Machine learning on large scale perturbation screens for SARS-CoV-2 host factors identifies β-catenin/CBP inhibitor PRI-724 as a potent antiviral

Expanding antiviral treatment options against SARS-CoV-2 remains crucial as the virus evolves under selection pressure which already led to the emergence of several drug resistant strains. Broad spectrum host-directed antivirals (HDA) are promising therapeutic options, however the robust identification of relevant host factors by CRISPR/Cas9 or RNA interference screens remains challenging due to low consistency in the resulting hits. To address this issue, we employed machine learning, based on experimental data from several knockout screens and a drug screen. We trained classifiers using genes essential for virus life cycle obtained from the knockout screens. The machines based their predictions on features describing cellular localization, protein domains, annotated gene sets from Gene Ontology, gene and protein sequences, and experimental data from proteomics, phospho-proteomics, protein interaction and transcriptomic profiles of SARS-CoV-2 infected cells. The models reached a remarkable performance suggesting patterns of intrinsic data consistency. The predicted HDF were enriched in sets of genes particularly encoding development, morphogenesis, and neural processes. Focusing on development and morphogenesis-associated gene sets, we found β-catenin to be central and selected PRI-724, a canonical β-catenin/CBP disruptor, as a potential HDA. PRI-724 limited infection with SARS-CoV-2 variants, SARS-CoV-1, MERS-CoV and IAV in different cell line models. We detected a concentration-dependent reduction in cytopathic effects, viral RNA replication, and infectious virus production in SARS-CoV-2 and SARS-CoV-1-infected cells. Independent of virus infection, PRI-724 treatment caused cell cycle deregulation which substantiates its potential as a broad spectrum antiviral. Our proposed machine learning concept supports focusing and accelerating the discovery of host dependency factors and identification of potential host-directed antivirals

Mindsets in social anxiety: a new look at selective information processing.

According to the Rubicon Model of Action Phases (in: J. Gollwitzer, 1996), Motivation, volition, and action, Enzyclopedia of psychology, series "motivation and emotion", Vol. 4, Hogrefe, Göttingen, 1996, pp. 531-582), different stages in goal pursuit are accompanied by different mindsets that enhance processing of mindset-congruous information. Before people engage in action, they usually deliberate possible goals for a given situation (deliberative mindset). Once a goal is chosen, they plan how to achieve this particular goal (implemental mindset). The present experiments tested the hypothesis that people with social anxiety show a reversal of mindsets when approaching social situations. In Experiment 1, 20 students were asked to either deliberate goals for a hypothetical social conflict (deliberation), or to think about steps to solve the conflict (implementation). An unexpected recognition test demonstrated different recognition memory for deliberation-related versus implementation-related information in the two groups, consistent with the hypothesis of different mindsets. In Experiment 2, 48 students who were either high or low in social anxiety were randomly assigned to either the deliberation or the implementation condition. Participants high in social anxiety showed a pattern in the recognition test that was consistent with a reversal of mindsets. When asked to plan social situations, they showed an inappropriate deliberative mindset. In contrast, they lacked a deliberative mindset when deliberating goals for the social situation. The result indicate that socially anxious people engage in information processing that interferes with successful goal attainment when approaching social situations

Mindsets in social anxiety: a new look at selective information processing

According to the Rubicon Model of Action Phases (in: J. Gollwitzer, 1996), Motivation, volition, and action, Enzyclopedia of psychology, series "motivation and emotion", Vol. 4, Hogrefe, Göttingen, 1996, pp. 531-582), different stages in goal pursuit are accompanied by different mindsets that enhance processing of mindset-congruous information. Before people engage in action, they usually deliberate possible goals for a given situation (deliberative mindset). Once a goal is chosen, they plan how to achieve this particular goal (implemental mindset). The present experiments tested the hypothesis that people with social anxiety show a reversal of mindsets when approaching social situations. In Experiment 1, 20 students were asked to either deliberate goals for a hypothetical social conflict (deliberation), or to think about steps to solve the conflict (implementation). An unexpected recognition test demonstrated different recognition memory for deliberation-related versus implementation-related information in the two groups, consistent with the hypothesis of different mindsets. In Experiment 2, 48 students who were either high or low in social anxiety were randomly assigned to either the deliberation or the implementation condition. Participants high in social anxiety showed a pattern in the recognition test that was consistent with a reversal of mindsets. When asked to plan social situations, they showed an inappropriate deliberative mindset. In contrast, they lacked a deliberative mindset when deliberating goals for the social situation. The result indicate that socially anxious people engage in information processing that interferes with successful goal attainment when approaching social situations

Die Entwicklung des Greifswalder Fragebogens zur Messung interprofessioneller Einstellungen

