Ephrin-B2 expression critically influences Nipah virus infection independent of its cytoplasmic tail

<p>Abstract</p> <p>Background</p> <p>Cell entry and cell-to-cell spread of the highly pathogenic Nipah virus (NiV) requires binding of the NiV G protein to cellular ephrin receptors and subsequent NiV F-mediated fusion. Since expression levels of the main NiV entry receptor ephrin-B2 (EB2) are highly regulated <it>in vivo </it>to fulfill the physiological functions in axon guidance and angiogenesis, the goal of this study was to determine if changes in the EB2 expression influence NiV infection.</p> <p>Results</p> <p>Surprisingly, transfection of increasing EB2 plasmid concentrations reduced cell-to-cell fusion both in cells expressing the NiV glycoproteins and in cells infected with NiV. This effect was attributed to the downregulation of the NiV glycoproteins from the cell surface. In addition to the influence on cell-to-cell fusion, increased EB2 expression significantly reduced the total amount of NiV-infected cells, thus interfered with virus entry. To determine if the negative effect of elevated EB2 expression on virus entry is a result of an increased EB2 signaling, receptor function of a tail-truncated and therefore signaling-defective ΔcEB2 was tested. Interestingly, ΔcEB2 fully functioned as NiV entry and fusion receptor, and overexpression also interfered with virus replication.</p> <p>Conclusion</p> <p>Our findings clearly show that EB2 signaling does not account for the striking negative impact of elevated receptor expression on NiV infection, but rather that the ratio between the NiV envelope glycoproteins and surface receptors critically influence cell-to-cell fusion and virus entry.</p

Career service papers - csp 21/2024

Themen dieser Ausgabe sind Veränderungen bei der Nachfrage nach Beschäftigung und Kompetenzen durch den Strukturwandel des Arbeitsmarktes, die berufliche Relevanz und der gesellschaftliche Wert des Studiums, Kompetenzen die auf dem Arbeitsmarkt erfolgreich machen, Konzepte und Veränderungen für die Gestaltung der Zukunft von Musikhochschulen und Strategien für das Finden eines individuell passenden Arbeitsplatzes trotz undurchsichtiger Auswahlverfahren. Artikelübersicht: Jana Fingerhut, Larissa Klemme, Luisa Kunze, Eric Thode: Wie der Strukturwandel die Nachfrage nach Beschäftigten und Kompetenzen am Arbeitsmarkt verändert Jonas Breetzke, Prof. Dr. Carla Bohndick: Ist mein Studium relevant? Wie Studierende den beruflichen und gesellschaftlichen Wert ihres Studiums wahrnehmen und wie Hochschulen ihn steigern können. Dr. Emilia Kmiotek-Meier, Lena Hoffmann, Dr. Carlo Klauth: Welche Kompetenzen brauchen Akademiker*innen, um auf dem Arbeitsmarkt erfolgreich zu sein? Carmen M. Thiel: „Wir brauchen Visionen, neue Konzepte und Veränderungen, um die Zukunft der Musikhochschulen positiv gestalten zu können.“ Prof. Dr. Uwe P. Kanning: Wie finde ich einen Arbeitsplatz, der zu mir passt? Professionelles Auftreten in unprofessionellen Auswahlverfahren

The pattern-recognition molecule H-ficolin in relation to diabetic kidney disease, mortality, and cardiovascular events in type 1 diabetes

H-ficolin recognizes patterns on microorganisms and stressed cells and can activate the lectin pathway of the complement system. We aimed to assess H-ficolin in relation to the progression of diabetic kidney disease (DKD), all-cause mortality, diabetes-related mortality, and cardiovascular events. Event rates per 10-unit H-ficolin-increase were compared in an observational follow-up of 2,410 individuals with type 1 diabetes from the FinnDiane Study. DKD progression occurred in 400 individuals. The unadjusted hazard ratio (HR) for progression was 1.29 (1.18-1.40) and 1.16 (1.05-1.29) after adjustment for diabetes duration, sex, HbA(1c), systolic blood pressure, and smoking status. After adding triglycerides to the model, the HR decreased to 1.07 (0.97-1.18). In all, 486 individuals died, including 268 deaths of cardiovascular causes and 192 deaths of complications to diabetes. HRs for all-cause mortality and cardiovascular mortality were 1.13 (1.04-1.22) and 1.05 (0.93-1.17), respectively, in unadjusted analyses. These estimates lost statistical significance in adjusted models. However, the unadjusted HR for diabetes-related mortality was 1.19 (1.05-1.35) and 1.18 (1.02-1.37) with the most stringent adjustment level. Our results, therefore, indicate that H-ficolin predicts diabetes-related mortality, but neither all-cause mortality nor fatal/non-fatal cardiovascular events. Furthermore, H-ficolin is associated with DKD progression, however, not independently of the fully adjusted model.Peer reviewe

