Dominantly inherited distal nemaline/cap myopathy caused by a large deletion in the nebulin gene

We report the first family with a dominantly inherited mutation of the nebulin gene (NEB). This 100kb in-frame deletion encompasses NEB exons 14-89, causing distal nemaline/cap myopathy in a three-generation family. It is the largest deletion characterized in NEB hitherto. The mutated allele was shown to be expressed at the mRNA level and furthermore, for the first time, a deletion was shown to cause the production of a smaller mutant nebulin protein. Thus, we suggest that this novel mutant nebulin protein has a dominant-negative effect, explaining the first documented dominant inheritance of nebulin-caused myopathy. The index patient, a young man, was more severely affected than his mother and grandmother. His first symptom was foot drop at the age of three, followed by distal muscle atrophy, slight hypomimia, high-arched palate, and weakness of the neck and elbow flexors, hands, tibialis anterior and toe extensors. Muscle biopsies showed myopathic features with type 1 fibre predominance in the index patient and nemaline bodies and cap-like structures in biopsies from his mother and grandmother. The muscle biopsy findings constitute a further example of nemaline bodies and cap-like structures being part of the same spectrum of pathological changes. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe

Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.Peer reviewe

Culture, cognition, and collaborative networks in organizations

Abstract: This paper examines the interplay of culture, cognition, and social networks in organizations with norms that emphasize cross-boundary collaboration. In such settings, social desirability concerns can induce a disparity between how people view themselves in conscious (deliberative) and less conscious (automatic) cognition. These differences have implications for the resulting pattern of intra-organizational collaborative ties. Based on a laboratory study and field data from a biotechnology firm, the authors find that: (a) people consciously reported more positive views of themselves as collaborative actors than they appeared to hold in less conscious cognition; (b) less conscious collaborative-independent self-views were associated with the choice to enlist organizationally distant colleagues in collaboration; and (c) these self-views were also associated with a person's likelihood of being successfully enlisted by organizationally distant colleagues (i.e., of supporting these colleagues in collaboration). By contrast, consciously reported collaborative-independent self-views were not associated with these choices. The study contributes to our understanding of how culture is internalized in individual cognition and how self-related cognition is linked to social structure through collaboration choices. It also demonstrates the limits of self-reports in settings with strong normative pressures and represents a novel integration of methods from cognitive psychology and network analysis

Effect of a weight loss intervention on anthropometric measures and metabolic risk factors in pre- versus postmenopausal women

<p>Abstract</p> <p>Background</p> <p>The present study examines changes in body weight, fat mass, metabolic and hormonal parameters in overweight and obese pre- and postmenopausal women who participated in a weight loss intervention.</p> <p>Methods</p> <p>Seventy-two subjects were included in the analysis of this single arm study (premenopausal: 22 women, age 43.7 ± 6.4 years, BMI 31.0 ± 2.4 kg/m²; postmenopausal: 50 women, age 58.2 ± 5.1 years, BMI 32.9 ± 3.7 kg/m²). Weight reduction was achieved by the use of a meal replacement and fat-reduced diet. In addition, from week 6 to 24 participants attended a guided exercise program. Body composition was analyzed with the Bod Pod^®. Blood pressures were taken at every visit and blood was collected at baseline and closeout of the study to evaluate lipids, insulin, cortisol and leptin levels.</p> <p>Results</p> <p>BMI, fat mass, waist circumference, systolic blood pressure, triglycerides, glucose, leptin and cortisol were higher in the postmenopausal women at baseline.</p> <p>Both groups achieved a substantial and comparable weight loss (pre- vs. postmenopausal: 6.7 ± 4.9 vs 6.7 ± 4.4 kg; n.s.). However, in contrast to premenopausal women, weight loss in postmenopausal women was exclusively due to a reduction of fat mass (-5.3 ± 5.1 vs -6.6 ± 4.1 kg; p < 0.01). In premenopausal women 21% of weight loss was attributed to a reduction in lean body mass.</p> <p>Blood pressure, triglycerides, HDL-cholesterol, and glucose improved significantly only in postmenopausal women whereas total cholesterol and LDL-cholesterol were lowered significantly in both groups.</p> <p>Conclusion</p> <p>Both groups showed comparable weight loss and in postmenopausal women weight loss was associated with a pronounced improvement in metabolic risk factors thereby reducing the prevalence of metabolic syndrome.</p

(Re) defining salesperson motivation: current status, main challenges, and research directions

The construct of motivation is one of the central themes in selling and sales management research. Yet, to-date no review article exists that surveys the construct (both from an extrinsic and intrinsic motivation context), critically evaluates its current status, examines various key challenges apparent from the extant research, and suggests new research opportunities based on a thorough review of past work. The authors explore how motivation is defined, major theories underpinning motivation, how motivation has historically been measured, and key methodologies used over time. In addition, attention is given to principal drivers and outcomes of salesperson motivation. A summarizing appendix of key articles in salesperson motivation is provided

Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics