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Sökning: WFRF:(Garcia C.) > Högskolan i Skövde

  • Resultat 1-4 av 4
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1.
  • Pagnamenta, A. T., et al. (författare)
  • An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy
  • 2021
  • Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 584-600
  • Tidskriftsartikel (refereegranskat)abstract
    • The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose 47000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 +/- 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.
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2.
  • Abulafia, C., et al. (författare)
  • Relationship between Cognitive and Sleep-wake Variables in Asymptomatic Offspring of Patients with Late-onset Alzheimer's Disease
  • 2017
  • Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Early neuropathological changes characteristic of late-onset Alzheimer's disease (LOAD) involve brain stem and limbic structures that regulate neurovegetative functions, including sleep-wake rhythm. Indeed, sleep pattern is an emerging biomarker and a potential pathophysiological mechanism in LOAD. We hypothesized that cognitively asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) would display a series of circadian rhythm abnormalities prior to the onset of objective cognitive alterations. We tested 31 children of patients with LOAD (O-LOAD) and 19 healthy individuals without family history of Alzheimer's disease (control subjects, CS) with basic tests of cognitive function, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function, and bodily temperature. Unexpectedly, O-LOAD displayed subtle but significant deficits in verbal episodic memory (Rey Auditory Verbal Learning Test delayed recall 10.6 +/- 0.4 vs. 8.6 +/- 0.6, t = 4.97, df = 49, p < 0.01) and language (Weschler's vocabulary 51.4 +/- 1.3 vs. 44.3 +/- 1.5, t = 2.49, df = 49, p < 0.001) compared to CS, even though all participants had results within the clinically normal range. O-LOAD showed a phase-delayed rhythm of body temperature (2.56 +/- 0.47 h vs. 3.8 +/- 0.26 h, t = 2.48, df = 40, p = 0.031). Cognitive performance in O-LOAD was associated with a series of cardiac autonomic sleep-wake variables; specifically indicators of greater sympathetic activity at night were related to poorer cognition. The present results suggest sleep pattern deserves further study as a potential neurobiological signature in LOAD, even in middle-aged, at risk individuals.
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3.
  • Barrera Diaz, Carlos Alberto, 1987-, et al. (författare)
  • Simulation-based multi-objective optimization for reconfigurable manufacturing system configurations analysis
  • 2020
  • Ingår i: Proceedings of the 2020 Winter Simulation Conference. - : IEEE. - 9781728194998 - 9781728195001 ; , s. 1527-1538, s. 1527-1538
  • Konferensbidrag (refereegranskat)abstract
    • The purpose of this study is to analyze the use of Simulation-Based Multi-Objective Optimization (SMO) for Reconfigurable Manufacturing System Configuration Analysis (RMS-CA). In doing so, this study addresses the need for efficiently performing RMS-CA with respect to the limited time for decision-making in the industry, and investigates one of the salient problems of RMS-CA: determining the minimum number of machines necessary to satisfy the demand. The study adopts an NSGA II optimization algorithm and presents two contributions to existing literature. Firstly, the study proposes a series of steps for the use of SMO for RMS-CA and shows how to simultaneously maximize production throughput, minimize lead time, and buffer size. Secondly, the study presents a qualitative comparison with the prior work in RMS-CA and the proposed use of SMO; it discusses the advantages and challenges of using SMO and provides critical insight for production engineers and managers responsible for production system configuration.
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