Zygosity Determination in Twin Studies: a Validation of Zygosity Questionnaires Using DNA in the German TwinLife Study

Lenau F, Hahn E, Peters A-L, Gottschling J, Thiel W, Spinath FM. Zygosity Determination in Twin Studies: a Validation of Zygosity Questionnaires Using DNA in the German TwinLife Study. TwinLife Working Paper Series. Vol 01. Bielefeld: Project TwinLife "Genetic and social causes of life chances" (Universität Bielefeld / Universität des Saarlandes); 2017.Zygosity determination using similarity ratings is frequently applied in twin studies. A correct determination of zygosity is essential for the estimation of heritability and environmental influences on phenotypes. Therefore, the present study examined the validity of two similarity questionnaires used in the German TwinLife study, in which data from 4,097 twin pairs and their families were assessed: twin children’s zygosities were determined with the Zygosity Questionnaire for Young Twins, which was administered in parent-report form. For adolescent twins, the Self Report Zygosity Questionnaire was used. For the present validation analyses, DNA samples of N = 328 twin pairs were collected via buccal swabs. In this DNA subsample, questionnaires were filled out by parents for n = 212 (aged 4 to 12 years) twin pairs while self-reports were collected from n = 116 adolescent twins (16 to 23 years of age). Using DNA-based zygosity as criteria, correct classification rates of 97% for parent- and 92% for self-reports were established and cross-validated. Additionally, classification rates based on a single item and variants of questionnaire based zygosity determination used in other twin studies were calculated and compared. Implications of incorrectly classified zygosity on genetic and environmental estimates in twin studies are discussed

Health-Enabling Technologies for Telerehabilitation of the Shoulder: A Feasibility and User Acceptance Study

BACKGROUND: After discharge from a rehabilitation center the continuation of therapy is necessary to secure already achieved healing progress and sustain (re-)integration into working life. To this end, home-based exercise programs are frequently prescribed. However, many patients do not perform their exercises as frequently as prescribed or even with incorrect movements. The telerehabilitation system AGT-Reha was developed to support patients with shoulder diseases during their home-based aftercare rehabilitation. OBJECTIVES: The presented pilot study AGT-Reha-P2 evaluates the technical feasibility and user acceptance of the home-based telerehabilitation system AGT-Reha. METHODS: A nonblinded, nonrandomized exploratory feasibility study was conducted over a 2-year period in patients' homes. Twelve patients completed a 3-month telerehabilitation exercise program with AGT-Reha. Primary outcome measures are the satisfying technical functionality and user acceptance assessed by technical parameters, structured interviews, and a four-dimensional questionnaire. Secondary endpoints are the medical rehabilitation success measured by the active range of motion and the shoulder function (pain and disability) assessed by employing the Neutral-0 Method and the standardized questionnaire "Shoulder Pain and Disability Index" (SPADI), respectively. To prepare an efficacy trial, various standardized questionnaires were included in the study to measure ability to work, capacity to work, and subjective prognosis of work capacity. The participants have been assessed at three measurement points: prebaseline (admission to rehabilitation center), baseline (discharge from rehabilitation center), and posttherapy. RESULTS: Six participants used the first version of AGT-Reha, while six other patients used an improved version. Despite minor technical problems, all participants successfully trained on their own with AGT-Reha at home. On average, participants trained at least once per day during their training period. Five of the 12 participants showed clinically relevant improvements of shoulder function (improved SPADI score > 11). The work-related parameters suggested a positive impact. All participants would recommend the system, ten participants would likely reuse it, and seven participants would have wanted to continue their use after 3 months. CONCLUSION: The findings show that home-based training with AGT-Reha is feasible and well accepted. Outcomes of SPADI indicate the effectiveness of aftercare with AGT-Reha. A controlled clinical trial to test this hypothesis will be conducted with a larger number of participants

