The structure and oxidation of the eye lens chaperone αA-crystallin

The small heat shock protein αA-crystallin is a molecular chaperone important for the optical properties of the vertebrate eye lens. It forms heterogeneous oligomeric ensembles. We determined the structures of human αA-crystallin oligomers by combining cryo-electron microscopy, cross-linking/mass spectrometry, NMR spectroscopy and molecular modeling. The different oligomers can be interconverted by the addition or subtraction of tetramers, leading to mainly 12-, 16- and 20-meric assemblies in which interactions between N-terminal regions are important. Cross-dimer domain-swapping of the C-terminal region is a determinant of αA-crystallin heterogeneity. Human αA-crystallin contains two cysteines, which can form an intramolecular disulfide in vivo. Oxidation in vitro requires conformational changes and oligomer dissociation. The oxidized oligomers, which are larger than reduced αA-crystallin and destabilized against unfolding, are active chaperones and can transfer the disulfide to destabilized substrate proteins. The insight into the structure and function of αA-crystallin provides a basis for understanding its role in the eye lens

COSMO-CLM regional climate simulations in the Coordinated Regional Climate Downscaling Experiment (CORDEX) framework: a review

In the last decade, the Climate Limited-area Modeling Community (CLM-Community) has contributed to the Coordinated Regional Climate Downscaling Experiment (CORDEX) with an extensive set of regional climate simulations. Using several versions of the COSMO-CLM-Community model, ERA-Interim reanalysis and eight global climate models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) were dynamically downscaled with horizontal grid spacings of 0.44∘ (∼ 50 km), 0.22∘ (∼ 25 km), and 0.11∘ (∼ 12 km) over the CORDEX domains Europe, South Asia, East Asia, Australasia, and Africa. This major effort resulted in 80 regional climate simulations publicly available through the Earth System Grid Federation (ESGF) web portals for use in impact studies and climate scenario assessments. Here we review the production of these simulations and assess their results in terms of mean near-surface temperature and precipitation to aid the future design of the COSMO-CLM model simulations. It is found that a domain-specific parameter tuning is beneficial, while increasing horizontal model resolution (from 50 to 25 or 12 km grid spacing) alone does not always improve the performance of the simulation. Moreover, the COSMO-CLM performance depends on the driving data. This is generally more important than the dependence on horizontal resolution, model version, and configuration. Our results emphasize the importance of performing regional climate projections in a coordinated way, where guidance from both the global (GCM) and regional (RCM) climate modeling communities is needed to increase the reliability of the GCM–RCM modeling chain

Comparative evaluation of Gram-positive membrane components in activating the innate immune system

Lipopolysaccharide (LPS) is the major immunostimulatory component of Gramnegative bacteria, but its counterpart in Gram-positive bacteria is still under discussion. Looking on the Gram-positive cell wall, three components are considered to be recognised by cells of the human innate immune system: Peptidoglycan (PGN), quantitatively the main component, lipoteichoic acid (LTA) as a similar amphiphile structure compared to LPS and lipoproteins (LP). To find out more about the immunostimulatory capacity of these membrane components, the first approach in this thesis was to screen public available literature for evidence, that cytokine release in humans is connected with one or more of the named components. This research was done systematically as a meta-analysis with the four well-known Koch-Dale (K/D) criteria with a restriction to human studies. Taken together, the results of the meta-analysis indicated that PGN and LPs might play a role in cytokine induction and therefore in immune recognition of Gram-positive bacteria in humans, but the evidence for LTA being the major immune stimulus in Gram-positive bacteria is strong as it is the only investigated molecule fulfilling all K/D criteria. The interesting findings of this meta-analysis needed to be investigated experimentally. The model organism for these investigations was Staphylococcus aureus (SA), which is a frequent human pathogen and often colonises humans asymptomatically, but is also able to induce severe infections in tissue or even spreading into the blood. In the second part of the thesis, three different SA 113 mutants, which were lacking lipoproteins (Δlgt) or wall teichoic acids (ΔTA) or possessed a reduced alanine content of the LTA (Δdlt) were compared to its corresponding wildtype with respect to their immunostimulatory capacity in human primary cells. We could finally show that the different mutants differ only marginally in their immunostilumatory capacity. Despite the strong evidence that LTA is a major immunostimulatory principle of Gram-positive bacteria, recent reports suggested that not LTA but lipoproteins are the dominant immunostimulatory structures of SA. Therefore we compared the LTA from SA 113 Δlgt and its corresponding wildtype in more detail. This study clearly shows major similarities between wt and lgt LTA, but differences in immunrecognition to synthetic lipoproteins. In summary, the results of this thesis contribute to the understanding of the innate immune response with the focus on cell wall components of Gram-positive bacteria. This may lead to new approaches to treatments against Gram-positive bacterial infections in the future

