Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Servant versus directive leadership and promotability: does leader gender matter?

Citation: Barthel A. D. T. & Buengeler C. (2023). Servant versus directive leadership and promotability: does leader gender matter? Frontiers in Psychology 14:957121. doi: 10.3389/fpsyg.2023.95712

Führung als erfolgreiche Einflussnahme in kritischen Momenten. Grundzüge, Implikationen und Forschungsperspektiven

Muster J, Büchner S, Hoebel T, Koepp T. Führung als erfolgreiche Einflussnahme in kritischen Momenten. Grundzüge, Implikationen und Forschungsperspektiven. In: Barthel C, ed. Managementmoden in der Verwaltung. Sinn und Unsinn. Wiesbaden: Springer VS; 2020: 285-305.In der Organisations- und Managementforschung ist Führung ein allgegenwärtiger Begriff. Die Literaturlage lässt dabei erkennen, welch großes Potenzial Führung zur Leistungssteigerung von Organisationen zugeschrieben wird. Angesichts dieser Relevanz erstaunt, wie wenig Führung als soziales Phänomen theoretisiert ist. Der vorliegende Beitrag schließt diese Lücke mit einer theoretisch integrierten Begriffsbestimmung von Führung. Führung wird als situativ erfolgreiche Einflussnahme in kritischen Momenten konzipiert, die sich in einer Sequenz von drei Ereignissen realisiert: Das Auslöseereignis ist eine soziale Situation, in der ein kritischer Moment entsteht, der Führung überhaupt notwendig macht (I). Darauf folgt ein kommunikativ erhobener Führungsanspruch, in dem Einflussmittel mobilisiert werden (II). Am Entstehen von Gefolgschaft (III) zeigt sich, ob Führung stattgefunden hat. Das vorgeschlagene Führungsverständnis nimmt einen dezidiert organisationssoziologischen Blickwinkel ein, indem es den Unterschied zwischen Führung und Hierarchie hervorhebt und für die Theoretisierung fruchtbar macht. Auf diese Weise erschließt sich ein problemsensibles, umfassendes, flexibles und zugleich trennscharfes Führungsverständnis. Dieser Blickwinkel berücksichtigt, dass Organisationen sich nicht immer an ihre eigenen Regeln halten, also z. B. Hierarchien nicht unumstößlich festlegen, wer in Führung geht. Er ermöglicht außerdem, interaktionale Dynamiken mitzubeobachten, die sich einer planvollen Steuerung entziehen. So wird erklärbar, dass nicht nur von oben nach unten geführt werden kann, sondern ebenfalls unter Gleichen oder von unten nach oben. Führung wird als das Ergebnis eines sozialen Prozesses zwischen allen Beteiligten konzipiert

From spores to fungal pellets: A new high-throughput image analysis highlights the structural development of Aspergillus niger

Many filamentous fungi are exploited as cell factories in biotechnology. Cultivated under industrially relevant submerged conditions, filamentous fungi can adopt different macromorphologies ranging from dispersed mycelia over loose clumps to pellets. Central to the development of a pellet morphology is the agglomeration of spores after inoculation followed by spore germination and outgrowth into a pellet population, which is usually very heterogeneous. As the dynamics underlying population heterogeneity is not yet fully understood, we present here a new high-throughput image analysis pipeline based on stereomicroscopy to comprehensively assess the developmental program starting from germination up to pellet formation. To demonstrate the potential of this pipeline, we used data from 44 sampling times harvested during a 48 h submerged batch cultivation of the fungal cell factory Aspergillus niger. The analysis of up to 1700 spore agglomerates and 1500 pellets per sampling time allowed the precise tracking of the morphological development of the overall culture. The data gained were used to calculate size distributions and area fractions of spores, spore agglomerates, spore agglomerates within pellets, pellets, and dispersed mycelia. This approach eventually enables the quantification of culture heterogeneities and pellet breakage.DFG, 315384307, Verallgemeinerte morphologische Modellierung aggregierender, filamentöser MikroorganismenDFG, 315305620, Untersuchung des Einflusses von Scherkräften auf das morphogenetische Gennetzwerk, die Zellintegrität, mikroskopische und makroskopische Morphologie von Aspergillus niger sowie Bildungsraten intra- und extrazellulärer ProdukteDFG, 427889137, Kontrolle von Monospezies und Multispezies Pellet-Heterogenitäten und deren Auswirkungen auf Produktbildung in der Zellfabrik Aspergillus nige

A versatile platform for activity determination of cytokines and growth factors based on the human TSLP (thymic stromal lymphopoietin) receptor

Cytokines and growth factors are signaling proteins involved in communication processes between cells. They are involved in the control of numerous essential physiological processes such as cell proliferation, gene transcription and differentiation; therefore being in the focus of basic and applied research. Many of them are also of relevance for human diseases. When observed as potential targets for pharmacological intervention and objects of structure/function studies, it is important to measure their biological activities, optionally along with potential inhibitors, in a convenient and rational manner. Such tests are frequently laborious to set up and their establishment is complicated by the necessity to employ problematic cell types and sophisticated assays. Here we present a robust and modular activity assay system which can be adapted to virtually all ligands that signal through dimerization of membrane receptors from different families. The technique rests on fusing ligandbinding domains of specific receptors to the transmembrane and intracellular components of the thymic stromal lymphopoietin (TSLP) receptor which translates signals into readily quantifiable luciferase expression in reporter cells. We show that the activation of various hematopoietic cytokine receptors, of receptor tyrosine kinases as well as of receptors bearing serine/threonine kinase domains by their respective ligands was faithfully reflected both upon transient and stable introduction of hybrid receptor and reporter gene constructs into the murine pro B cell line Ba/F3. Moreover, we demonstrate the suitability of this platform for the functional characterization of cytokine/growth factor receptor inhibitors