Neural processing of emotional facial stimuli in specific phobia: An fMRI study

Background Patients with specific phobia (SP) show altered brain activation when confronted with phobia-specific stimuli. It is unclear whether this pathogenic activation pattern generalizes to other emotional stimuli. This study addresses this question by employing a well-powered sample while implementing an established paradigm using nonspecific aversive facial stimuli. Methods N = 111 patients with SP, spider subtype, and N = 111 healthy controls (HCs) performed a supraliminal emotional face-matching paradigm contrasting aversive faces versus shapes in a 3-T magnetic resonance imaging scanner. We performed region of interest (ROI) analyses for the amygdala, the insula, and the anterior cingulate cortex using univariate as well as machine-learning-based multivariate statistics based on this data. Additionally, we investigated functional connectivity by means of psychophysiological interaction (PPI). Results Although the presentation of emotional faces showed significant activation in all three ROIs across both groups, no group differences emerged in all ROIs. Across both groups and in the HC > SP contrast, PPI analyses showed significant task-related connectivity of brain areas typically linked to higher-order emotion processing with the amygdala. The machine learning approach based on whole-brain activity patterns could significantly differentiate the groups with 73% balanced accuracy. Conclusions Patients suffering from SP are characterized by differences in the connectivity of the amygdala and areas typically linked to emotional processing in response to aversive facial stimuli (inferior parietal cortex, fusiform gyrus, middle cingulate, postcentral cortex, and insula). This might implicate a subtle difference in the processing of nonspecific emotional stimuli and warrants more research furthering our understanding of neurofunctional alteration in patients with SP.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Peer Reviewe

Interaction of developmental factors and ordinary stressful life events on brain structure in adults

An interplay of early environmental and genetic risk factors with recent stressful life events (SLEs) in adulthood increases the risk for adverse mental health outcomes. The interaction of early risk and current SLEs on brain structure has hardly been investigated. Whole brain voxel-based morphometry analysis was performed in N = 786 (64.6% female, mean age = 33.39) healthy subjects to identify correlations of brain clusters with commonplace recent SLEs. Genetic and early environmental risk factors, operationalized as those for severe psychopathology (i.e., polygenic scores for neuroticism, childhood maltreatment, urban upbringing and paternal age) were assessed as modulators of the impact of SLEs on the brain. SLEs were negatively correlated with grey matter volume in the left medial orbitofrontal cortex (mOFC, FWE p = 0.003). This association was present for both, positive and negative, life events. Cognitive-emotional variables, i.e., neuroticism, perceived stress, trait anxiety, intelligence, and current depressive symptoms did not account for the SLE-mOFC association. Further, genetic and environmental risk factors were not correlated with grey matter volume in the left mOFC cluster and did not affect the association between SLEs and left mOFC grey matter volume. The orbitofrontal cortex has been implicated in stress-related psychopathology, particularly major depression in previous studies. We find that SLEs are associated with this area. Important early life risk factors do not interact with current SLEs on brain morphology in healthy subjects

Identification of transdiagnostic psychiatric disorder subtypes using unsupervised learning

Psychiatric disorders show heterogeneous symptoms and trajectories, with current nosology not accurately reflecting their molecular etiology and the variability and symptomatic overlap within and between diagnostic classes. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify psychiatric patient clusters that share clinical and genetic features and may profit from similar therapies. We used high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N = 1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, showed general well-being. Clusters 1-3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. Depressed patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N = 622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction area under the receiver operating characteristic curve (AUC) = 81%;significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatments

Genetic Approach for the Fast Discovery of Phenazine Producing Bacteria

A fast and efficient approach was established to identify bacteria possessing the potential to biosynthesize phenazines, which are of special interest regarding their antimicrobial activities. Sequences of phzE genes, which are part of the phenazine biosynthetic pathway, were used to design one universal primer system and to analyze the ability of bacteria to produce phenazine. Diverse bacteria from different marine habitats and belonging to six major phylogenetic lines were investigated. Bacteria exhibiting phzE gene fragments affiliated to Firmicutes, Alpha- and Gammaproteobacteria, and Actinobacteria. Thus, these are the first primers for amplifying gene fragments from Firmicutes and Alphaproteobacteria. The genetic potential for phenazine production was shown for four type strains belonging to the genera Streptomyces and Pseudomonas as well as for 13 environmental isolates from marine habitats. For the first time, the genetic ability of phenazine biosynthesis was verified by analyzing the metabolite pattern of all PCR-positive strains via HPLC-UV/MS. Phenazine production was demonstrated for the type strains known to produce endophenazines, 2-hydroxy-phenazine, phenazine-1-carboxylic acid, phenazine-1,6-dicarboxylic acid, and chlororaphin as well as for members of marine Actinobacteria. Interestingly, a number of unidentified phenazines possibly represent new phenazine structures

Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia

<p>Abstract</p> <p>Background</p> <p>Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E₂and PGD₂.</p> <p>Findings</p> <p>We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE₂and PGD₂without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE₂and PGD₂. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE₂and PGD₂levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE₂in non-stimulated microglia.</p> <p>Conclusion</p> <p>Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p