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

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

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

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

Modular termination verification for non-blocking concurrency

© Springer-Verlag Berlin Heidelberg 2016.We present Total-TaDA, a program logic for verifying the total correctness of concurrent programs: that such programs both terminate and produce the correct result. With Total-TaDA, we can specify constraints on a thread’s concurrent environment that are necessary to guarantee termination. This allows us to verify total correctness for nonblocking algorithms, e.g. a counter and a stack. Our specifications can express lock- and wait-freedom. More generally, they can express that one operation cannot impede the progress of another, a new non-blocking property we call non-impedance. Moreover, our approach is modular. We can verify the operations of a module independently, and build up modules on top of each other

Horn-Coupled, Commercially-Fabricated Aluminum Lumped-Element Kinetic Inductance Detectors for Millimeter Wavelengths

We discuss the design, fabrication, and testing of prototype horn-coupled, lumped-element kinetic inductance detectors (LEKIDs) designed for cosmic microwave background (CMB) studies. The LEKIDs are made from a thin aluminum film deposited on a silicon wafer and patterned using standard photolithographic techniques at STAR Cryoelectronics, a commercial device foundry. We fabricated twenty-element arrays, optimized for a spectral band centered on 150 GHz, to test the sensitivity and yield of the devices as well as the multiplexing scheme. We characterized the detectors in two configurations. First, the detectors were tested in a dark environment with the horn apertures covered, and second, the horn apertures were pointed towards a beam-filling cryogenic blackbody load. These tests show that the multiplexing scheme is robust and scalable, the yield across multiple LEKID arrays is 91%, and the noise-equivalent temperatures (NET) for a 4 K optical load are in the range 26\thinspace\pm6 \thinspace \mu \mbox{K} \sqrt{\mbox{s}}

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

The diagonalization method in quantum recursion theory

As quantum parallelism allows the effective co-representation of classical mutually exclusive states, the diagonalization method of classical recursion theory has to be modified. Quantum diagonalization involves unitary operators whose eigenvalues are different from one.Comment: 15 pages, completely rewritte

Initial data for fluid bodies in general relativity

We show that there exist asymptotically flat almost-smooth initial data for Einstein-perfect fluid's equation that represent an isolated liquid-type body. By liquid-type body we mean that the fluid energy density has compact support and takes a strictly positive constant value at its boundary. By almost-smooth we mean that all initial data fields are smooth everywhere on the initial hypersurface except at the body boundary, where tangential derivatives of any order are continuous at that boundary. PACS: 04.20.Ex, 04.40.Nr, 02.30.JrComment: 38 pages, LaTeX 2e, no figures. Accepted for publication in Phys. Rev.

Asymptotically Hyperbolic Non Constant Mean Curvature Solutions of the Einstein Constraint Equations

We describe how the iterative technique used by Isenberg and Moncrief to verify the existence of large sets of non constant mean curvature solutions of the Einstein constraints on closed manifolds can be adapted to verify the existence of large sets of asymptotically hyperbolic non constant mean curvature solutions of the Einstein constraints.Comment: 19 pages, TeX, no figure