Concentration or representation : the struggle for popular sovereignty

There is a tension in the notion of popular sovereignty, and the notion of democracy associated with it, that is both older than our terms for these notions themselves and more fundamental than the apparently consensual way we tend to use them today. After a review of the competing conceptions of 'the people' that underlie two very different understandings of democracy, this article will defend what might be called a 'neo-Jacobin' commitment to popular sovereignty, understood as the formulation and imposition of a shared political will. A people's egalitarian capacity to concentrate both its collective intelligence and force, from this perspective, takes priority over concerns about how best to represent the full variety of positions and interests that differentiate and divide a community

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.

International audienceAlthough multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P ≤ 2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P ≤ 3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P ≤ 4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

Advantage of Whole Exome Sequencing over Allele-specific and Targeted Segment Sequencing, in Detection of Novel <i>TULP1</i> Mutation in Leber Congenital Amaurosis

<div><p></p><p><i>Background</i>: Leber congenital amaurosis (LCA) is a severe form of retinal dystrophy with marked underlying genetic heterogeneity. Until recently, allele-specific assays and Sanger sequencing of targeted segments were the only available approaches for attempted genetic diagnosis in this condition. A broader next-generation sequencing (NGS) strategy, such as whole exome sequencing, provides an improved molecular genetic diagnostic capacity for patients with these conditions.</p><p><i>Materials and Methods</i>: In a child with LCA, an allele-specific assay analyzing 135 known LCA-causing variations, followed by targeted segment sequencing of 61 regions in 14 causative genes was performed. Subsequently, exome sequencing was undertaken in the proband, unaffected consanguineous parents and two unaffected siblings. Bioinformatic analysis used two independent pipelines, BWA-GATK and SOAP, followed by Annovar and SnpEff to annotate the variants.</p><p><i>Results</i>: No disease-causing variants were found using the allele-specific or targeted segment Sanger sequencing assays. Analysis of variants in the exome sequence data revealed a novel homozygous nonsense mutation (c.1081C > T, p.Arg361*) in <i>TULP1</i>, a gene with roles in photoreceptor function where mutations were previously shown to cause LCA and retinitis pigmentosa. The identified homozygous variant was the top candidate using both bioinformatic pipelines.</p><p><i>Conclusions</i>: This study highlights the value of the broad sequencing strategy of exome sequencing for disease gene identification in LCA, over other existing methods. NGS is particularly beneficial in LCA where there are a large number of causative disease genes, few distinguishing clinical features for precise candidate disease gene selection, and few mutation hotspots in any of the known disease genes.</p></div

Baseline Results (ICD-9 codes) on Test Set.

<p>Baseline Results (ICD-9 codes) on Test Set.</p

ASD Algorithm Project Overview.

<p>ASD–Autism Spectrum Disorder; ICD-9 –International Classification of Diseases 9^th edition; DSM IV–Diagnostic and Statistical Manual of Mental Diseases 4^th edition; ML—machine learning</p

ASD Rule-based Algorithm.

<p>ASD–Autism Spectrum Disorder; EHR–Electronic Health Records; ICD-9 –International Classification of Diseases 9^th edition; DSM IV–Diagnostic and Statistical Manual of Mental Diseases 4^th edition; PDD-NOS–pervasive developmental disorder not otherwise specified; sections 3a., 3b., 3c. refer to DSM IV ASD classification for Autism, Asperger’s and PDD-NOS, respectively</p

Rule Based Results

<p>Rule Based Results</p