Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment

A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential "multiple-hit" cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including 36 microtubule transport and cytoskeletal regulation

Revealing the footprints of squark gluino production through Higgs search experiments at the Large Hadron Collider at 7 TeV and 14 TeV

The invariant mass distribution of the di-photons from the decay of the lighter scalar Higgs boson(h) to be carefully measured by dedicated h search experiments at the LHC may be distorted by the di-photons associated with the squark-gluino events with much larger cross sections in Gauge Mediated Supersymmetry Breaking (GMSB) models. This distortion if observed by the experiments at the Large Hadron Collider at 7 TeV or 14 TeV, would disfavour not only the standard model but various two Higgs doublet models with comparable h - masses and couplings but without a sector consisting of new heavy particles decaying into photons. The minimal GMSB (mGMSB) model constrained by the mass bound on h from LEP and that on the lightest neutralino from the Tevatron, produce negligible effects. But in the currently popular general GMSB(GGMSB) models the tail of the above distribution may show statistically significant excess of events even in the early stages of the LHC experiments with integrated luminosity insufficient for the discovery of h. We illustrate the above points by introducing several benchmark points in various GMSB models - minimal as well as non-minimal. The same conclusion follows from a detailed parameter scan in a simplified GGMSB model recently employed by the CMS collaboration to interpret their searches in the di-photon + \etslash channel. Other observables like the effective mass distribution of the di-photon + X events may also reveal the presence of new heavy particles beyond the Higgs sector. The contamination of the h mass peak and simple remedies are also discussed.Comment: 23 pages, 7 figures, title and organization of the paper is changed, detailed parameter scan in a simplified GGMSB model is added, conclusions and old numerical results remain unchange

The Ordered Extension of Pseudopodia by Amoeboid Cells in the Absence of External Cues

Eukaryotic cells extend pseudopodia for movement. In the absence of external cues, cells move in random directions, but with a strong element of persistence that keeps them moving in the same direction Persistence allows cells to disperse over larger areas and is instrumental to enter new environments where spatial cues can lead the cell. Here we explore cell movement by analyzing the direction, size and timing of ∼2000 pseudopodia that are extended by Dictyostelium cells. The results show that pseudpopod are extended perpendicular to the surface curvature at the place where they emerge. The location of new pseudopods is not random but highly ordered. Two types of pseudopodia may be formed: frequent splitting of an existing pseudopod, or the occasional extension of a de novo pseudopod at regions devoid of recent pseudopod activity. Split-pseudopodia are extended at ∼60 degrees relative to the previous pseudopod, mostly as alternating Right/Left/Right steps leading to relatively straight zigzag runs. De novo pseudopodia are extended in nearly random directions thereby interrupting the zigzag runs. Persistence of cell movement is based on the ratio of split versus de novo pseudopodia. We identify PLA2 and cGMP signaling pathways that modulate this ratio of splitting and de novo pseudopodia, and thereby regulate the dispersal of cells. The observed ordered extension of pseudopodia in the absence of external cues provides a fundamental insight into the coordinated movement of cells, and might form the basis for movement that is directed by internal or external cues

Coronary artery dominance and the risk of adverse clinical events following percutaneous coronary intervention: insights from the prospective, randomised TWENTE trial

Aims: To investigate the prognostic value of coronary dominance for various adverse clinical events following the implantation of drug-eluting stents. Methods and results: We assessed two-year follow-up data of 1,387 patients from the randomised TWENTE trial. Based on the origin of the posterior descending coronary artery, coronary circulation was categorised into left and non-left dominance (i.e., right and balanced). Target vessel-related myocardial infarction (MI) was defined according to the updated Academic Research Consortium (ARC) definition (2x upper reference limit of creatine kinase [CK], confirmed by CK-MB elevation), and periprocedural MI (PMI) as MI ≤48 hours following PCI. One hundred and thirty-six patients (9.8%) had left and 1,251 (90.2%) non-left dominance. Target lesions were more frequently located in dominant arteries (p<0.005). Left dominance was associated with more severe calcifications (p=0.006) and more bifurcation lesions (p=0.031). Non-left dominance tended to be less frequent in men (p=0.09). Left coronary dominance was associated with more target vessel-related MI (14 [10.3%] vs. 62 [5.0%], p=0.009). Left dominance independently predicted PMI (adjusted HR 2.19, 95% CI: 1.15-4.15, p=0.017), while no difference in other clinical endpoints was observed between dominance groups. Conclusions: In the population of the TWENTE trial, we observed a higher incidence of periprocedural myocardial infarction in patients who had left coronary dominance. - See more at: http://www.pcronline.com/eurointervention/ahead_of_print/201402-11/#sthash.p3Zkzx7X.dp

Precisely timed oculomotor and parietal EEG activity in perceptual switching

Blinks and saccades cause transient interruptions of visual input. To investigate how such effects influence our perceptual state, we analyzed the time courses of blink and saccade rates in relation to perceptual switching in the Necker cube. Both time courses of blink and saccade rates showed peaks at different moments along the switching process. A peak in blinking rate appeared 1,000 ms prior to the switching responses. Blinks occurring around this peak were associated with subsequent switching to the preferred interpretation of the Necker cube. Saccade rates showed a peak 150 ms prior to the switching response. The direction of saccades around this peak was predictive of the perceived orientation of the Necker cube afterwards. Peak blinks were followed and peak saccades were preceded by transient parietal theta band activity indicating the changing of the perceptual interpretation. Precisely-timed blinks, therefore, can initiate perceptual switching, and precisely-timed saccades can facilitate an ongoing change of interpretation

Large scale analytic calculations in quantum field theories

We present a survey on the mathematical structure of zero- and single scale quantities and the associated calculation methods and function spaces in higher order perturbative calculations in relativistic renormalizable quantum field theories.Comment: 25 pages Latex, 1 style fil

Evolutionary Breakpoints in the Gibbon Suggest Association between Cytosine Methylation and Karyotype Evolution

Gibbon species have accumulated an unusually high number of chromosomal changes since diverging from the common hominoid ancestor 15–18 million years ago. The cause of this increased rate of chromosomal rearrangements is not known, nor is it known if genome architecture has a role. To address this question, we analyzed sequences spanning 57 breaks of synteny between northern white-cheeked gibbons (Nomascus l. leucogenys) and humans. We find that the breakpoint regions are enriched in segmental duplications and repeats, with Alu elements being the most abundant. Alus located near the gibbon breakpoints (<150 bp) have a higher CpG content than other Alus. Bisulphite allelic sequencing reveals that these gibbon Alus have a lower average density of methylated cytosine that their human orthologues. The finding of higher CpG content and lower average CpG methylation suggests that the gibbon Alu elements are epigenetically distinct from their human orthologues. The association between undermethylation and chromosomal rearrangement in gibbons suggests a correlation between epigenetic state and structural genome variation in evolution

Phenomenology of Non-Custodial Warped Models

We study the effect of bulk fermions on electroweak precision observables in a recently proposed model with warped extra dimensions and no custodial symmetry. We find that the top-quark mass, together with the corrections to the Zbb vertex and the one-loop contribution to the T parameter, which is finite, impose important constraints that single out a well defined region of parameter space. New massive vector bosons can be as light as 1.5 TeV and have large couplings to the t_R quark, and suppressed couplings to the t_L, b_L and lighter quarks. We discuss the implications for searches of models with warped extra dimensions at the LHC.Comment: Most relevant one-loop contributions to EWP observables included, physics results partially changed. References added. 29 pages, 14 Figure