202,092 research outputs found

    Tourette syndrome as a motor disorder revisited – Evidence from action coding

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    Because tics are the defining clinical feature of Tourette syndrome, it is conceptualized predominantly as a motor disorder. There is some evidence though suggesting that the neural basis of Tourette syndrome is related to perception–action processing and binding between perception and action. However, binding processes have not been examined in the motor domain in these patients. If it is particularly perception–action binding but not binding processes within the motor system, this would further corroborate that Tourette syndrome it is not predominantly, or solely, a motor disorder. Here, we studied N = 22 Tourette patients and N = 24 healthy controls using an established action coding paradigm derived from the Theory of Event Coding framework and concomitant EEG-recording addressing binding between a planned but postponed, and an interleaved immediate reaction with different levels of overlap of action elements. Behavioral performance during interleaved action coding was normal in Tourette syndrome. Response locked lateralized readiness potentials reflecting processes related to motor execution were larger in Tourette syndrome, but only in simple conditions. However, pre-motor processes including response preparation and configuration reflected by stimulus-locked lateralized readiness potentials were normal. This was supported by a Bayesian data analysis providing evidence for the null hypothesis. The finding that processes integrating different action-related elements prior to motor execution are normal in Tourette syndrome suggests that Tourette it is not solely a motor disorder. Considering other recent evidence, the data show that changes in “binding” in Tourette syndrome are specific for perception–action integration but not for action coding

    Dysregulation of FOXG1 by ring chromosome 14

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    In this study we performed molecular characterization of a patient with an extra ring chromosome derived from chromosome 14, with severe intellectual disability, epilepsy, cerebral paresis, tetraplegia, osteoporosis and severe thoraco-lumbal scoliosis. Array CGH analysis did not show any genomic imbalance but conventional karyotyping and FISH analysis revealed the presence of an interstitial 14q12q24.3 deletion and an extra ring chromosome derived from the deleted material. The deletion and ring chromosome breakpoints were identified at base-pair level by mate-pair and Sanger sequencing. Both breakpoints disrupted putative long non-coding RNA genes (TCONS00022561;RP11-148E17.1) of unknown function. However, the proximal breakpoint was 225 kb downstream of the forkhead box G1 gene (FOXG1), within the known regulatory landscape of FOXG1. The patient represents the first case of a r(14) arising from an interstitial excision where the phenotype is compatible with dysregulation of FOXG1. In turn, the phenotypic overlap between the present case, the FOXG1 syndrome and the r(14) syndrome supports that dysregulation of FOXG1 may contribute to the classical r(14)-syndrome, likely mediated by dynamic mosaicism

    Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

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    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∌8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

    Identity-by-descent analysis of a large Tourette’s syndrome pedigree from Costa Rica implicates genes involved in neuronal development and signal transduction:Molecular psychiatry

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    Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data

    Novel frameshift mutation in the CHD7 gene associated with CHARGE syndrome with preaxial polydactyly

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    We report a male patient with multiple congenital anomalies, including coloboma, Fallot tetralogy, bilateral choanal atresia, dysmorphic features (low set malformed ears, fronto-maxillary facial angle deviation, hypertelorism, retrognathism), micropenis, preaxial polydactyly and ureter stenosis. The major abnormalities had been diagnosed in prenatal period by ultrasound examination and the clinical diagnosis of CHARGE syndrome was established in postnatal periode by sequence analysis of the CHD7 coding region pointing to a novel heterozygous 4-basepair deletion in exon 3 that leads to an early stop codon and truncated CHD7 protein. Based on previous literature reports this is the first case of CHARGE syndrome with preaxial polydactyly characterized by this frameshift mutation. This case report allows further delineation of CHARGE syndrome polymorphism

    Use of International Classification of Diseases, Ninth Revision Codes for Obesity: Trends in the United States from an Electronic Health Record-Derived Database.

