A Major Role for Side-Chain Polyglutamine Hydrogen Bonding in Irreversible Ataxin-3 Aggregation

The protein ataxin-3 consists of an N-terminal globular Josephin domain (JD) and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers the neurodegenerative disorder spinocerebellar ataxia type 3, when it is expanded beyond a critical threshold. The disease results from misfolding and aggregation, although the pathway and structure of the aggregation intermediates are not fully understood. In order to provide insight into the mechanism of the process, we monitored the aggregation of a normal (AT3Q24) ataxin-3, an expanded (AT3Q55) ataxin-3, and the JD in isolation. We observed that all of them aggregated, although the latter did so at a much slower rate. Furthermore, the expanded AT3Q55 displayed a substantially different behavior with respect to the two other variants in that at the latest stages of the process it was the only one that did the following: i) lost its reactivity towards an anti-oligomer antibody, ii) generated SDS-insoluble aggregates, iii) gave rise to bundles of elongated fibrils, and iv) displayed two additional bands at 1604 and 1656 cm−1 in FTIR spectroscopy. Although these were previously observed in other aggregated polyglutamine proteins, no one has assigned them unambiguously, yet. By H/D exchange experiments we show for the first time that they can be ascribed to glutamine side-chain hydrogen bonding, which is therefore the hallmark of irreversibly SDS-insoluble aggregated protein. FTIR spectra also showed that main-chain intermolecular hydrogen bonding preceded that of glutamine side-chains, which suggests that the former favors the latter by reorganizing backbone geometry

Verbleib von Soziologie-AbsolventInnen der Philipps-Universität Marburg

Soziologie ist an der Philipps-Universität in den 1960er Jahren als akademisches Studienfach entstanden und ab 1972 ausgebaut worden. Neben den beiden Kernbereichen 'Soziologische Theorien' und 'Methoden empirischer Sozialforschung' konnten Studierende Ende der 1990er Jahre zwischen sechs speziellen Soziologien ihre Schwerpunktsetzung wählen. Nach 30 Jahren Soziologie-Studium in Marburg erschien es sinnvoll, Daten und Informationen über den Verbleib der bisherigen Absolventinnen und Absolventen zusammenzutragen. Dieser Aufgabe stellte sich eine Gruppe von Soziologiestudierenden im Grundstudium (2./3. bzw. 3./4. Fachsemester) zusammen mit ihrem Tutor und ihrer Dozentin im Rahmen eines über zwei Semester laufenden Empirischen Praktikums (Oktober 2003 bis Juli 2004). In Anlehnung an Verbleibs- und Studienabbruchs-Studien anderer Hochschulen wurden Fragestellungen für verschiedene Teiluntersuchungen und Erhebungsinstrumente entwickelt, Interviewtechniken trainiert, Daten erhoben und quantitativ bzw. qualitativ ausgewertet sowie der abschließende Forschungsbericht geschrieben. Die Grundgesamtheit wurde (wegen der schwierigen Adressrecherche) auf die Abschlussjahrgänge 1990 bis 2003 beschränkt. Durchgeführt wurden: eine postalische Fragebogenuntersuchung aller erreichbaren AbsolventInnen (realisiert 88 Befragungen); drei berufsbiografische Interviews mit AbsolventInnenen der Jahre 1991-1996-2001; vier perspektivische Leitfadeninterviews (problemzentriert) mit AbsolventInnen des Jahres 2003; zwei Leitfadeninterviews mit einem Abbrecher bzw. einem Studienfachwechsler; Experteninterviews mit potenziellen ArbeitgebervertreterInnen. Für die Analysen wurden je nach Datenstandard statistische Verfahren, qualitative Inhaltsanalyse oder sequenzielle Analyse eingesetzt. Die Befunde ermöglichen Einschätzungen hinsichtlich der damaligen Diplom- und Magisterstudiengänge in Marburg - hinsichtlich Bachelor- und Master-Studiengängen oder für andere Hochschulen müsste eine Studie entsprechend modifiziert werden

National identity predicts public health support during a global pandemic (vol 13, 517, 2022) : National identity predicts public health support during a global pandemic (Nature Communications, (2022), 13, 1, (517), 10.1038/s41467-021-27668-9)

Publisher Copyright: © The Author(s) 2022.In this article the author name ‘Agustin Ibanez’ was incorrectly written as ‘Augustin Ibanez’. The original article has been corrected.Peer reviewe

National identity predicts public health support during a global pandemic.

