Severe/critical COVID-19 early warning system based on machine learning algorithms using novel imaging scores.

BACKGROUND: Early identification of severe/critical coronavirus disease 2019 (COVID-19) is crucial for timely treatment and intervention. Chest computed tomography (CT) score has been shown to be a significant factor in the diagnosis and treatment of pneumonia, however, there is currently a lack of effective early warning systems for severe/critical COVID-19 based on dynamic CT evolution. AIM: To develop a severe/critical COVID-19 prediction model using a combination of imaging scores, clinical features, and biomarker levels. METHODS: This study used an improved scoring system to extract and describe the chest CT characteristics of COVID-19 patients. The study also took into consideration the general clinical indicators such as dyspnea, oxygen saturation, alternative lengthening of telomeres (ALT), and androgen suppression treatment (AST), which are commonly associated with severe/critical COVID-19 cases. The study employed lasso regression to evaluate and rank the significance of different disease characteristics. RESULTS: The results showed that blood oxygen saturation, ALT, IL-6/IL-10, combined score, ground glass opacity score, age, crazy paving mode score, qsofa, AST, and overall lung involvement score were key factors in predicting severe/critical COVID-19 cases. The study established a COVID-19 severe/critical early warning system using various machine learning algorithms, including XGBClassifier, Logistic Regression, MLPClassifier, RandomForestClassifier, and AdaBoost Classifier. The study concluded that the prediction model based on the improved CT score and machine learning algorithms is a feasible method for early detection of severe/critical COVID-19 evolution. CONCLUSION: The findings of this study suggest that a prediction model based on improved CT scores and machine learning algorithms is effective in detecting the early warning signals of severe/critical COVID-19.

Status of mandatory treatment of mentally ill offenders without criminal responsibility in China: Information from 5,262 mandatory treatment judgments.

Background: To avoid public health risks, all governments ensure monitoring and treatment of mentally ill persons if they offend and assess their level of criminal responsibility. The Criminal Procedure Law of the People's Republic of China (2013) instituted special procedures. However, there are few articles in English which explain the implementation of mandatory treatment procedures in China. Methods: We collected 5,262 qualified documents from 2013 to 2021 from the China Judgments Documents Online. We analyzed social demographic characteristics, trial-related information as well as the mandatory treatment-related content, to investigate the mandatory treatment of China's mentally ill offenders without criminal responsibility, from 2013 to 2021. Simple descriptive statistics and chi-square tests were used to compare differences among several types of documents. Results: There was an overall change trend of the number of documents: increasing year by year from 2013 to 2019 after the implementation of the new law, but with sharp decrease in 2020 and 2021 during covid-19 pandemic. From 2013 to 2021, a total of 3,854 people had applications made for mandatory treatment, of whom 3,747 (97.2%) were given mandatory treatment, 107 (2.8%) had applications rejected. "Schizophrenia and other psychotic disorders" was the most common diagnosis in both groups and all offenders receiving mandatory treatment (3,747, 100.0%) were considered to have no criminal responsibility. A total of 1,294 patients had applications made for relief of mandatory treatment, of whom 827 (63.9%) were subsequently approved for relief, 467 (36.1%) were rejected. A total of 118 patients had applications for relief two or more times, and 56 (47.5%) were finally relieved. Conclusion: Our study presents the Chinese model of a criminal mandatory treatment system to the international community which has been in operation since the implementation of the new law. Legislatory changes and covid-19 pandemic can have effect on the number of mandatory treatment cases. Patients, their close relatives and mandatory treatment institutions have the right to apply for relief from mandatory treatment, but the final decision in China is taken by the court.

A Novel Multifunctional 5,6-Dimethoxy-Indanone-Chalcone-Carbamate Hybrids Alleviates Cognitive Decline in Alzheimer's Disease by Dual Inhibition of Acetylcholinesterase and Inflammation.

