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We report here the nuclear magnetic resonance 19F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.
Background: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C.
Methodology/Principal Findings: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome.
Conclusions/Significance: Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.
Durch einen Vergleich nach ca. 30 Jahren wiederholter Vegetationsaufnahmen von Glatthaferwiesen an Straßenrändern des Raumes Halle/S. konnten die in der Zwischenzeit stattgefundenen anthropogenen Veränderungen der straßenbegleitenden Vegetation am konkreten Beispiel belegt werden. Zur Interpretation der Veränderungen in der Artenzusammensetzung wurden besonders Zeigerwert-, Hemerobie- und Strategietypenspektren herangezogen. Veränderungen äußern sich vor allem in einer Abnahme der Diversität durch Zunahme euryöker Ubiquisten und einer Erhöhung des Hemerobiegrades. Die Ursachen für diesen Wandel sind besonders in der Intensivierung der Produktion auf den angrenzenden landwirtschaftlichen Nutzflächen und einer weitestgehenden Auflassung der Nutzung der Straßenränder selbst zu sehen, die sich in deren Eutrophierung äußern.
Poster presentation: Background Maraviroc is a new drug used to treat HIV infection from the new class of drugs called CCR5 entry inhibitors. As the active principle of these drugs is to block the CCR5-receptor on the surface of the target cells, it has to be known if the virus in the patient is using only CCR5 as co-receptor or if there are populations that can also use CXCR4. Therefore, an assay to determine the tropism has to be performed before starting a therapy. Besides phenotypic assays like the TROFILE® assay by Monogram, used in the approval studies, there exist several genotyping systems like geno2pheno-coreceptor, Wetcat (providing five different genotypic tropism schemes) and WebPSSM. ...
The Feldbach district is situated near the town of Feldbach in the southeastern province of Styria, Austria. Since 2007, a climate observation network of 151 climate stations within an area of approximately 20 x 15 km (grid cell 1.4 × 1.4 km) has provided a unique collection of spatial and temporal meteorological data. Examining short-lived ruderal and arable weed communities, we search for correlations and spatial patterns between the community composition and climate data. Do such plant communities respond to temperature differences within an agricultural landscape and on a regional scale? Data of 277 relevés from short-lived weed communities were collected across the investigated area during the summer of 2011. Relevés were assigned to the corresponding climate stations and classified. Average Ellenberg indicator values for temperature were calculated for each relevé and community cluster. Measured temperature data were assigned and correlated with community data by applying linear regression and redundancy analyses (RDA). The classification resulted in six associations; the two most frequently observed associations were divided into subtypes resulting in 13 vegetation clusters that could be analyzed further. A significant relationship could be found only between the clusters of arable weed communities and the average winter temperatures. Site variables explain twice as much variance as measured climate variables; this ratio changes to 50 : 50 when we analyzed only arable field community data. No clear spatial patterns concerning mean annual temperature were visible. However, the Setaria faberi subtype of the Echinochloo-Setarietum and the Sorghum halepense subtype of the Convolvulo-Agropyretum show a tendency toward a temperature-induced spatial pattern, such that both were sensitive to winter temperature. On a regional scale, the occurrence and composition of short-lived ruderal plant communities correlated weakly with climate variables. However, the studied arable weed communities showed a certain tendency to follow small-scale temperature differences, especially those of average winter temperature. We conclude that short-lived weed communities have the potential to be indicators for global warming, but the spatial temperature gradients are not clear enough in our approach to allow the production of better regression models and elucidation of distinct spatial patterns.
Unter diesem Titel trafen sich mehr als 180 Tagungsgäste aus allen botanischen Gruppierungen - Naturschutzfachvereinigungen, Universitätsinstitute, Sammlungen, Behörden und Ämter sowie Freiberufliche - vom 18. bis 20. November 2005 im Göttinger Albrecht-von-Haller-Institut für Pflanzenwissenschaften der Georg-August-Universität. Eingeladen hatte die Abteilung Vegetationsanalyse und Phytodiversität (Erwin Bergmeier) des AvH-Instituts und der Bundesfachausschuss Botanik des NABU in Zusammenarbeit mit den botanischen Vereinigungen der Länder (Christian Berg, Michael Ristow). Ausgangspunkt der Tagung war die Einsicht, es mangele in Deutschland zunehmend an Strukturen, um Konzepte und Ziele aufzugreifen, die im internationalen Naturschutz angestoßen worden sind, und sie als Chancen zu nutzen. So sind die Ziele der ,Globalen Strategie zum Schutz der Pflanzenwelt' (Global Strategy for Plant Conservation, GSPC), dem wohl wichtigsten Instrument des internationalen Florenschutzes, bei uns noch viel zu wenig bekannt. Auch fehlt ein nationales Forum, in dem Ideen und Erfahrungen im botanischen Naturschutz ausgetauscht werden können. Ziel der Tagung war es daher, Wege zur Umsetzung der GSPC zu diskutieren und allgemein einen Prozess in Gang zu bringen, um den Informations- und Ideenaustausch zu verbessern, eben ein Netzwerk für alle, die dem Florenschutz verpflichtet sind, zu fördern.