Introduction: The implementation of interprofessional education (IPE) could be a potential approach to dealing with increasing complexity in health care. And thus, encouraging interprofessional collaborations to minimize errors in patient care. However, empirical evidence regarding the effectiveness of IPE is inconclusive. One reason for this is a lack of valid and reliable evaluation instruments. This study aims to illustrate the first steps of the development and validation of a German evaluation instrument for the measurement of interprofessional attitudes. Methods: To achieve high psychometric quality, we first selected relevant attitude dimensions and specified criteria for the wording of the items. The a priori developed factor structure was evaluated via factor analysis and the internal consistencies of the scales were analysed in a sample of medical students and nursing trainees, both participants of an IPE course (n=338). Stability was evaluated in an additional sample of nursing trainees (n=14). Results: The Factor analysis revealed three dimensions. Whereby, the two factors "Relevance of learning interprofessional communicational techniques" (German: Wichtigkeit Techniken interprofessioneller Kommunikation zu lernen) (alpha=.85) and "Doubts, dismissal and perceived barriers" (German: Zweifel, Ablehnung und wahrgenommene Barrieren) (alpha=.73) revealed good to acceptable internal consistency. Third-factor "Attitude towards another profession" (German: Einstellung zur anderen Berufsgruppe) (alpha=.62) remained below a desired internal consistency of alpha>.70. Factors "Doubts, dismissal and perceived barriers", as well as "Attitude towards another profession" showed sufficient stability for pre-/post-measurements. Discussion: The Greifswald Questionnaire for the Measurement of Interprofessional Attitudes is the first version of a three-dimensional tool to evaluate IPE in German-speaking countries. Results showed insufficient item difficulty in the tested sample, which resulted in an insufficient internal consistency, and retest reliability for some factors. Further studies are required to investigate item difficulty, internal consistency and retest reliability in a postgraduate sample.Einleitung: In einem komplexer werdenden Gesundheitssystem sind Maßnahmen nötig, um Kompetenzen der interprofessionellen Zusammenarbeit zu fördern und somit das Fehlerpotential bei der Versorgung von Patienten zu minimieren. Eine Maßnahme, um dies zu erreichen, könnte die Integration von interprofessionellem Lernen (IPL) in die Ausbildung von Gesundheitsberufen sein. Es fehlen bisher allerdings belastbare Befunde, die die Wirksamkeit von IPL belegen. Eine Ursache hierfür ist die geringe Validität und Reliabilität verfügbarer Evaluationsinstrumente.Die vorliegende Publikation beschreibt erste Schritte der Validierung eines deutschsprachigen Evaluationsinstrumentes zur Messung interprofessioneller Einstellungen. Methoden: Um eine möglichste hohe Validität und Reliabilität zu erreichen, wurden zunächst geeignete Fragebogendimensionen ausgewählt sowie methodische Kriterien für die Itemkonstruktion festgelegt. An einer Stichprobe von Studierenden der Humanmedizin sowie Auszubildenden der Gesundheits- und Krankenpflege, die gemeinsam an einem IPL-Kurs teilnahmen, wurden die a priori festgelegten Skalen faktorenanalytisch überprüft und hinsichtlich ihrer internen Konsistenz analysiert (N=338). Die Stabilität der Dimensionen wurde an einer weiteren Stichprobe von 14 Auszubildenden der Gesundheits- und Krankenpflege untersucht. Ergebnisse: Es wurden drei Einstellungsdimensionen extrahiert. Die Dimensionen Wichtigkeit Techniken interprofessioneller Kommunikation zu lernen (alpha=.85) sowie Zweifel, Ablehnung und wahrgenommene Barrieren (alpha=.73) sind gut bis akzeptabel intern konsistent. Unterhalb eines angestrebten Niveaus von alpha>.7 blieb die Dimension Einstellung zur anderen Berufsgruppe (alpha=.62). Eine ausreichende Stabilität für Prä-/Post-Erhebungen konnte für die Dimensionen Zweifel, Ablehnung und wahrgenommene Barrieren und Einstellung zur anderen Berufsgruppe nachgewiesen werden.Diskussion: Mit dem Greifswalder Fragebogen zur Messung interprofessioneller Einstellungen (GreiFMIE) liegt die erste Version eines dreifaktoriellen Fragebogens zur Evaluation von IPL vor. In der untersuchten Stichprobe erwies sich die Itemschwierigkeit als zu leicht, wodurch sich für einige Fragebogen-Dimensionen nicht ausreichende interne Konsistenzen und Retest-Reliabilitäten ergaben. Weiterführende Untersuchungen sollen zeigen, ob eine höhere Itemschwierigkeit bei postgraduierten Gesundheitsberufen vorliegt

Adverse effects of long and straight multiwalled carbon nanotubes on cytoskeleton, nuclear lamina, and genome-wide transcriptome of primary human mesothelial cells

Question Certain long and straight multiwalled carbon nanotubes (MWCNTs) have shown carcinogenic potential in animal models after intraperitoneal application. Nonetheless, the underlying mechanisms are still unclear. Owing to their fiber-like structure, the long and straight MWCNTs seem to cause more adverse effects than e.g. tangled types. These effects include the potential to cause malignant mesothelioma, a cancer originating from mesothelial cells, and often associated with asbestos exposure. Methods To gain insights into pertinent disease mechanisms, we analyzed the biological effects of two tailor-made MWCNTs (CNT2: slightly curved, diameter 0.050 μm, length 4.18 μm; CNT 6: straight, diameter 0.049 μm, length 10.9 μm), and a reference MWCNT (JRC NM-401: straight, diameter 0.067 μm, length 4.04 μm). These MWCNTs were tested for sterility and endotoxin content, and were free of relevant contamination. As a disease-relevant cell model, we used primary human peritoneal mesothelial cells (LP9) treated as submerged cultures for 24 h with 5 μg/cm2 of the different fibers. Results Immunofluorescence of alpha-tubulin, a protein that forms part of microtubules (a major cytoskeleton component), showed extensive abnormalities. Similarly, we observed depletion of lamin B1 (LMNB1), which is one of the structural proteins of the nuclear lamina and important in the maintenance of nuclear structure and function. After microarray analysis, we found many differentially-expressed genes relative to untreated control, i.e. 7609, 7478, 5742 for NM-401, CNT2, and CNT6, respectively. Bioinformatic analyses revealed many common significantly activated pathways and molecular functions, associated with inflammation and carcinogenesis, notably lung cancer. The top activated canonical pathways include IL6, IL8, and p38 MAPK signaling. Conclusion In conclusion, our results show that exposure to certain long and straight MWCNTs can lead to marked disturbance of cellular structure and the transcriptome of mesothelial cells, eventually contributing to carcinogenesis