Backgrounds: Alzheimer's disease (AD) is a multifactorial neurodegenerative disease. The treatment of AD through multiple pathological targets may generate therapeutic efficacy better. The multifunctional molecules that simultaneously hit several pathological targets have been of great interest in the intervention of AD. Methods: Here, we combined the chalcone scaffold with carbamate moiety and 5,6-dimethoxy-indanone moiety to generate a novel multi-target-directed ligand (MTDL) molecule (E)-3-((5,6-dimethoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)-methyl)phenylethyl(methyl) carbamate (named AP5). In silico approaches were used to virtually predict the binding interaction of AP5 with AChE, the drug-likeness, and BBB penetrance, and later validated by evaluation of pharmacokinetics (PK) in vivo by LC-MS/MS. Moreover, studies were conducted to examine the potential of AP5 for inhibiting AChE and AChE-induced amyloid-ß (Aß) aggregation, attenuating neuroinflammation, and providing neuroprotection in the APP/PS1 model of AD. Results: We found that AP5 can simultaneously bind to the peripheral and catalytic sites of AChE by molecular docking. AP5 exhibited desirable pharmacokinetic (PK) characteristics including oral bioavailability (67.2%), >10% brain penetrance, and favorable drug-likeness. AP5 inhibited AChE activity and AChE-induced Aß aggregation in vivo and in vitro. Further, AP5 lowered Aß plaque deposition and insoluble Aß levels in APP/PS1 mice. Moreover, AP5 exerted anti-inflammatory responses by switching microglia to a disease-associated microglia (DAM) phenotype and preventing A1 astrocytes formation. The phagocytic activity of microglial cells to Aß was recovered upon AP5 treatment. Importantly, chronic AP5 treatment significantly prevented neuronal and synaptic damage and memory deficits in AD mice. Conclusion: Together, our work demonstrated that AP5 inhibited the AChE activity, decreased Aß plaque deposition by interfering Aß aggregation and promoting microglial Aß phagocytosis, and suppressed inflammation, thereby rescuing neuronal and synaptic damage and relieving cognitive decline. Thus, AP5 can be a new promising candidate for the treatment of AD.

Systematic analyses of the resistance potential of drugs targeting SARS-CoV-2 main protease (preprint)

Drugs that target the main protease (Mpro) of SARS-CoV-2 are effective therapeutics that have entered clinical use. Wide-scale use of these drugs will apply selection pressure for the evolution of resistance mutations. To understand resistance potential in Mpro, we performed comprehensive surveys of amino acid changes that can cause resistance in a yeast screen to nirmatrelvir (contained in the drug Paxlovid), and ensitrelvir (Xocova) that is currently in phase III trials. The most impactful resistance mutation (E166V) recently reported in multiple viral passaging studies with nirmatrelvir showed the strongest drug resistance score for nirmatrelvir, while P168R had the strongest resistance score for ensitrelvir. Using a systematic approach to assess potential drug resistance, we identified 142 resistance mutations for nirmatrelvir and 177 for ensitrelvir. Among these mutations, 99 caused apparent resistance to both inhibitors, suggesting a strong likelihood for the evolution of cross-resistance. Many mutations that exhibited inhibitor-specific resistance were consistent with distinct ways that each inhibitor protrudes beyond the substrate envelope. In addition, mutations with strong drug resistance scores tended to have reduced function. Our results indicate that strong pressure from nirmatrelvir or ensitrelvir will select for multiple distinct resistant lineages that will include both primary resistance mutations that weaken interactions with drug while decreasing enzyme function and secondary mutations that increase enzyme activity. The comprehensive identification of resistance mutations enables the design of inhibitors with reduced potential of developing resistance and aids in the surveillance of drug resistance in circulating viral populations.

[Research Progress in the Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Drugs Targeting Spike Protein].

The coronavirus disease 2019(COVID-19) caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is spreading around the world,while the specific drugs targeting SARS-CoV-2 are still under development.On the basis of the biological characteristics of SARS-CoV-2 and the key protein(spike protein) for viral replication,this paper introduces the research progress in the action sites of related drugs,providing information for clinical application and ideas for development of anti-SARS-CoV-2 drugs.

MiniSeg: An Extremely Minimum Network Based on Lightweight Multiscale Learning for Efficient COVID-19 Segmentation.

