Back to Work – mit Peer Support : der Einbezug von Peers in die Reintegration von Menschen nach erworbener Hirnschädigung in den ersten Arbeitsmarkt

Einleitung: Für viele Menschen ist nach erworbener Hirnschädigung die Rückkehr zur Arbeit ein priorisiertes Ziel und stellt gleichzeitig eine enorme Herausforderung dar. In der Vergangenheit ist bereits belegt worden, dass Betroffene von Peer Support in unterschiedlichen Settings profitieren. Ziel: Es wird aufgezeigt, welche Herausforderungen Menschen nach erworbener Hirnschädigung in der Arbeitsreintegration erleben und daraus abgeleitet, wie bisherige Erfahrungen mit Peer Support in der Arbeitswiedereingliederung unterstützend eingesetzt werden könnten. Methode: Anhand einer Literaturrecherche sind neun Studien und ein Review ausgesucht und kritisch beurteilt worden. Die Ergebnisse sind mittels einer Template-Analyse auf das Model of Human Occupation übertragen, kategorisiert und interpretiert worden. Ergebnisse: Menschen nach erworbener Hirnschädigung erleben vielfältige Herausforderungen in der Arbeitsreintegration. Die Erfahrungen aus anderen Settings zeigen, dass Peers den Betroffenen zu mehr Akzeptanz und einem besseren Selbstbild verhelfen können, indem sie eine Vorbildfunktion übernehmen und spezifische Bewältigungsstrategien vermitteln. Peer Support-Programme bringen jedoch logistische Herausforderungen mit sich und bedürfen einer ausreichenden Supervision. Schlussfolgerung: Die Ergebnisse deuten darauf hin, dass sich Peer Support auf die Arbeitsreintegration von Menschen nach erworbener Hirnschädigung positiv auswirkt. Es kann allerdings kein deckender Übertrag gemacht werden, sondern es braucht weiterführende Forschung für das neurologische Setting

