88 research outputs found
Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study
No full textBackground Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterised by early-onset episodes of hemiplegia, dystonia, various paroxysmal symptoms, and developmental impairment. Almost all cases of AHC are sporadic but AHC concordance in monozygotic twins and dominant transmission in a family with a milder phenotype have been reported. Thus, we aimed to identify de-novo mutations associated with this disease. Methods We recruited patients with clinically characterised AHC from paediatric neurology departments in Germany and with the aid of a parental support group between Sept, 2004, and May 18, 2012. We used whole-exome sequencing of three proband-parent trios to identify a disease-associated gene and then tested whether mutations in the gene were also present in the remaining patients and their healthy parents. We analysed genotypes and characterised their associations with the phenotypic spectrum of the disease. Findings We studied 15 female and nine male patients with AHC who were aged 8-35 years. ATP1A3 emerged as the disease-associated gene in AHC. Whole-exome sequencing showed three heterozygous de-novo missense mutations. Sequencing of the 21 remaining affected individuals identified disease-associated mutations in ATP1A3 in all patients, including six de-novo missense mutations and one de-novo splice-site mutation. Because ATP1A3 is also the gene associated with rapid-onset dystonia-parkinsonism (DYT12, OMIM 128235) we compared the genotypes and phenotypes of patients with AHC in our cohort with those of patients with rapid-onset dystonia-parkinsonism reported in the scientific literature. We noted overlapping clinical features, such as abrupt onset of dystonic episodes often triggered by emotional stress, a rostrocaudal (face to arm to leg) gradient of involvement, and signs of brainstem dysfunction, as well as clearly differentiating clinical characteristics, such as episodic hemiplegia and quadriplegia. Interpretation Mutation analysis of the ATP1A3 gene in patients who met clinical criteria for AHC allows for definite genetic diagnosis and sound genetic counselling. AHC and rapid-onset dystonia-parkinsonism are allelic diseases related to mutations in ATP1A3 and form a phenotypical continuum of a dystonic movement disorder
Methoden zur Analyse molekularer Hochdurchsatzdaten vom Modellsystem bis zur translationalen Forschung
No full textA mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2
No full textAuditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted due to genetic or environmental factors. Autosomal-dominant auditory neuropathy type 2 (AUNA2) was linked either to chromosomal bands 12q24 or 13q34 in a large German family in 2017. By whole genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family. ATP11A encodes a P-type ATPase that translocates phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane. The deletion affects both isoforms of ATP11A and activates a cryptic splice site leading to the formation of an alternative last exon. ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of auditory neuropathy. By combining whole genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2
Standardized high-throughput evaluation of cell-based compound screens
No full textAbstract Background High-throughput screening of pharmaceutical compound activity in tissue culture experiments requires time-consuming repeated analysis of the large amounts of data generated. Automation of the evaluation procedure and assessment of measurement accuracy can save time and improve the comparability of results. Results We present a tool for simultaneous evaluation of an arbitrary number of compound screens including a standardized statistical validation. It is provided as a novel R package with a Tcl/Tk-based GUI for convenient use in the lab and runs on usual platforms like Linux, Windows and Mac OS. In a compound screen of lung cancer cells, the tool was successfully and efficiently applied for data analysis. Conclusion The package provides an efficient and intuitive platform for automatic evaluation of compound screens, improving the performance and standardization of data analysis.</p
Challenges in the Setup of Large-scale Next-Generation Sequencing Analysis Workflows
No full textWhile Next-Generation Sequencing (NGS) can now be considered an established analysis technology for research applications across the life sciences, the analysis workflows still require substantial bioinformatics expertise. Typical challenges include the appropriate selection of analytical software tools, the speedup of the overall procedure using HPC parallelization and acceleration technology, the development of automation strategies, data storage solutions and finally the development of methods for full exploitation of the analysis results across multiple experimental conditions. Recently, NGS has begun to expand into clinical environments, where it facilitates diagnostics enabling personalized therapeutic approaches, but is also accompanied by new technological, legal and ethical challenges. There are probably as many overall concepts for the analysis of the data as there are academic research institutions. Among these concepts are, for instance, complex IT architectures developed in-house, ready-to-use technologies installed on-site as well as comprehensive Everything as a Service (XaaS) solutions. In this mini-review, we summarize the key points to consider in the setup of the analysis architectures, mostly for scientific rather than diagnostic purposes, and provide an overview of the current state of the art and challenges of the field
Author response: Antagonistic modulation of NPY/AgRP and POMC neurons in the arcuate nucleus by noradrenalin
No full textIn the arcuate nucleus of the hypothalamus (ARH) satiety signaling (anorexigenic) pro-opiomelanocortin (POMC)-expressing and hunger signaling (orexigenic) agouti-related peptide (AgRP)-expressing neurons are key components of the neuronal circuits that control food intake and energy homeostasis. Here, we assessed whether the catecholamine noradrenalin directly modulates the activity of these neurons in mice. Perforated patch clamp recordings showed that noradrenalin changes the activity of these functionally antagonistic neurons in opposite ways, increasing the activity of the orexigenic NPY/AgRP neurons and decreasing the activity of the anorexigenic POMC neurons. Cell type-specific transcriptomics and pharmacological experiments revealed that the opposing effect on these neurons is mediated by the activation of excitatory α(1A) - and β- adrenergic receptors in NPY/AgRP neurons, while POMC neurons are inhibited via α(2A) - adrenergic receptors. Thus, the coordinated differential modulation of the key hypothalamic neurons in control of energy homeostasis assigns noradrenalin an important role to promote feeding
Bibliographical essays,
No full textMemorial volume, containing all of Proctor's bibliographical essays and papers, with a memoir prefixed. Edited by A. W. Pollard."Two hundred copies printed. no. 158 [signed] A. W. P."Robert Proctor [memoir]--Report of Proctor memorial fund.--Accipies woodcut.--On two plates in Sotheby's 'Principia typographica.'--Marcus Reinhard and Johann Grüninger.--Incunabula at Grenoble.--The 'Gutenberg' Bible.--A short view of Berthelet's editions of the statues of Henry VIII.--On two Lyonnese editions of the 'Ars moriendi'.--Ulrich von Ellenbog and the press of S. Ulrich at Augsburg.--The French royal Greek types and the Eton Chrysostom.--The early printers of Köln.--Tracts on early printing: I. List of the founts of type and woodcut devices used by the printers of the southern Netherlands in the fifteenth century. II. A note on Eberhard Frommolt of Basel, printer. III. Additions to Campbell's 'Annales de la typographie neérlandaise au 15e siècle.--Table of supplements to Campbell.--Author-register.--Index.Mode of access: Internet
Ein verteiltes Medienarchiv für bioakustische Datenbestände
No full textIn diesem Beitrag stellen wir eine Projektinitiative zum Aufbau eines verteilten Medienarchivs für bioakustische Datenbestände vor. Im Zuge dieser von der Deutschen Forschungsgemeinschaft (DFG) geförderten Initiative wurde zunächst aufbauend auf den momentan in Digitalisierung befindlichen Datenbeständen des Tierstimmenarchivs der Humboldt Universität (HU) zu Berlin ein internetbasiertes In- formationssystem zur örtlich verteilten Forschungskooperation im Bereich Bioakustik konzipiert und realisiert. Ein wesentliches Ziel der aktuellen Projektphase stellt darauf aufbauend die konkrete Anbindung von deutschlandweit verfügbaren bioakustischen Medienbeständen dar
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