The rapid spread of the new pandemic, i.e., coronavirus disease 2019 (COVID-19), has severely threatened global health. Deep-learning-based computer-aided screening, e.g., COVID-19 infected area segmentation from computed tomography (CT) image, has attracted much attention by serving as an adjunct to increase the accuracy of COVID-19 screening and clinical diagnosis. Although lesion segmentation is a hot topic, traditional deep learning methods are usually data-hungry with millions of parameters, easy to overfit under limited available COVID-19 training data. On the other hand, fast training/testing and low computational cost are also necessary for quick deployment and development of COVID-19 screening systems, but traditional methods are usually computationally intensive. To address the above two problems, we propose MiniSeg, a lightweight model for efficient COVID-19 segmentation from CT images. Our efforts start with the design of an attentive hierarchical spatial pyramid (AHSP) module for lightweight, efficient, effective multiscale learning that is essential for image segmentation. Then, we build a two-path (TP) encoder for deep feature extraction, where one path uses AHSP modules for learning multiscale contextual features and the other is a shallow convolutional path for capturing fine details. The two paths interact with each other for learning effective representations. Based on the extracted features, a simple decoder is added for COVID-19 segmentation. For comparing MiniSeg to previous methods, we build a comprehensive COVID-19 segmentation benchmark. Extensive experiments demonstrate that the proposed MiniSeg achieves better accuracy because its only 83k parameters make it less prone to overfitting. Its high efficiency also makes it easy to deploy and develop. The code has been released at https://github.com/yun-liu/MiniSeg.

Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses (preprint)

With the spread of SARS-CoV-2 throughout the globe to cause the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (Mpro) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from beluga whale. Comparison with the apo structure of SW1 Mpro, which we also present here, enabled identifying structural arrangements upon inhibitor binding at the active site. The binding modes and interactions of two covalent inhibitors, PF-00835231 (lufotrelvir) bound to HKU15 and GC376 bound to SW1 Mpro, reveal features that may be leveraged to target diverse coronaviruses and toward structure-based design of pan-CoV inhibitors.

Bullet screen in pre-clinical undergraduate pharmacology education: a survey study.

BACKGROUND: The lack of interaction and communication in pharmacology courses, especially since the onset of the coronavirus disease 2019 (COVID-19) pandemic, which required a fast shift to remote learning at medical schools, leads to an unsatisfactory learning outcome. New interactive teaching approaches are required to improve pharmacology learning attention and interaction in remote education and traditional classrooms. METHODS: We introduced bullet screens to pharmacology teaching. Then, a survey was distributed to first-, second- and third-year pre-clinical undergraduate medical and nursing students at the Shanghai Jiao Tong University School of Medicine from November 2020 to March 2022. We evaluated the essential features, instructional effectiveness, and entertainment value of bullet screens. Responses to structured and open-ended questions about the strengths and weaknesses of the bullet screen and overall thoughts were coded and compared between medical and nursing students. RESULTS: In terms of essential features, bullet screens have a high degree of acceptability among students, and this novel instructional style conveniently increased classroom interaction. Considering instructional effectiveness, bullet screen may stimulate students' in-depth thinking. Meanwhile, students tended to use bullet-screen comments as a way to express their support rather than to make additional comments or to express their different viewpoints. The entertainment value of bullet screen was noteworthy. The lack of ideas might lead to relative differences between medical and nursing students, indicating that guiding the appropriate use of bullet screen is necessary. CONCLUSIONS: The bullet screen may be popularized as an auxiliary teaching approach to promote interaction between teachers and students in the classroom as well as during remote education. It is an interesting and beneficial tool in pharmacology courses, yet there are several aspects of this device that should be improved for popularization.

Probing Molecular Interactions of Antibody Drugs, Silicone Oil, and Surfactant at Buried Interfaces In Situ.

Antibody drugs have been rapidly developed to cure many diseases including COVID-19 infection. Silicone oil is commonly used as a lubricant coating material for devices used in the pharmaceutical industry to store and administer antibody drug formulations. However, the interaction between silicone oil and antibody molecules could lead to the adsorption, denaturation, and aggregation of antibody molecules, impacting the efficacy of antibody drugs. Here, we studied the molecular interactions between antibodies and silicone oil in situ in real time. The effect of the surfactant on such interactions was also investigated. Specifically, the adsorption dynamics of a bispecific antibody (BsAb) onto a silicone oil surface without and with different concentrations of the surfactant PS80 in antibody solutions were monitored. Also the possible lowest effective PS80 concentrations that can prevent the adsorption of BsAb as well as a monoclonal antibody (mAb) onto silicone oil were measured. It was found that different concentrations of PS80 are required for preventing the adsorption of different antibodies. Both BsAB and mAB denature on silicone oil without a surfactant. However, for a low surfactant concentration in the solution, although the surfactant could not completely prevent the antibody from adsorption, it could maintain the native structures of adsorbed BsAb and mAb antibodies on silicone oil. This is important knowledge, showing that to prevent antibody aggregation on silicone oil it is not necessary to add surfactant to a concentration high enough to completely minimize protein adsorption.