Structural and functional investigations of plant metallothioneins

Summary Metallothioneins (MTs) are small cysteine-rich proteins coordinating various transition metal ions preferably with the electron configuration d10. They are ubiquitously present in most phyla, and next to phytochelatins they represent a successful molecular concept for metal complexation in cells. Although MTs have been studied for decades still limited information is available. Especially plant MTs are not examined sufficiently, neither in structural nor in functional aspects. This study deals mainly with elucidating the structural and functional characteristics of the plant MT2 (cicMT2) from chickpea (Cicer arietinum). As a typical member of the plant MT subgroup p2, it has an N- and C-terminal metal binding region with a long cysteine-devoid linker region in between. The binding of five divalent metal ions (mainly Zn2+ and Cd2+ ions) to the 14 thiolate groups of the cysteines leads to a single metal-thiolate cluster. Recent studies showed the incorporation of sulfide ions into the metal-thiolate cluster of cicMT2. Although the presence of sulfide ions in plant and other MTs has already been reported previously, many details remained unclear. The further in vitro characterization with various analytical techniques could enlighten the features of the cluster in terms of mono- and divalent metal ions, stability, sulfide-modulated increase in cluster size, the influence of the environment on the various isoforms, and the mechanism of the incorporation itself. From our findings we can conclude that sulfide ion incorporation is highly influenced by the metal ion and sulfide ion availability in the experimental setup. While a clear incorporation of sulfide ions can be shown with divalent metal ions, also a change in cluster structure can be reported for monovalent metal ions but its specific features are still under discussion. The size of the cadmium-sulfide-thiolate cluster shows a dependence on the initial available free sulfide ion concentration. In case of cicMT2, the cluster can be enlarged to a multiple size of the one without sulfide ions. Evaluation of the mechanism of sulfide containing Cd2+-thiolate cluster formation reveals a slight distortion or opening of the preformed cluster structure by sulfide ions prior to insertion of additional metal ions into the cluster. To probe the general ability of metallothioneins to form sulfide containing metal-thiolate clusters, analogous experiments were performed with a mammalian MT revealing a probable role of the long cysteine- free linker region present in most plant MTs. Further, determination of the overall 3D structure of cicMT2 was attempted by nuclear magnetic resonance spectroscopy. The obtained spectra indicate intrinsically disordered structures, which might however even be favorable for the metal related function of the protein. Next to the structural features of cicMT2, the function of a variety of plant MTs was approached with yeast complementation assays. These experiments will require further efforts. All in all, we elaborated different aspects of plant metallothioneins, yet a lot of facets are hidden in the dark. Zusammenfassung Metallothionine (MTs) sind kleine cystein-reiche Proteine, die bevorzugt Übergangsmetalle mit einer d10 Elektronenkonfiguration binden. Sie kommen in einem grossen Teil der bekannten Lebensformen vor und repräsentieren neben den Phytochelatinen ein erfolgreiches molekulares Konzept für die Metallkomplexierung in Zellen. Obwohl MTs seit Jahrzehnten studiert werden, sind die vorhandenen Informationen immer noch beschränkt. Insbesondere die pflanzlichen MTs sind wenig untersucht, weder in struktureller noch funktioneller Hinsicht. Diese Studie behandelt hauptsächlich strukturelle und funktionelle Aspekte des pflanzlichen MT2 (cicMT2) der Kichererbse (Cicer arietinum). Als typisches Mitglied der pflanzlichen MT-Untergruppe p2 hat cicMT2 eine N- und C-terminale Metallbindungsregion mit einer dazwischengeschalteten cystein-freien Linkerregion. Die Bindung von fünf zweiwertigen Metallionen (hauptsächlich Zn2+- und Cd2+-Ionen) an die 14 Thiolatgruppen der Cysteine führt zu einem einzelnen Metall-Thiolat-Cluster. Jüngste Studien zeigen die zusätzliche Koordination von Sulfidionen im Metall-Thiolat-Cluster von cicMT2. Obwohl die Anwesenheit von Sulfidionen schon früher nachgewiesen wurde, sind noch viele Details unklar. Die weitere in vitro Charakterisierung konnte die Eigenschaften des Clusters bezüglich ein- und zweiwertiger Metallionen, Stabilität, Sulfid-moduliertem Anstieg der Clustergrösse, den Einfluss der Umgebung auf die verschiedenen Isoformen und den Mechanismus der Aufnahme selbst aufklären. Von unseren Resultaten können wir auf die starke Abhängigkeit der Sulfid-Aufnahme von der Metall- und Sulfidionen-Verfügbarkeit schliessen. Während mit zweiwertigen Metallionen die Sulfid-Aufnahme klar bestätigt werden konnte, wurde mit einwertigen Metallionen zwar eine Änderung in der Cluster-Struktur gezeigt, jedoch verbunden mit offenen Fragen zu den spezifischen Eigenschaften. Die anfängliche Konzentration an frei verfügbaren Sulfidionen bestimmt die Grösse des Cadmium-Sulfid-Thiolate-Clusters. Im Falle von cicMT2 konnte gezeigt werden, dass der Cluster in Gegenwart von Sulfidionen signifikant mehr Metallionen binden kann als in ihrer Abwesenheit. Die Untersuchung des Bildungsmechanismus des Sulfidionen enthaltenden Clusters zeigt eine Sulfid-induzierte geringe Verformung oder Öffnung der vorhandenen Clusterstruktur vor dem Einbau zusätzlicher Metallionen. Um die prinzipielle Existenz von Sulfid-enthaltenden Metall-Thiolat-Clustern in MTs abzuschätzen, wurden analoge Experimente mit Säugetier-Metallothioninen durchgeführt, die eine mögliche Rolle des langen cystein-freien Linkers in gewissen pflanzlichen MTs aufdeckten. Des Weiteren gab es Bestrebungen, die dreidimensionale Struktur des cicMT2 mit Kernspinresonanzspektroskopie zu untersuchen. Die Spektren lieferten Hinweise auf intrinsische ungeordnete Strukturen, die durchaus von Bedeutung für die funktionellen Interaktionen mit den Metallionen sein könnten. Neben den strukturellen Analysen bezüglich cicMT2 versuchten wir, die Funktion von einer Vielfalt pflanzlicher MTs mit der Komplementierung von Hefen zu untersuchen, was allerdings nicht abgeschlossen werden konnte. Alles in allem konnten wir Licht auf verschiedene Aspekte der pflanzlichen Metallothionine werfen, es liegen jedoch noch immer viele Facetten im Dunkeln verborgen