FM in der Spitalhygiene : past – present – future

Die Spitalhygiene stellt ein besonders komplexes Fachgebiet der Hygiene dar. Damit möglichst umfassend aufgezeigt werden kann, was bisher im Kontext Spitalhygiene als Standard galt, welche Schnittstellen zum FM vorliegen, und welche Veränderungen in diesem Bereich zu erwarten sind, ist es wichtig, verschiedene Sichtweisen und Einschätzungen auszuweisen. Für den vorliegenden Artikel wurden daher verschiedene Perspektiven und Aufgabenbereiche berücksichtigt. Die hier zu Wort kommenden Protagonisten der Spitalhygiene sind Akteure, die Schlüsselpositionen in unterschiedlichen Funktions- und Verantwortungs-bereichen bekleiden. Sie gehen in ihrer Arbeit und in ihren Aufträgen kollaborativ mit Aufgabenbereichen des FM um, und umgekehrt. Im konkreten Fall sind dies die Verantwortungsträger aus zwei Schweizer Spitälern, von national und global agierenden Dienstleistungs-Unternehmen aus dem Bereich Reinigung und Hygiene, von einem Beratungsunternehmen mit Mandats-Schwerpunkt Hygiene sowie von einer kantonalen Behörde, die im Auftrag der Gesundheitsdirektion ihre Arbeit verrichtet. Der vorliegende Beitrag soll Anforderungen, Bedürfnisse und Interessen zusammengetragen, und kann dadurch als aktuelles und weit gefasstes Stimmungsbild verstanden werden

Evidence for the detection of non-endotoxin pyrogens by the whole blood monocyte activation test

Threats of pyrogenicity were discovered more than a century ago. Measures to determine the safety of parenterals and, more recently, medical devices and cell therapies for human use have been in place for 70 years. Currently, there are three testing possibilities available: the Rabbit Pyrogen Test, the Limulus Amebocyte Lysate test (Bacterial Endotoxin Test), and test systems using human whole blood or human monocytes, called Monocyte Activation Test (MAT). The MAT is based on the human fever reaction and thus most closely reflects the human situation. Unfortunately, regulations and testing guidelines are not fully harmonized, despite formal international validation. Furthermore, data showing that the MAT is capable of covering the totality of possible pyrogens relevant to humans were not included in the MAT validations of the last decade. For this review we collate evidence from published literature, unpublished data of our own, and results from the international validation study to show that there is overwhelming scientific evidence to conclude that the whole blood MAT reliably detects non-endotoxin pyrogens. Therefore, further validation exercises do not seem warranted

COSMO-CLM regional climate simulations in the Coordinated Regional Climate Downscaling Experiment (CORDEX) framework: a review

In the last decade, the Climate Limited-area Modeling Community (CLM-Community) has contributed to the Coordinated Regional Climate Downscaling Experiment (CORDEX) with an extensive set of regional climate simulations. Using several versions of the COSMO-CLM-Community model, ERA-Interim reanalysis and eight global climate models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) were dynamically downscaled with horizontal grid spacings of 0.44 degrees (similar to 50 km), 0.22 degrees (similar to 25 km), and 0.11 degrees (similar to 12 km) over the CORDEX domains Europe, South Asia, East Asia, Australasia, and Africa. This major effort resulted in 80 regional climate simulations publicly available through the Earth System Grid Federation (ESGF) web portals for use in impact studies and climate scenario assessments. Here we review the production of these simulations and assess their results in terms of mean near-surface temperature and precipitation to aid the future design of the COSMO-CLM model simulations. It is found that a domain-specific parameter tuning is beneficial, while increasing horizontal model resolution (from 50 to 25 or 12 km grid spacing) alone does not always improve the performance of the simulation. Moreover, the COSMO-CLM performance depends on the driving data. This is generally more important than the dependence on horizontal resolution, model version, and configuration. Our results emphasize the importance of performing regional climate projections in a coordinated way, where guidance from both the global (GCM) and regional (RCM) climate modeling communities is needed to increase the reliability of the GCM-RCM modeling chain.11Ysciescopu

COSMO-CLM regional climate simulations in the CORDEX framework: a review

In the last decade, the Climate Limited-area Modeling (CLM) Community has contributed to the Coordinated Regional Climate Downscaling Experiment (CORDEX) with an extensive set of regional climate simulations. Using several versions of the COSMO-CLM community model, ERA-Interim reanalysis and eight Global Climate Models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) were dynamically downscaled with horizontal grid spacings of 0.44◦(∼50 km), 0.22◦ (∼25 km) and 0.11◦ (∼12 km) over the CORDEX domains Europe, South Asia, East Asia, Australasia and Africa. This major effort resulted in 80 regional climate simulations publicly available through the Earth System Grid Federation (ESGF) web portals for use in impact studies and climate scenario assessments. Here we review the production of these simulations and assess their results in terms of mean near-surface temperature and precipitation to aid the future design of the COSMO-CLM model simulations. It is found that a domain-specific parameter tuning is beneficial, while increasing horizontal model resolution (from 50 to 25 or 12 km grid spacing) alone does not always improve the performance of the simulation. Moreover, the COSMO-CLM performance depends on the driving data. This is generally more important than the dependence on horizontal resolution, model version and configuration. Our results emphasize the importance of performing regional climate projections in a coordinated way, where guidance from both the global (GCM) and regional (RCM) climate modelling communities is needed to increase the reliability of the GCM-RCM modelling chain