Undiagnosed HIV Infections May Drive HIV Transmission in the Era of "Treat All": A Deep-Sampling Molecular Network Study in Northeast China during 2016 to 2019.

Universal antiretroviral therapy (ART, "treat all") was recommended by the World Health Organization in 2015; however, HIV-1 transmission is still ongoing. This study characterizes the drivers of HIV transmission in the "treat all" era. Demographic and clinical information and HIV pol gene were collected from all newly diagnosed cases in Shenyang, the largest city in Northeast China, during 2016 to 2019. Molecular networks were constructed based on genetic distance and logistic regression analysis was used to assess potential transmission source characteristics. The cumulative ART coverage in Shenyang increased significantly from 77.0% (485/630) in 2016 to 93.0% (2598/2794) in 2019 (p < 0.001). Molecular networks showed that recent HIV infections linked to untreated individuals decreased from 61.6% in 2017 to 28.9% in 2019, while linking to individuals with viral suppression (VS) increased from 9.0% to 49.0% during the same time frame (p < 0.001). Undiagnosed people living with HIV (PLWH) hidden behind the links between index cases and individuals with VS were likely to be male, younger than 25 years of age, with Manchu nationality (p < 0.05). HIV transmission has declined significantly in the era of "treat all". Undiagnosed PLWH may drive HIV transmission and should be the target for early detection and intervention.

The Cholesterol-Binding Sequence in Monomeric C-Reactive Protein Binds to the SARS-CoV-2 Spike Receptor-Binding Domain and Blocks Interaction With Angiotensin-Converting Enzyme 2.

The receptor-binding domain (RBD) of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the human angiotensin-converting enzyme 2 (ACE2) receptor, which is a prerequisite for the virus to enter the cell. C-reactive protein (CRP) is an important marker of inflammation and is a putative soluble pattern recognition receptor. Clinical elevation of CRP levels in patients with COVID-19 is one of the characteristics of the disease; however, whether CRP is involved in COVID-19 pathogenesis is unknown. Here, we report that monomeric CRP (mCRP) can bind to the SARS-CoV-2 spike RBD and competitively inhibit its binding to ACE2. Furthermore, truncated mutant peptide competition assays and surface plasmon resonance binding experiments showed that the cholesterol-binding sequence (CBS, amino acids 35-47) in mCRP was critical for mediating the binding of mCRP to spike RBD. In a cell model of spike RBD and ACE2 interaction, the CBS motif effectively reduced the binding of spike RBD to ACE2 overexpressed on the cell surface. Thus, this study highlights the pattern recognition function of mCRP in innate immunity and provides a preliminary theoretical basis for the development of the CBS motif in mCRP into a functional peptide with both diagnostic significance and potential therapeutic capabilities.

Clinical and epidemiological investigation of a child with asymptomatic COVID-19 infection following reoccurrence.

Objective: To investigate the case of a child infected with coronavirus disease 2019 (COVID-19) who had subsequent viral reactivation. Methods: We retrospectively analyzed the clinical manifestations, epidemiological data, laboratory and imaging examinations, treatment, and follow-up of the child. And then, we searched related literature using PubMed. Results: The 9-year-old boy was exposed to COVID-19 in Malawi and tested positive for NAT in Haikou, China. He was asymptomatic and admitted to our hospital. After six negative NATs, he was discharged from the hospital and quarantined in a hotel. His infection was reactivated again after 22 days (interval between first and last positive NATs). The cycle threshold (Ct) values of positive tests were 25 and 31, and the gene sequencing viral loads were very low. The viral strain Kenya/P2601/2020, a variant of the hCoV-19/Wuhan/IVDC-HB-01/2019 genome (GISAID accession IL: EPI_ISL_402119), was found when polymerase chain reaction enrichment was used to sequence the virus. However, people around him tested negative for COVID-19. Conclusion: First, we confirmed the reactivation of COVID-19 in a child. The risk of recurrent infection with SARS-CoV-2 was low, and the policy of strictly isolating patients carrying long-term viral ribonucleic acid should be reconsidered. The interval positivity was most likely due to incorrect sampling and/or testing methods. SGS and aB testing are recommended for children with viral reactivation. Second, SARS-CoV-2 viral reactivation cannot be ruled out. The possible mechanisms, such as prolonged infection and viral latent reactivation, need further investigation.