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics

Global diversity and antimicrobial resistance of typhoid fever pathogens : insights from a meta-analysis of 13,000 Salmonella Typhi genomes

DATA AVAILABILITY : All data analysed during this study are publicly accessible. Raw Illumina sequence reads have been submitted to the European Nucleotide Archive (ENA), and individual sequence accession numbers are listed in Supplementary file 2. The full set of n=13,000 genome assemblies generated for this study are available for download from FigShare: https://doi.org/10.26180/21431883. All assemblies of suitable quality (n=12,849) are included as public data in the online platform Pathogenwatch (https://pathogen.watch). The data are organised into collections, which each comprise a neighbour-joining phylogeny annotated with metadata, genotype, AMR determinants, and a linked map. Each contributing study has its own collection, browsable at https://pathogen.watch/collections/all?organismId= 90370. In addition, we have provided three large collections, each representing roughly a third of the total dataset presented in this study: Typhi 4.3.1.1 (https://pathogen.watch/collection/ 2b7mp173dd57-clade-4311), Typhi lineage 4 (excluding 4.3.1.1) (https://pathogen.watch/collection/ wgn6bp1c8bh6-clade-4-excluding-4311), and Typhi lineages 0-3 (https://pathogen.watch/collection/ 9o4bpn0418n3-clades-0-1-2-and-3). In addition, users can browse the full set of Typhi genomes in Pathogenwatch and select subsets of interest (e.g. by country, genotype, and/or resistance) to generate a collection including neighbour-joining tree for interactive exploration.SUPPLEMENTARY FILES : Available at https://elifesciences.org/articles/85867/figures#content. SUPPLEMENTARY FILE 1. Details of local ethical approvals provided for studies that were unpublished at the time of contributing data to this consortium project. Most data are now published, and the citations for the original studies are provided here. National surveillance programs in Chile (Maes et al., 2022), Colombia (Guevara et al., 2021), France, New Zealand, and Nigeria (Ikhimiukor et al., 2022b) were exempt from local ethical approvals as these countries allow sharing of non-identifiable pathogen sequence data for surveillance purposes. The US CDC Internal Review Board confirmed their approval was not required for use in this project (#NCEZID-ARLT- 10/ 20/21-fa687). SUPPLEMENTARY FILE 2. Line list of 13,000 genomes included in the study. SUPPLEMENTARY FILE 3. Source information recorded for genomes included in the study. ^Indicates cases included in the definition of ‘assumed acute illness’. SUPPLEMENTARY FILE 4. Summary of genomes by country. SUPPLEMENTARY FILE 5. Genotype frequencies per region (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 6. Genotype frequencies per country (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 7. Antimicrobial resistance (AMR) frequencies per region (N, %, 95% confidence interval; aggregated 2010–2020). SUPPLEMENTARY FILE 8. Antimicrobial resistance (AMR) frequencies per country (N, %, 95% confidence interval; annual and aggregated, 2010–2020). SUPPLEMENTARY FILE 9. Laboratory code master list. Three letter laboratory codes assigned by the consortium.BACKGROUND : The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS : This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS : Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS : The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies.Fellowships from the European Union (funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council.https://elifesciences.org/am2024Medical MicrobiologySDG-03:Good heatlh and well-bein

Author Correction: National identity predicts public health support during a global pandemic

Correction to: Nature Communications https://doi.org/10.1038/s41467-021-27668-9, published online 26 January 2022

New Saccharin Salt of Chlordiazepoxide: Structural and Physicochemical Examination

Since the formation of organic salts can improve the solubility, bioavailability, and stability of active pharmaceutical ingredients, the aim of this work was to prepare an organic salt of chlordiazepoxide with saccharin. To achieve this goal, the saccharin salt of chlordiazepoxide was obtained from a physical mixture of both components by grinding them with a small volume of solvent and by crystallizing them with complete evaporation of the solvent. The resulting salt was examined by methods such as Powder X-ray Diffraction (PXRD), Single Crystal X-ray Diffraction (SCXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared (FT-IR), and Raman spectroscopy. The results of the studies proved that saccharin salt of chlordiazepoxide crystallizes in the orthorhombic Pbca space group with one chlordiazepoxide cation and one saccharin anion in the asymmetric unit. In the crystal of the title compound, the chlordiazepoxide cation and the saccharin anion interact through strong N–H···O hydrogen bonds and weak C–H···O hydrogen bonds. The disappearance of the N–H band in the FT-IR spectrum of saccharin may indicate a shift of this proton towards chlordiazepoxide, while the disappearance of the aromatic bond band in the chlordiazepoxide ring in the Raman spectrum may suggest the formation of intermolecular hydrogen bonds between chlordiazepoxide molecules. The melting point of the salts differs from that of the starting compounds. Thermal decomposition of the salt begins above 200 °C and shows at least two overlapping stages of mass loss. In summary, the results of the research showed that the crystalline salt of the saccharin and chlordiazepoxide can be obtained by various methods: grinding with the addition of acetonitrile and crystallization from acetonitrile or a mixture of methanol with methylene chloride