Transition Pathways towards Design Principles of Self-Sovereign Identity

Society\u27s accelerating digital transformation during the COVID-19 pandemic highlighted clearly that the Internet lacks a secure, efficient, and privacy-oriented model for identity. Self-sovereign identity (SSI) aims to address core weaknesses of siloed and federated approaches to digital identity management from both users\u27 and service providers\u27 perspectives. SSI emerged as a niche concept in libertarian communities, and was initially strongly associated with blockchain technology. Later, when businesses and governments began to invest, it quickly evolved towards a mainstream concept. To investigate this evolution and its effects on SSI, we conduct design science research rooted in the theory of technological transition pathways. Our study identifies nine core design principles of SSI as deployed in relevant applications, and discusses associated competing political and socio-technical forces in this space. Our results shed light on SSI\u27s key characteristics, its development pathway, and tensions in the transition between regimes of digital identity management

Transition Pathways towards Design Principles of Self-Sovereign Identity

Society’s accelerating digital transformation during the COVID-19 pandemic highlighted clearly that the Internet lacks a secure, efficient, and privacy-oriented model for identity. Self-sovereign identity (SSI) aims to address core weaknesses of siloed and federated approaches to digital identity management from both users’ and service providers’ perspectives. SSI emerged as a niche concept in libertarian communities, and was initially strongly associated with blockchain technology. Later, when businesses and governments began to invest, it quickly evolved towards a mainstream concept. To investigate this evolution and its effects on SSI, we conduct design science research rooted in the theory of technological transition pathways. Our study identifies nine core design principles of SSI as deployed in relevant applications, and discusses associated competing political and socio-technical forces in this space. Our results shed light on SSI’s key characteristics, its development pathway, and tensions in the transition between regimes of digital identity managemen

Secondary prevention of venous thromboembolism: Predictors and outcomes of guideline adherence in a long-term prospective cohort study.

Background Prevention of recurrent venous thromboembolism (VTE) is considered a main goal of VTE management. However, the extent to which physicians adhere to the recommendations from evidence-based guidelines is unknown. Aim From a large, prospective clinical cohort, we aimed to (1) quantify the adherence of treatment recommendations to evidence-based guidelines and establish its predictors, and (2) estimate its impact on clinical outcomes and costs in patients with VTE. Methods We included 6'243 consecutive patients with VTE treated at the university outpatient unit. Detailed clinical characteristics and treatment recommendations were recorded. Adherence of treatment recommendations to evidence-based guidelines at risk assessment was assessed in terms of duration of anticoagulant treatment. Data on death were obtained from the Swiss Central Compensation Office. Health care claims data recorded between 2014 and 2019 were retrieved from Helsana, one of the largest Swiss health insurance companies. Results The adherence to evidence-based guidelines was 36.1%. Among patients with non-adherence, overtreatment was present in 70.1%. Significant patient-related predictors of guideline adherence were (a) age above 50 years, (b) male sex, (c) pulmonary embolism, (d) unprovoked VTE, (e) multiple VTE, (f) laboratory tests not ordered, and (g) various cardiovascular comorbidities. Non-adherence was not significantly associated with mortality, hospitalization, admission to nursing home, and costs. Conclusions The adherence to evidence-based guidelines was low, and several unrelated predictors appeared. Although these results need to be confirmed in other settings, they highlight the need for implementation of evidence-based guidelines in clinical practice

Platform independent protein-based cell-of-origin subtyping of diffuse large B-cell lymphoma in formalin-fixed paraffin-embedded tissue

Diffuse large B-cell lymphoma (DLBCL) is commonly classified by gene expression profiling according to its cell of origin (COO) into activated B-cell (ABC)-like and germinal center B-cell (GCB)-like subgroups. Here we report the application of label-free nano-liquid chromatography - Sequential Window Acquisition of all THeoretical fragment-ion spectra - mass spectrometry (nanoLC-SWATH-MS) to the COO classification of DLBCL in formalin-fixed paraffin-embedded (FFPE) tissue. To generate a protein signature capable of predicting Affymetrix-based GCB scores, the summed log(2)-transformed fragment ion intensities of 780 proteins quantified in a training set of 42 DLBCL cases were used as independent variables in a penalized zero-sum elastic net regression model with variable selection. The eight-protein signature obtained showed an excellent correlation (r=0.873) between predicted and true GCB scores and yielded only 9 (21.4%) minor discrepancies between the three classifications: ABC, GCB, and unclassified. The robustness of the model was validated successfully in two independent cohorts of 42 and 31 DLBCL cases, the latter cohort comprising only patients aged >75 years, with Pearson correlation coefficients of 0.846 and 0.815, respectively, between predicted and NanoString nCounter based GCB scores. We further show that the 8-protein signature is directly transferable to both a triple quadrupole and a Q Exactive quadrupole-Orbitrap mass spectrometer, thus obviating the need for proprietary instrumentation and reagents. This method may therefore be used for robust and competitive classification of DLBCLs on the protein level