The Cholesterol-Binding Sequence in Monomeric C-Reactive Protein Binds to the SARS-CoV-2 Spike Receptor-Binding Domain and Blocks Interaction With Angiotensin-Converting Enzyme 2

The receptor-binding domain (RBD) of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the human angiotensin-converting enzyme 2 (ACE2) receptor, which is a prerequisite for the virus to enter the cell. C-reactive protein (CRP) is an important marker of inflammation and is a putative soluble pattern recognition receptor. Clinical elevation of CRP levels in patients with COVID-19 is one of the characteristics of the disease;however, whether CRP is involved in COVID-19 pathogenesis is unknown. Here, we report that monomeric CRP (mCRP) can bind to the SARS-CoV-2 spike RBD and competitively inhibit its binding to ACE2. Furthermore, truncated mutant peptide competition assays and surface plasmon resonance binding experiments showed that the cholesterol-binding sequence (CBS, amino acids 35-47) in mCRP was critical for mediating the binding of mCRP to spike RBD. In a cell model of spike RBD and ACE2 interaction, the CBS motif effectively reduced the binding of spike RBD to ACE2 overexpressed on the cell surface. Thus, this study highlights the pattern recognition function of mCRP in innate immunity and provides a preliminary theoretical basis for the development of the CBS motif in mCRP into a functional peptide with both diagnostic significance and potential therapeutic capabilities.

Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance.

Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (Mpro) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 Mpro bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of Mpro, map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed Mpro inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.

Ethical review of off-label drugs during the COVID-19 pandemic.

High-quality scientific research is very important in attempting to effectively control the coronavirus disease 2019 (COVID-19) pandemic and ensure people's health and safety. Chloroquine (CQ) and hydroxychloroquine (HCQ) have received much attention. This article comprehensively investigates the ethical review of off-label CQ and HCQ research during the COVID-19 pandemic with regard to strictly abiding by review standards, improving review efficiency, ensuring the rights and interests of subjects and that ethics committees conduct independent reviews, and achieving full ethics supervision of research conducted during an emergency. Research must be both rigorous and prudent to ensure the best outcome, with the maximization of benefits as the core principle. Standardization of the application, implementation and ethical review processes are needed to prevent unnecessary risk.

[Impacts of Changes in Meteorological Conditions During COVID-19 Lockdown on PM2.5 Concentrations over the Jing-Jin-Ji Region].

The Chinese government triggered the immediate implementation of a lockdown policy in China following the outbreak of the COVID-19 pandemic, leading to drastic decreases in air pollutant emissions. However, concentrations of PM2.5 and other pollutants increased during the COVID-19 lockdown over the Jing-Jin-Ji region compared with those averaged over 2015-2019, and two PM2.5 pollution events occurred during the lockdown. Using the ERA5 reanalysis data, we found that the Jing-Jin-Ji region during the COVID-19 lockdown was characterized by higher relative humidity, lower planetary boundary layer height, and anomalous updraft. These conditions were favorable for condensation and the secondary formation of aerosols and prevented turbulent diffusion of pollutants. Furthermore, we conducted sensitivity tests using the WRF-Chem model and found that ρ(PM2.5) increased by 20-55 µg·m-3(60%-170%) over the middle region of Jing-Jin-Ji during the COVID-19 lockdown due to changes in meteorological conditions. Furthermore, the enhanced aerosol chemistry and unfavorable diffusion conditions were identified as the key factors driving increases in PM2.5 concentrations during the lockdown. Planetary boundary layer height and relative humidity may become the important factors in forecasting PM2.5 pollution events over the Jing-Jin-Ji region under the background of emission reduction.

