Estimating sigma-meson couplings from D \to 3\pi decays

Using recent experimental evidence from E791 on the sigma meson in D \to 3\pi decays, we study the relevant couplings in D \to \sigma \pi and \sigma \to \pi\ pi within the accepted theoretical framework for non leptonic D decays. We also review the linear sigma model, finding that it gives a description which is consistent with the experimental data.Comment: 6 pages, no figures. Final version accepted for publication as a Brief Report in Physical Review

Testing "microscopic" theories of glass-forming liquids

We assess the validity of "microscopic" approaches of glass-forming liquids based on the sole k nowledge of the static pair density correlations. To do so we apply them to a benchmark provided by two liquid models that share very similar static pair density correlation functions while disp laying distinct temperature evolutions of their relaxation times. We find that the approaches are unsuccessful in describing the difference in the dynamical behavior of the two models. Our study is not exhausti ve, and we have not tested the effect of adding corrections by including for instance three-body density correlations. Yet, our results appear strong enough to challenge the claim that the slowd own of relaxation in glass-forming liquids, for which it is well established that the changes of the static structure factor with temperature are small, can be explained by "microscopic" appr oaches only requiring the static pair density correlations as nontrivial input.Comment: 10 pages, 7 figs; Accepted to EPJE Special Issue on The Physics of Glasses. Arxiv version contains an addendum to the appendix which does not appear in published versio

New games, new rules: big data and the changing context of strategy

Big data and the mechanisms by which it is produced and disseminated introduce important changes in the ways information is generated and made relevant for organizations. Big data often represents miscellaneous records of the whereabouts of large and shifting online crowds. It is frequently agnostic, in the sense of being produced for generic purposes or purposes different from those sought by big data crunching. It is based on varying formats and modes of communication (e.g., texts, image and sound), raising severe problems of semiotic translation and meaning compatibility. Crucially, the usefulness of big data rests on their steady updatability, a condition that reduces the time span within which this data is useful or relevant. Jointly, these attributes challenge established rules of strategy making as these are manifested in the canons of procuring structured information of lasting value that addresses specific and long-term organizational objectives. The developments underlying big data thus seem to carry important implications for strategy making, and the data and information practices with which strategy has been associated. We conclude by placing the understanding of these changes within the wider social and institutional context of longstanding data practices and the significance they carry for management and organizations

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5’ splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

REST repression of neuronal genes requires components of the hSWI.SNF complex

A function of the transcription factor REST is to block the expression of neuronal phenotypic traits in nonneuronal cells. Previous studies have shown that REST-mediated repression requires histone deacetylase activity and that recruitment of deacetylases is mediated by two co-repressors, Sin3A and CoREST. In this study, we show that a repressor domain in CoREST interacts with BRG1-associated factor (BAF) 57, a component of the hSWI\ub7SNF complex. In vivo, BAF57 occupies the neuronal sodium channel gene (Nav1.2) promoter, and targeting to this gene requires REST. In addition to BAF57, the ATPase BRG1 and BAF170, other members of the hSWI\ub7SNF complex, are also present in the REST\ub7CoREST repressor complex. Microinjection of specific antibodies against BRG1, BAF57, or BAF170 into Rat1 fibroblasts relieves repression of RE1 reporter genes. Together, our data suggest that ATP-dependent chromatin remodeling, as well as histone deacetylation, is needed for REST-mediated repression

Gliomatosis cerebri: Review of 22 patients

Introduction: Gliomatosis cerebri is a diffuse astrocytic neoplasm that involves more than two lobes of the brain. Treatment is not well defined and the prognosis is considered poor. Methods: Retrospective analysis of 22 patients with gliomatosis cerebri. Results: We identified 17 men and 5 women (median age 54 years) seen in a Division of Neuro-oncology over a 6 year period. Patients presented with focal sensorimotor or visual deficits (86.4%), seizures (36.4%), cognitive dysfunction (27.3%), or headache (27.3%), suggesting in some cases stroke, migraine, or limbic encephalitis. All patients had bilateral involvement; the regions involved included, temporal (19), basal ganglia (18), frontal (17), parietal (17), corpus callosum (10), and occipital (9). The most frequent pathological findings were Grade III astrocytoma (36.4%), Grade II astrocytoma (22.7%), and Grade IV astrocytoma (18.3%). Nine patients were diagnosed within the first month of symptom development, 11 between the first month and 1 year, and 2 after one year. Seventeen patients received treatment with chemotherapy, radiotherapy or both, and 12 patients (70.6%) had a clinical or radiological response. The median follow-up was 13 months, median progression free survival 6 months, and median survival 9.5 months (15 months if the patients received treatment). Eight patients had thromboembolic events. Conclusions: Gliomatosis cerebri has a variable clinical course. Treatment often results in clinical responses. In this study de median survival of patients who received treatment was similar to that reported in series of glioblastoma multiforme. Resumen: Introducción: La gliomatosis cerebral es un tumor astrocítico difuso que afecta a más de dos lóbulos cerebrales. El tratamiento no está bien definido y el pronóstico es malo. Métodos: Estudio retrospectivo clínico-radiológico de 22 pacientes diagnosticados de gliomatosis cerebral en una unidad de neurooncología. Resultados: En un periodo de 6 años, identificamos a 17 varones y 5 mujeres (media de edad, 54 años). Los síntomas iniciales fueron déficits focales sensitivo-motores o visuales (86,4%), crisis epilépticas (36,4%), deterioro cognitivo (27,3%) y cefalea (27,3%); en algunos casos los síntomas semejaban ictus, migraña o encefalitis límbica. Todos los pacientes tenían afectación radiológica bilateral; las regiones más afectadas fueron: temporal (19 pacientes), ganglios basales (18), frontal (17), parietal (17), cuerpo calloso (10) y occipital (9). Los diagnósticos histológicos más frecuentes fueron astrocitoma de grado III (36,4%), astrocitoma de grado II (22,7%) y astrocitoma de grado IV (18,3%). Nueve pacientes fueron diagnosticados en el primer mes del desarrollo de los síntomas; 11, entre el primer mes y 1 año, y 2, después de 1 año. Diecisiete pacientes recibieron quimioterapia, radioterapia o ambas, de los que 12 (70,6%) tuvieron respuesta clínica o radiológica. La media de seguimiento fue 13 meses; el tiempo libre de progresión, 6 meses, y el tiempo de supervivencia, 9,5 meses (15 meses cuando los pacientes recibieron tratamiento); 8 pacientes desarrollaron complicaciones tromboembólicas. Conclusiones: La gliomatosis cerebral tiene un curso clínico variable. Los pacientes generalmente responden al tratamiento. En este estudio la media de supervivencia de los pacientes tratados es similar a la de las series de glioblastoma multiforme. Keywords: Gliomatosis cerebri, Treatment, Survival, Palabras clave: Gliomatosis cerebral, Tratamiento, Supervivenci