Effect of mobile telephones on sperm quality: A systematic review and meta-analysis.

types: REVIEWThis is an open access article that is freely available in ORE or from the publisher's web site. Please cite the published version.© 2014 The Authors. Published by Elsevier Ltd.Mobile phones are owned by most of the adult population worldwide. Radio-frequency electromagnetic radiation (RF-EMR) from these devices could potentially affect sperm development and function. Around 14% of couples in high- and middle-income countries have difficulty conceiving, and there are unexplained declines in semen quality reported in several countries. Given the ubiquity of mobile phone use, the potential role of this environmental exposure needs to be clarified. A systematic review was therefore conducted, followed by meta-analysis using random effects models, to determine whether exposure to RF-EMR emitted from mobile phones affects human sperm quality. Participants were from fertility clinic and research centres. The sperm quality outcome measures were motility, viability and concentration, which are the parameters most frequently used in clinical settings to assess fertility. We used ten studies in the meta-analysis, including 1492 samples. Exposure to mobile phones was associated with reduced sperm motility (mean difference -8.1% (95% CI -13.1, -3.2)) and viability (mean difference -9.1% (95% CI -18.4, 0.2)), but the effects on concentration were more equivocal. The results were consistent across experimental in vitro and observational in vivo studies. We conclude that pooled results from in vitro and in vivo studies suggest that mobile phone exposure negatively affects sperm quality. Further study is required to determine the full clinical implications for both sub-fertile men and the general population.Open Access funded by Natural Environment Research CouncilJessica Elliott-Friend is supported by a Natural Environment Research Council PhD scholarship NE/J500185/

Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily

With over 450 genes, solute carriers (SLCs) constitute the largest transporter superfamily responsible for the uptake and efflux of nutrients, metabolites, and xenobiotics in human cells. SLCs are associated with a wide variety of human diseases, including cancer, diabetes, and metabolic and neurological disorders. They represent an important therapeutic target class that remains only partly exploited as therapeutics that target SLCs are scarce. Additionally, many small molecules reported in the literature to target SLCs are poorly characterized. Both features may be due to the difficulty of developing SLC transport assays that fulfill the quality criteria for high-throughput screening. Here, we report one of the main limitations hampering assay development within the RESOLUTE consortium: the lack of a resource providing high-quality information on SLC tool compounds. To address this, we provide a systematic annotation of tool compounds targeting SLCs. We first provide an overview on RESOLUTE assays. Next, we present a list of SLC-targeting compounds collected from the literature and public databases; we found that most data sources lacked specificity data. Finally, we report on experimental tests of 19 selected compounds against a panel of 13 SLCs from seven different families. Except for a few inhibitors, which were active on unrelated SLCs, the tested inhibitors demonstrated high selectivity for their reported targets. To make this knowledge easily accessible to the scientific community, we created an interactive dashboard displaying the collected data in the RESOLUTE web portal (https://re-solute.eu). We anticipate that our open-access resources on assays and compounds will support the development of future drug discovery campaigns for SLCs

Involvement of the Modifier Gene of a Human Mendelian Disorder in a Negative Selection Process

BACKGROUND:Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA) in patients with familial Mediterranean fever (FMF), a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA. METHODOLOGY/PRINCIPAL FINDINGS:HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%), and Karabakh, where RA is rare (2.5%). Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4%) as compared to Armenian patients (24%) (p = 5.10(-5)). Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE) in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE). CONCLUSIONS/SIGNIFICANCE:The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

Publisher Copyright: © 2022, The Author(s).We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI’s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.Peer reviewe