Comparative miRNA transcriptomics of macaques and mice reveals MYOC is an inhibitor for Cryptococcus neoformans invasion into the brain.

Cryptococcal meningoencephalitis (CM) is emerging as an infection in HIV/AIDS patients shifted from primarily ART-naive to ART-experienced individuals, as well as patients with COVID-19 and immunocompetent hosts. This fungal infection is mainly caused by the opportunistic human pathogen Cryptococcus neoformans. Brain or central nervous system (CNS) dissemination is the deadliest process for this disease; however, mechanisms underlying this process have yet to be elucidated. Moreover, illustrations of clinically relevant responses in cryptococcosis are currently limited due to the low availability of clinical samples. In this study, to explore the clinically relevant responses during C. neoformans infection, macaque and mouse infection models were employed and miRNA-mRNA transcriptomes were performed and combined, which revealed cytoskeleton, a major feature of HIV/AIDS patients, was a centric pathway regulated in both infection models. Notably, assays of clinical immune cells confirmed an enhanced macrophage "Trojan Horse" in patients with HIV/AIDS, which could be shut down by cytoskeleton inhibitors. Furthermore, myocilin, encoded by MYOC, was found to be a novel enhancer for the macrophage "Trojan Horse," and an enhanced fungal burden was achieved in the brains of MYOC-transgenic mice. Taken together, the findings from this study reveal fundamental roles of the cytoskeleton and MYOC in fungal CNS dissemination, which not only helps to understand the high prevalence of CM in HIV/AIDS but also facilitates the development of novel therapeutics for meningoencephalitis caused by C. neoformans and other pathogenic microorganisms.

United Against Rabies Forum: The One Health Concept at Work.

Human deaths from rabies are preventable and can be eliminated by applying a systematic One Health approach. However, this ancient disease still threatens the lives of millions of people in up to 150 countries and kills an estimated 59, 000 people every year. Rabies today is largely a disease of poverty, almost always linked to dog bites, with most deaths occurring in neglected communities in Africa and Asia. The disease places an immense economic burden on its victims, a cost that far outweighs the investment needed to control it. A global framework for rabies elimination in humans is set out in Zero by 30: The Global Strategic Plan to end human deaths from dog-mediated rabies by 2030. Despite the existence of proven control strategies and agreement on the path to eliminating human rabies deaths, mortality numbers from rabies remain high, and COVID-19 has set back efforts even further. But COVID-19 has also highlighted the value of a One Health approach to zoonotic disease and pandemic prevention. Rabies control programs offer a practical route to building One Health capacities that can also address other zoonotic threats, including those with pandemic potential. The United Against Rabies Forum aims to accelerate progress on rabies elimination while applying a One Health approach. The Forum promotes cross-sector collaboration among stakeholders and supports countries in their rabies elimination efforts. Increased political engagement and resource mobilization, both internationally and nationally, will be needed to achieve global rabies goals and can also make One Health implementation a reality.

Defining the Substrate Envelope of SARS-CoV-2 Main Protease to Predict and Avoid Drug Resistance (preprint)

Coronaviruses, as exemplified by SARS-CoV-2, can evolve and spread rapidly to cause severe disease morbidity and mortality. Direct acting antivirals (DAAs) are highly effective in decreasing disease burden especially when they target essential viral enzymes, such as proteases and polymerases, as demonstrated in HIV-1 and HCV and most recently SARS-CoV-2. Optimization of these DAAs through iterative structure-based drug design has been shown to be critical. Particularly, the evolutionarily conserved molecular mechanisms underlying viral replication can be leveraged to develop robust antivirals against rapidly evolving viral targets. The main protease (Mpro) of SARS-CoV-2, which is evolutionarily constrained to recognize and cleave 11 specific sites to promote viral maturation, exemplifies one such target. In this study we define the substrate envelope of Mpro by determining the molecular basis of substrate recognition, through nine high-resolution cocrystal structures of SARS-CoV-2 Mpro with the viral cleavage sites. These structures enable identification of evolutionarily vulnerable sites beyond the substrate envelope that may be susceptible to drug resistance and compromise binding of the newly developed Mpro inhibitors.