Nachhaltige Unternehmensführung und Wertschöpfung - Identifikation wertschöpfender Parameter der nachhaltigen Unternehmensführung bei kleinen und mittleren Unternehmen

Ziel dieser Arbeit ist es, geeignete forschungsbasierte Nachhaltigkeitsmanagement-Ansätze für kleine und mittlere Unternehmen (KMU) zu entwickeln, indem der Wertbeitrag nachhaltiger Geschäftspraktiken zum wirtschaftlichen Nutzen, zur Risikominderung und zur Innovationsleistung sowie die Einflussfaktoren, die das Ergebnis dieses Beitrags moderieren, untersucht werden. Im Vergleich zu ihrem Beitrag zum Bruttoinlandsprodukt sind KMUs in der Nachhaltigkeitsforschung unterrepräsentiert. Die aktuelle Nachhaltigkeitsforschung skizziert das komplexe Zusammenspiel von Einflussfaktoren und Wertbeiträgen und unterstreicht den Bedarf an Handlungsfeldern, die für KMU praktikabel sind. Auf Basis einer systematischen Literaturanalyse, welche die Analyse von 139 Referenzen aus 116 Studien umfasst, und in Kombination mit einem auf Interviews basierenden Ansatz, der eine Stichprobe von 14 Interviews mit Unternehmen umfasst, die sich aktiv mit nachhaltigen Geschäftspraktiken beschäftigen, zeigt diese Arbeit sowohl die positiven als auch negativen Wertbeiträge auf, die durch die Einführung nachhaltiger Geschäftspraktiken generiert werden. Zudem werden die wichtigsten Einflussfaktoren identifiziert, die das Ergebnis des Wertbeitrags moderieren. Die Bedeutsamkeit dieser Arbeit liegt darin, dass sie durch die Kombination verschiedener methodischer Ansätze indikative Ergebnisse für konkrete Handlungsfelder für KMU liefert. Die Ergebnisse dieser Arbeit geben darüber hinaus Aufschluss darüber, wie zukünftige KMU-Nachhaltigkeitsforschung gestaltet werden kann, um ein greifbares Ergebnis zu gewährleisten, das den KMU Entscheidungsgrundlagen für die Einführung nachhaltiger Geschäftspraktiken liefert

Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide

Abstract Background Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. Objective We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. Results 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100–800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. Conclusion AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.Identification of new causative genes in spinocerebellar degenerations by combination of whole genome scan, next-generation sequencing and biological validation in vitro and in vivoInfrastructure de Recherche Translationnelle pour les Biothérapies en NeurosciencesEuropean Union’s Horizon 2020 research and innovation programm

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

[Hereditary peripheral neuropathies]

International audienc

[Hereditary neuropathies].

International audienc

Les syndromes myasthéniques congénitaux avec anomalies cinétiques du récepteur à l’acétylcholine

Les syndromes myasthéniques congénitaux (SMC) sont des affections génétiquement et phénotypiquement très hétérogènes responsables d’un déficit de la transmission neuromusculaire. Les formes dites post-synaptiques sont les plus fréquentes des SMC, et parmi elles, le déficit en récepteur à l’acétylcholine (low expressor) est le mécanisme physiopathologique le plus souvent en cause. Les SMC avec anomalies cinétiques du récepteur à l’acétylcholine sont beaucoup plus rares et à l’origine de tableaux cliniques à l’issue parfois dramatique. On en dénombre deux types : le syndrome du canal lent et le syndrome du canal rapide. Leur diagnostic et leur prise en charge thérapeutique sont spécifiques à chaque type. Dans ce travail, nous détaillerons leurs aspects phénotypiques respectifs en les illustrant par les observations de trois familles algériennes

La grande variabilité phénotypique des mutations du gène

Le gène RYR1 (Ryanodine-Receptor-1) code pour une protéine-clé dans le processus de couplage excitation-contraction de la fibre musculaire. Ce récepteur est le principal canal de libération du calcium à partir du réticulum endoplasmique [