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    Obesity is a potentially modifiable risk factor for many diseases, and a better understanding of its impact on health care utilization, costs, and medical outcomes is needed. The ability to accurately evaluate obesity outcomes depends on a correct identification of the population with obesity. The primary objective of this study was to determine the prevalence and accuracy of International Classification of Diseases, Ninth Revision (ICD-9) coding for overweight and obesity within a US primary care electronic health record (EHR) database compared against actual body mass index (BMI) values from recorded clinical patient data; characteristics of patients with obesity who did or did not receive ICD-9 codes for overweight/obesity also were evaluated. The study sample included 5,512,285 patients in the database with any BMI value recorded between January 1, 2014, and June 30, 2014. Based on BMI, 74.6% of patients were categorized as being overweight or obese, but only 15.1% of patients had relevant ICD-9 codes. ICD-9 coding prevalence increased with increasing BMI category. Among patients with obesity (BMI ≄30 kg/m2), those coded for obesity were younger, more often female, and had a greater comorbidity burden than those not coded; hypertension, dyslipidemia, type 2 diabetes mellitus, and gastroesophageal reflux disease were the most common comorbidities. KEY FINDINGS: US outpatients with overweight or obesity are not being reliably coded, making ICD-9 codes undependable sources for determining obesity prevalence and outcomes. BMI data available within EHR databases offer a more accurate and objective means of classifying overweight/obese status

    Distributed intelligent robotics : research & development in fault-tolerant control and size/position identification : a thesis presented in partial fulfilment of the requirements for the degree of Master of Engineering in Computer Systems Engineering at Massey University

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    This thesis presents research conducted on aspects of intelligent robotic systems. In the past two decades, robotics has become one of the most rapidly expanding and developing fields of science. Robotics can be considered as the science of using artificial intelligence in the physical world. Many areas of study exist in robotics. Among these, two fields that are of paramount importance in real world applications are fault tolerance, and sensory systems. Fault tolerance is necessary since a robot in the real world could encounter internal faults, and may also have to continue functioning under adverse conditions. Sensory mechanisms are essential since a robot will possess little intelligence if it does not have methods of acquiring information about its environment. Both these fields are researched in this thesis. In particular, emphasis is placed on distributed intelligent autonomous systems. Experiments and simulations have been conducted to investigate design for fault tolerance. A suitable platform was also chosen for an implementation of a visual system, as an example of a working sensory mechanism

    Massive-Scale RNA-Seq Analysis of Non Ribosomal Transcriptome in Human Trisomy 21

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    Hybridization- and tag-based technologies have been successfully used in Down syndrome to identify genes involved in various aspects of the pathogenesis. However, these technologies suffer from several limits and drawbacks and, to date, information about rare, even though relevant, RNA species such as long and small non-coding RNAs, is completely missing. Indeed, none of published works has still described the whole transcriptional landscape of Down syndrome. Although the recent advances in high-throughput RNA sequencing have revealed the complexity of transcriptomes, most of them rely on polyA enrichment protocols, able to detect only a small fraction of total RNA content. On the opposite end, massive-scale RNA sequencing on rRNA-depleted samples allows the survey of the complete set of coding and non-coding RNA species, now emerging as novel contributors to pathogenic mechanisms. Hence, in this work we analysed for the first time the complete transcriptome of human trisomic endothelial progenitor cells to an unprecedented level of resolution and sensitivity by RNA-sequencing. Our analysis allowed us to detect differential expression of even low expressed genes crucial for the pathogenesis, to disclose novel regions of active transcription outside yet annotated loci, and to investigate a plethora of non-polyadenilated long as well as short non coding RNAs. Novel splice isoforms for a large subset of crucial genes, and novel extended untranslated regions for known genes—possibly novel miRNA targets or regulatory sites for gene transcription—were also identified in this study. Coupling the rRNA depletion of samples, followed by high-throughput RNA-sequencing, to the easy availability of these cells renders this approach very feasible for transcriptome studies, offering the possibility of investigating in-depth blood-related pathological features of Down syndrome, as well as other genetic disorders
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