SARS-CoV-2 contains a positive single-stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 RNA elements were identified as conserved between SARS-CoV and SARS-CoV-2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these elements fold independently, in line with data from in vivo and ex-vivo structural probing experiments. These elements contain non-base-paired regions that potentially harbor ligand-binding pockets. Here, we performed an NMR-based screening of a poised fragment library of 768 compounds for binding to these RNAs, employing three different 1H-based 1D NMR binding assays. The screening identified common as well as RNA-element specific hits. The results allow selection of the most promising of the 15 RNA elements as putative drug targets. Based on the identified hits, we derive key functional units and groups in ligands for effective targeting of the RNA of SARS-CoV-2.
Background: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
Methodology/Principal Findings: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99–1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12–2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13–1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis.
Conclusions/Significance: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.
Background and Aims: The prevalence of hepatitis C virus (HCV) antibodies in Germany has been estimated to be in the range of 0.4–0.63%. Screening for HCV is recommended in patients with elevated ALT levels or significant risk factors for HCV transmission only. However, 15–30% of patients report no risk factors and ALT levels can be normal in up to 20–30% of patients with chronic HCV infection. The aim of this study was to assess the HCV seroprevalence in patients visiting two tertiary care emergency departments in Berlin and Frankfurt, respectively.
Methods: Between May 2008 and March 2010, a total of 28,809 consecutive patients were screened for the presence of anti-HCV antibodies. Anti-HCV positive sera were subsequently tested for HCV-RNA.
Results: The overall HCV seroprevalence was 2.6% (95% CI: 2.4–2.8; 2.4% in Berlin and 3.5% in Frankfurt). HCV-RNA was detectable in 68% of anti-HCV positive cases. Thus, the prevalence of chronic HCV infection in the overall study population was 1.6% (95% CI 1.5–1.8). The most commonly reported risk factor was former/current injection drug use (IDU; 31.2%) and those with IDU as the main risk factor were significantly younger than patients without IDU (p<0.001) and the male-to-female ratio was 72% (121 vs. 46 patients; p<0.001). Finally, 18.8% of contacted HCV-RNA positive patients had not been diagnosed previously.
Conclusions: The HCV seroprevalence was more than four times higher compared to current estimates and almost one fifth of contacted HCV-RNA positive patients had not been diagnosed previously.
Semi-dry grasslands were once widely distributed communities, but today they represent some of the most vulnerable habitats in Central Europe. European and national legislation and non-governmental organizations have managed to protect some of the remaining fragments. However, despite their status as Natura 2000 habitats, they are often endangered due to improper management, fragmentation and edge effects from adjacent croplands. By using a sample of 44 semi-dry hay meadows in the south-eastern Alpine Foreland of Styria, we investigated how species-richness and trait composition of semi-dry grassland species respond to variation in patch size, connectivity, abiotic site factors and management regimes. We used linear regression models to identify the most important drivers for richness of typical semi-dry grassland species and thus conservation value. The number of typical semi-dry grassland species was highest in well-connected fragments, i.e. units that shared two or more borders with neighbouring species-rich grasslands. Furthermore, large semi-dry grasslands (> 8000 m²) had highest numbers of semi-dry grassland species and highest relevance for conservation; no difference was found among smaller fragment sizes. Unregular management was associated with increased presence of competitive species which replaced stress-tolerant specialists. Our study indicates that under eutrophication, small fragment size and isolation, only large semi-dry grasslands can sustain a high number of species with high conservation value. The conservation value of smaller semi-dry grassland fragments could be improved by buffer zones, adapted mowing treatments and periodical sheep grazing.