The prevalence and distribution of <i>Dirofilaria repens</i> in dogs in the The prevalence and distribution of Dirofilaria repens in dogs in the Mazovian Province of Central-Eastern Poland

The aim of this study was to determine the prevalence and distribution of canine dirofilariosis from different districts of the Mazovian Province in central-eastern Poland. 462 dogs aged from 1.5–14 years were examined for dirofilariosis. Blood samples were examined for the presence of microfilariae using the Knott method, as well as the method of Kingston and Morton, after centrifugation in haematocrit microtubes in order to determine the intensity of infection as the number of microfilariae in 60 microliters of blood. The species of microfilariae found were determined after staining on the basis of the morphological characters. Samples were also examined using Canine Heartworm Antigen Test Kit SNAP HTWM (IDEXX, USA) that allows the detection of circulating antigens of females of [i]Dirofilaria immitis[/i]. The positive samples were examined using multiplex PCR assay for species confirmation. Microfilariae belonging to the species D. repens were found in the blood samples of dogs originating from the city of Warsaw and from 18 districts of Mazovian Province. The mean prevalence of that species observed in the province was 25.8%. The range of intensity counted with the number of microfilariae found in 60 microliters of blood amounted to between 1 – 150; median intensity 9 microfilariae. The highest prevalence, reaching 52.9% and the highest median intensity of infection reaching 28 microfilariae, was found in Radom district. The lowest prevalence, amounting to 4.2%, was registered in Grójec district; however, the lowest median intensity reaching 6 microfilariae was noted in Żyrardów district. The infected dogs had not been outside of Poland, which means that this is an autochthonous infection. Microfilariae and antigens of [i]D. immitis[/i] were not found in any examined blood samples. Results of the presented study show that autochthonous dirofilariosis caused by nematodes [i]D. repens[/i] commonly occurs in the area of the Mazovian Province

Geno2pheno([HCV]) - A Web-based Interpretation System to Support Hepatitis C Treatment Decisions in the Era of Direct-Acting Antiviral Agents

The face of hepatitis C virus (HCV) therapy is changing dramatically. Direct-acting antiviral agents (DAAs) specifically targeting HCV proteins have been developed and entered clinical practice in 2011. However, despite high sustained viral response (SVR) rates of more than 90%, a fraction of patients do not eliminate the virus and in these cases treatment failure has been associated with the selection of drug resistance mutations (RAMs). RAMs may be prevalent prior to the start of treatment, or can be selected under therapy, and furthermore they can persist after cessation of treatment. Additionally, certain DAAs have been approved only for distinct HCV genotypes and may even have subtype specificity. Thus, sequence analysis before start of therapy is instrumental for managing DAA-based treatment strategies. We have created the interpretation system geno2pheno([HCV]) (g2p([HCV])) to analyse HCV sequence data with respect to viral subtype and to predict drug resistance. Extensive reviewing and weighting of literature related to HCV drug resistance was performed to create a comprehensive list of drug resistance rules for inhibitors of the HCV protease in non-structural protein 3 (NS3-protease: Boceprevir, Paritaprevir, Simeprevir, Asunaprevir, Grazoprevir and Telaprevir), the NS5A replicase factor (Daclatasvir, Ledipasvir, Elbasvir and Ombitasvir), and the NS5B RNA-dependent RNA polymerase (Dasabuvir and Sofosbuvir). Upon submission of up to eight sequences, g2p([HCV]) aligns the input sequences, identifies the genomic region(s), predicts the HCV geno- and subtypes, and generates for each DAA a drug resistance prediction report. g2p([HCV]) offers easy-to-use and fast subtype and resistance analysis of HCV sequences, is continuously updated and freely accessible under http://hcv.geno2pheno.org/index.php. The system was partially validated with respect to the NS3-protease inhibitors Boceprevir, Telaprevir and Simeprevir by using data generated with recombinant, phenotypic cell culture assays obtained from patients' virus variants