Social Cohesion, Structural Holes, and a Tale of Two Measures

EMBARGOED - author can archive pre-print or post-print on any open access repository after 12 months from publication. Publication date is May 2013 so embargoed until May 2014.This is an author’s accepted manuscript (deposited at arXiv arXiv:1211.0719v2 [physics.soc-ph] ), which was subsequently published in Journal of Statistical Physics May 2013, Volume 151, Issue 3-4, pp 745-764. The final publication is available at link.springer.com http://link.springer.com/article/10.1007/s10955-013-0722-

Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants

Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants.Genetics of disease, diagnosis and treatmen

The Territorial Agglomerations of Firms: A Social Capital Perspective from the Spanish Tile Industry

Using the Social Capital theoretical framework, territorial agglomerations of firms, such as in the industrial district, can be identified as dense strong-tie networks and are thus suitable for exploiting activities. This paper addresses the possible exploring limitations of these clustered firms. Following alternative explanations, such as the structural holes and weak tie approaches, it is proposed that local institutions may play a role as intermediary agents between external disperse networks and internal dense networks, therefore enabling these firms to deal with the requirements of an ever-changing environment. The paper also develops an empirical section where the Spanish ceramic tile industrial district is described in order to illustrate theoretical arguments. Findings suggested a number of ways in which local institutions may facilitate the creation of value for firms. Particularly, local institutions interact with many external firms and institutions and undertake research projects with local firms. In addition, some quantification of the participation of firms in the activities carried out by institutions is offered, suggesting explanations for the barriers that prevent firms from gaining direct access to external networks. Copyright 2005 Blackwell Publishing Ltd..