopment, such as autism. A current paper makes a significant advance to schizophrenia genetics by establishing an association with rare copy number variants (CNV), which are over-represented in neurodevelopmental genes

Enhanced Integrin α4β1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes.

Diabetes is associated with a deficit of circulating endothelial progenitor cells (EPCs), which has been attributed to their defective mobilization from the bone marrow. The basis for this mobilization defect is not completely understood, and we sought to determine if hyperglycemic conditions enhanced EPC adhesion. We found that culturing EPCs in high glucose media increased adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1β (PRKAR1β), activation of protein kinase A (PKA), and phosphorylation of α4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1β, or expression of a phosphorylation-defective α4-integrin variant (α4[S988A]). Using a model of type 1 diabetes, we showed that α4(S988A)-expressing mice have more circulating EPCs than their wild-type counterparts. Moreover, diabetic α4(S988A) mice demonstrate enhanced revascularization after hind limb ischemia. Thus, we have identified a novel signaling mechanism activating PKA in diabetes (downregulation of an inhibitory regulatory subunit) that leads to deficits of circulating EPCs and impaired vascular repair, which could be reversed by α4-integrin mutation

Impact of Observed and Controlled Water Intake on Reticulorumen Temperature in Lactating Dairy Cattle

Dairy precision technologies helps producers monitor individual animals. Reticulorumen temperature boluses are a way to monitor core body temperature; however, factors such as water intake affects reticulorumen temperature. This research determined the effect of natural water intake and a controlled water drench on reticulorumen temperature (RT) in dairy cattle. In observational study part 1, tie- stall cows (n = 4) with RT transponders were observed for natural water intake (recorded by in line water meters) for 48 h. In experiment part 2, a randomized Latin square design with cows (n = 12) restricted on feed for 4 h, were drenched daily with a water quantity of 6.7 L, 11.4 L or 22.7 L, and at controlled water temperature of 1.7 °C, 7.2 °C, 15.5 °C, or 29.4 °C. Descriptively, observational study 1 had (Mean ± SD 0.27 ± 0.31 L ingested per drinking event (n = 84) and RT decline from baseline was 2.29 ± 1.82 °C. For the experiment, a 48-h specific rolling baseline temperature range (BTR) was calculated for each cow prior to the experiment to determine time required for RT to reach BTR, and time to return to BTR. In part 2 of the experiment, as water quantity increased, RT had a greater maximum degree drop from baseline. Water temperature and water quantity interaction influenced time required for BTR to reestablish. The coldest water temperature at the highest drench quantity affected time for BTR to reestablish the longest (103 min). Results from this study suggest that an algorithm could be designed to predict water intake events for producers using reticulorumen temperature

Antitumor activity of an anti-CD98 antibody.

CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors

Association of a green tea extract with serum immunoglobulin G status and neonatal vitality in newborn dairy calves

Poor vigor at birth has been associated with reduced IgG absorption from colostrum and a reduced vitality in neonatal dairy calves. Some natural compounds, such as green tea extract, may improve vitality in compromised calves. The objective of this randomized controlled trial was to evaluate the potential of supplementing a green tea extract (15 mL) to calves to improve vigor and activity behavior for the first 72 h postnatal. Also, this study aimed to investigate the influence of green tea extract supplementation on calf serum IgG concentration and the apparent efficiency of absorption (AEA) of colostral IgG. Holstein calves (n = 24) weighing 42.49 ± 1.07 kg postnatal received a complete random assignment at 3 h of one 15-mL dose of green tea extract (Calf Perk, TechMix) or distilled water orally before tube feeding colostrum replacer (Premolac Plus IgG, Zinpro) at 4 h postnatal. Two observers assessed for calving time and dystocia by live video stream to retrieve all calves within 2 h postnatal. One veterinarian performed a baseline vigor assessment based on heart rate and response to stimuli on all calves at 2.5 h, before colostrum feeding at 3.75 h, as well as at 24, 48, and 72 h postnatal. Calf blood samples were taken to assess total IgG by radial immunodiffusion assay at 2.5, 6, 12, 24, 48, and 72 h. Calf vitality was also observed continuously by video for all calves to determine whether treatment was associated with attempts to stand, lying time, and exploration of their pen environment for the first 24 h. We used an ordinal logistic model to evaluate the odds of green tea extract improving a calf\u27s vigor category from 2.5 h postnatal to 72 h of age. Vigor score was categorized as abnormal (≤4), average (5), or alert (≥6), with hour as a fixed effect. We also ran mixed linear models to evaluate the effect of extract on total IgG and AEA, with time and dystocia as fixed effects. Five dystocia calves were enrolled (2 control, 3 extract), but assistance was minor (e.g., manual assistance and all were assisted within 1 h). Baseline vigor scores and baseline total IgG were not different between groups. Vigor score category was not associated with green tea extract supplementation (odds ratio 1.17; 95% CI: 0.43–3.15) but increased with time compared with controls. We observed no association of treatment with total IgG or AEA in the calves, suggesting green tea extract does not compromise IgG absorption. Calf vitality, lying behavior, and exploratory behavior were not associated with green tea extract treatment. Our findings suggest that green tea extract supplementation does not affect AEA and serum IgG concentration in calves. Future research should evaluate whether green tea extract improves vitality in calves experiencing severe dystocia

Transcriptomic analysis of autistic brain reveals convergent molecular pathology.

Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder

Black hole collisions from Brill-Lindquist initial data: predictions of perturbation theory

The Misner initial value solution for two momentarily stationary black holes has been the focus of much numerical study. We report here analytic results for an astrophysically similar initial solution, that of Brill and Lindquist (BL). Results are given from perturbation theory for initially close holes and are compared with available numerical results. A comparison is made of the radiation generated from the BL and the Misner initial values, and the physical meaning is discussed.Comment: 11 pages, revtex3.0, 5 figure

Non-uniqueness in conformal formulations of the Einstein constraints

Standard methods in non-linear analysis are used to show that there exists a parabolic branching of solutions of the Lichnerowicz-York equation with an unscaled source. We also apply these methods to the extended conformal thin sandwich formulation and show that if the linearised system develops a kernel solution for sufficiently large initial data then we obtain parabolic solution curves for the conformal factor, lapse and shift identical to those found numerically by Pfeiffer and York. The implications of these results for constrained evolutions are discussed.Comment: Arguments clarified and typos corrected. Matches published versio