Prion Replication in the Mammalian Cytosol: Functional Regions within a Prion Domain Driving Induction, Propagation, and Inheritance

Prions of lower eukaryotes are transmissible protein particles that propagate by converting homotypic soluble proteins into growing protein assemblies. Prion activity is conferred by so-called prion domains, regions of low complexity that are often enriched in glutamines and asparagines (Q/N). The compositional similarity of fungal prion domains with intrinsically disordered domains found in many mammalian proteins raises the question of whether similar sequence elements can drive prion-like phenomena in mammals. Here, we define sequence features of the prototype Saccharomyces cerevisiae Sup35 prion domain that govern prion activities in mammalian cells by testing the ability of deletion mutants to assemble into self-perpetuating particles. Interestingly, the amino-terminal Q/N-rich tract crucially important for prion induction in yeast was dispensable for the prion life cycle in mammalian cells. Spontaneous and template-assisted prion induction, growth, and maintenance were preferentially driven by the carboxy-terminal region of the prion domain that contains a putative soft amyloid stretch recently proposed to act as a nucleation site for prion assembly. Our data demonstrate that preferred prion nucleation domains can differ between lower and higher eukaryotes, resulting in the formation of prions with strikingly different amyloid cores

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC-TOF-MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface-bound fucose. The reduced ICAM-1 expression and the loss of cell surface-bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable "steady state" after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions

Wound healing in rabbit corneas after flapless refractive lenticule extraction with a 345 nm ultraviolet femtosecond laser

Purpose To characterize corneal wound healing in a rabbit model after flapless refractive lenticule extraction with a 345 nm ultraviolet femtosecond laser. Setting Departments of Ophthalmology and Anatomy II, University of Erlangen-Nürnberg and Wavelight GmbH, Erlangen, Germany. Design Methods Flapless refractive lenticule extraction was performed in 1 eye each of 20 New Zealand white rabbits (−5.0 diopters). Groups of 4 animals were euthanized after 48 hours, 1 week, 2 weeks, 4 weeks, and 3 months, respectively. Corneal samples were prepared for histology and fluorescence microscopy. To assess corneal cell death, proliferation, and myofibroblastic transdifferentiation, terminal uridine deoxynucleotidyl nick end-labeling (TUNEL) assay as well as immunostaining for Ki67 and α-smooth muscle actin (αSMA) were performed on sagittal cryosections. Results Histology revealed a zone of keratocyte depletion with a thickness of approximately 50 μm around the extraction site. At 48 hours, pronounced TUNEL staining of keratocytes was detected around the interface (159.9 cells/mm ± 18.4 [SD]), which steadily decreased to 74.9 ± 19.8 cells/mm at 1 week and 5.7 ± 4.8 cells/mm at 2 weeks. Ki67 staining of keratocytes was evident at 48 hours (10.0 ± 3.8 cells/mm), which then decreased at 1 week (5.2 ± 1.7 cells/mm) and 2 weeks (0.4 ± 0.5 cells/mm). From 4 weeks onward, no TUNEL or Ki67 staining was detected. The corneal stroma was αSMA-negative at all timepoints. Conclusion Application of the 345 nm laser showed no signs of problematic repair processes in the cornea, which supports the initiation of the clinical phase

A global inventory of mountains for bio-geographical applications

Mountains are hotspots of biodiversity. Yet, evaluating their importance in global biodiversity inventories requires the adoption of a pertinent definition of mountains. Here, we first compare the well-established WCMC and GMBA definitions, which both use geographical information systems. We show that the WCMC approach arrives at twice the global mountain area and much higher human population numbers than the GMBA one, which is explained by the inclusion of (mostly) low latitude hill country below 600 m elevation. We then present an inventory of the world’s mountains based on the GMBA definition. In this inventory, each of the 1003 entries corresponds to a polygon drawn around a mountain or a mountain range and includes the name of the delineated object, the area of mountainous terrain it covers stratified into different bioclimatic belts (all at 2.5′ resolution), and demographic information. Taken together, the 1003 polygons cover 13.8 Mio km2 of mountain terrain, of which 3.3 Mio km2 are in the alpine and nival belts. This corresponds to 83.7% of the global mountain area sensu GMBA, and 94% of the alpine/nival area. The 386 Mio people inhabiting mountainous terrain within polygons represent 75% of the people globally inhabiting mountains sensu GMBA. This inventory offers a robust framework for the integration of mountain biota in regional and larger scale biodiversity assessments, for biogeography, bioclimatology, macroecology, and conservation research, and for the exploration of a multitude of socio-ecological and climate change-related research questions in mountain biota, including the potential pressure on alpine ecosystems

Integration und berufliche Ausbildung: Expertise

Die Expertise entwickelt Handlungsempfehlungen zur Verbesserung der Ausbildungslage junger Menschen mit Migrationshintergrund. Diese Handlungsempfehlungen orientieren sich an zentralen Forschungsergebnissen zu den Partizipationsmöglichkeiten junger Migranten und Migrantinnen an beruflicher Ausbildung. Im Vordergrund stehen hierbei die interkulturellen Potenziale junger Fachkräfte sowie die Ausbildungschancen junger Menschen mit Migrationshintergrund. Die qualitativ angelegte Untersuchung des Bundesinstituts für Berufsbildung zum Einsatz interkultureller Kompetenzen zeigt auf, wie junge Fachkräfte mit Migrationshintergrund diese in ihrem Berufsalltag einsetzen. Dies betrifft sowohl Berufe, deren Tätigkeiten sich auf das Inland konzentrieren, wie Arzthelferinnen und Einzelhandelskaufleute, als auch solche mit Auslandskontakten, wie Speditions- und Außenhandelskaufleute. Der Einsatz interkultureller Kompetenzen weist berufsübergreifende Ähnlichkeiten, aber auch berufsspezifische Unterschiede auf. Die Ausbildungschancen und damit auch die Aussichten auf eine tragfähige berufliche Integration haben sich im vergangenen Jahrzehnt für junge Menschen mit Migrationshintergrund in Deutschland überproportional verschlechtert. Angesichts der erklärten bildungspolitischen Zielsetzung der Bundesregierung wie der Sozialparteien, allen jungen Menschen in Deutschland eine voll qualifizierende Berufsausbildung zu ermöglichen, ist eine breit angelegte und abgestimmte Qualifizierungsoffensive für junge Menschen mit Migrationshintergrund wünschenswert. Die Handlungsempfehlungen plädieren für ein integriertes und abgestimmtes Förder-Programm dessen Maßnahmen sich an folgenden Zielsetzungen orientieren sollen: a) eine qualifizierte Ausbildung für alle; b) Potenziale ausschöpfen und c) berufliche Qualifizierungsnetzwerke lokal und regional fördern. (IAB

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOXPRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U. S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS- 3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC-TOF-MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface-bound fucose. The reduced ICAM-1 expression and the loss of cell surface-bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a '' stable-steady state '' after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions

Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa

Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1)