Total network controllability analysis discovers explainable drugs for Covid-19 treatment (preprint)

Background The active pursuit of network medicine for drug repurposing, particularly for combating Covid-19, has stimulated interest in the concept of structural control capability in cellular networks. We sought to extend this theory, focusing on the defense rather than control of the cell against viral infections. Accordingly, we extended structural controllability to total structural controllability and introduced the concept of control hubs. Perturbing any control hub may render the cell uncontrollable by exogenous stimuli like viral infections, so control hubs are ideal drug targets.Results We developed an efficient algorithm to identify all control hubs, applying it to the largest homogeneous network of human protein interactions, including interactions between human and SARS-CoV-2 proteins. Our method recognized 65 druggable control hubs with enriched antiviral functions. Utilizing these hubs, we categorized potential drugs into four groups: antiviral and anti-inflammatory agents, drugs acting on the central nervous system, dietary supplements, and compounds enhancing immunity. An exemplification of our approach's effectiveness, Fostamatinib, a drug initially developed for chronic immune thrombocytopenia, is now in clinical trials for treating Covid-19. Preclinical trial data demonstrated that Fostamatinib could reduce mortality rates, ICU stay length, and disease severity in Covid-19 patients.Conclusions Our findings confirm the efficacy of our novel strategy that leverages control hubs as drug targets. This approach provides insights into the molecular mechanisms of potential therapeutics for Covid-19, making it a valuable tool for interpretable drug discovery.

Total controllability analysis discovers explainable drugs for Covid-19 treatment (preprint)

Network medicine has been pursued for Covid-19 drug repurposing. One such approach adopts structural controllability, a theory for controlling a network (the cell). Motivated to protect the cell from viral infections, we extended this theory to total controllability and introduced a new concept of control hubs. Perturbation to any control hub renders the cell uncontrollable by exogenous stimuli, e.g., viral infections, so control hubs are ideal drug targets. We developed an efficient algorithm for finding all control hubs and applied it to the largest homogenous human protein-protein interaction network. Our new method outperforms several popular gene-selection methods, including that based on structural controllability. The final 65 druggable control hubs are enriched with functions of cell proliferation, regulation of apoptosis, and responses to cellular stress and nutrient levels, revealing critical pathways induced by SARS-CoV-2. These druggable control hubs led to drugs in 4 major categories: antiviral and anti-inflammatory agents, drugs on central nerve systems, and dietary supplements and hormones that boost immunity. Their functions also provided deep insights into the therapeutic mechanisms of the drugs for Covid-19 therapy, making the new approach an explainable drug repurposing method. A remarkable example is Fostamatinib that has been shown to lower mortality, shorten the length of ICU stay, and reduce disease severity of hospitalized Covid-19 patients. The drug targets 10 control hubs, 9 of which are kinases that play key roles in cell differentiation and programmed death. One such kinase is RIPK1 that directly interacts with viral protein nsp12, the RdRp of the virus. The study produced many control hubs that were not targets of existing drugs but were enriched with proteins on membranes and the NF-$\kappa$B pathway, so are excellent candidate targets for new drugs.

The prevalence and risk factors for anxiety in frontline nurses under COVID-19 pandemic based on a large cross-sectional study using the propensity score-matched method (preprint)

Introduction: We determined the prevalence of anxiety and the associated risk factors in in frontline nurses under COVID-19 pandemic. Methods: This cross-sectional study was conducted from February 20, 2020 to March 20, 2020 and involved 562 frontline nurses. The effective response rate was 87.68%. After propensity score matched, there were 532 participants left. Extensive characteristics, including demographics, dietary habits, life-related factors, work-related factors, and psychological factors were collected based on a self-reported questionnaire. Specific scales measured the levels of sleep quality, physical activity, anxiety, perceived organization support and psychological capital. Adjusted odds ratios and 95% confidence intervals were determined by binary paired logistic regression.Results: Of the nurses enrolled in the study, 33.60% had anxiety. Five independent risk factors were identified for anxiety: poor sleep quality (OR=1.235), experienced major events (OR=1.653), lower resilience and optimism of psychological capital (OR=0.906, and OR=0.909) and no visiting friend constantly (OR=0.629). Conclusions: This study revealed a considerable high prevalence of anxiety in frontline nurses during the COVID-19 outbreak, and identified five risk factors, which were poor sleep quality, experienced major events, lower resilience and optimism of psychological capital, and no visiting friend rarely. Protecting mental health of nurses is important for COVID-19 pandemic control and their wellbeing. These findings enrich the existing theoretical model of anxiety and demonstrated a critical need for additional strategies that could address the mental health in frontline nurses for policymakers.