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Estee Y Cramer; Evan L Ray; Velma K Lopez; Johannes Bracher; Andrea Brennen; Alvaro J Castro Rivadeneira; Aaron Gerding; Tilmann Gneiting; Katie H House; Yuxin Huang; Dasuni Jayawardena; Abdul H Kanji; Ayush Khandelwal; Khoa Le; Anja Muhlemann; Jarad Niemi; Apurv Shah; Ariane Stark; Yijin Wang; Nutcha Wattanachit; Martha W Zorn; Youyang Gu; Sansiddh Jain; Nayana Bannur; Ayush Deva; Mihir Kulkarni; Srujana Merugu; Alpan Raval; Siddhant Shingi; Avtansh Tiwari; Jerome White; Spencer Woody; Maytal Dahan; Spencer Fox; Kelly Gaither; Michael Lachmann; Lauren Ancel Meyers; James G Scott; Mauricio Tec; Ajitesh Srivastava; Glover E George; Jeffrey C Cegan; Ian D Dettwiller; William P England; Matthew W Farthing; Robert H Hunter; Brandon Lafferty; Igor Linkov; Michael L Mayo; Matthew D Parno; Michael A Rowland; Benjamin D Trump; Sabrina M Corsetti; Thomas M Baer; Marisa C Eisenberg; Karl Falb; Yitao Huang; Emily T Martin; Ella McCauley; Robert L Myers; Tom Schwarz; Daniel Sheldon; Graham Casey Gibson; Rose Yu; Liyao Gao; Yian Ma; Dongxia Wu; Xifeng Yan; Xiaoyong Jin; Yu-Xiang Wang; YangQuan Chen; Lihong Guo; Yanting Zhao; Quanquan Gu; Jinghui Chen; Lingxiao Wang; Pan Xu; Weitong Zhang; Difan Zou; Hannah Biegel; Joceline Lega; Timothy L Snyder; Davison D Wilson; Steve McConnell; Yunfeng Shi; Xuegang Ban; Robert Walraven; Qi-Jun Hong; Stanley Kong; James A Turtle; Michal Ben-Nun; Pete Riley; Steven Riley; Ugur Koyluoglu; David DesRoches; Bruce Hamory; Christina Kyriakides; Helen Leis; John Milliken; Michael Moloney; James Morgan; Gokce Ozcan; Chris Schrader; Elizabeth Shakhnovich; Daniel Siegel; Ryan Spatz; Chris Stiefeling; Barrie Wilkinson; Alexander Wong; Sean Cavany; Guido Espana; Sean Moore; Rachel Oidtman; Alex Perkins; Zhifeng Gao; Jiang Bian; Wei Cao; Juan Lavista Ferres; Chaozhuo Li; Tie-Yan Liu; Xing Xie; Shun Zhang; Shun Zheng; Alessandro Vespignani; Matteo Chinazzi; Jessica T Davis; Kunpeng Mu; Ana Pastore y Piontti; Xinyue Xiong; Andrew Zheng; Jackie Baek; Vivek Farias; Andreea Georgescu; Retsef Levi; Deeksha Sinha; Joshua Wilde; Nicolas D Penna; Leo A Celi; Saketh Sundar; Dave Osthus; Lauren Castro; Geoffrey Fairchild; Isaac Michaud; Dean Karlen; Elizabeth C Lee; Juan Dent; Kyra H Grantz; Joshua Kaminsky; Kathryn Kaminsky; Lindsay T Keegan; Stephen A Lauer; Joseph C Lemaitre; Justin Lessler; Hannah R Meredith; Javier Perez-Saez; Sam Shah; Claire P Smith; Shaun A Truelove; Josh Wills; Matt Kinsey; RF Obrecht; Katharine Tallaksen; John C. Burant; Lily Wang; Lei Gao; Zhiling Gu; Myungjin Kim; Xinyi Li; Guannan Wang; Yueying Wang; Shan Yu; Robert C Reiner; Ryan Barber; Emmanuela Gaikedu; Simon Hay; Steve Lim; Chris Murray; David Pigott; B. Aditya Prakash; Bijaya Adhikari; Jiaming Cui; Alexander Rodriguez; Anika Tabassum; Jiajia Xie; Pinar Keskinocak; John Asplund; Arden Baxter; Buse Eylul Oruc; Nicoleta Serban; Sercan O Arik; Mike Dusenberry; Arkady Epshteyn; Elli Kanal; Long T Le; Chun-Liang Li; Tomas Pfister; Dario Sava; Rajarishi Sinha; Thomas Tsai; Nate Yoder; Jinsung Yoon; Leyou Zhang; Sam Abbott; Nikos I I Bosse; Sebastian Funk; Joel Hellewell; Sophie R Meakin; James D Munday; Katharine Sherratt; Mingyuan Zhou; Rahi Kalantari; Teresa K Yamana; Sen Pei; Jeffrey Shaman; Turgay Ayer; Madeline Adee; Jagpreet Chhatwal; Ozden O Dalgic; Mary A Ladd; Benjamin P Linas; Peter Mueller; Jade Xiao; Michael L Li; Dimitris Bertsimas; Omar Skali Lami; Saksham Soni; Hamza Tazi Bouardi; Yuanjia Wang; Qinxia Wang; Shanghong Xie; Donglin Zeng; Alden Green; Jacob Bien; Addison J Hu; Maria Jahja; Balasubramanian Narasimhan; Samyak Rajanala; Aaron Rumack; Noah Simon; Ryan Tibshirani; Rob Tibshirani; Valerie Ventura; Larry Wasserman; Eamon B O'Dea; John M Drake; Robert Pagano; Jo W Walker; Rachel B Slayton; Michael Johansson; Matthew Biggerstaff; Nicholas G Reich.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.02.03.21250974

ABSTRACT

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. In 2020, the COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized hundreds of thousands of specific predictions from more than 50 different academic, industry, and independent research groups. This manuscript systematically evaluates 23 models that regularly submitted forecasts of reported weekly incident COVID-19 mortality counts in the US at the state and national level. One of these models was a multi-model ensemble that combined all available forecasts each week. The performance of individual models showed high variability across time, geospatial units, and forecast horizons. Half of the models evaluated showed better accuracy than a naive baseline model. In combining the forecasts from all teams, the ensemble showed the best overall probabilistic accuracy of any model. Forecast accuracy degraded as models made predictions farther into the future, with probabilistic accuracy at a 20-week horizon more than 5 times worse than when predicting at a 1-week horizon. This project underscores the role that collaboration and active coordination between governmental public health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks. f


Subject(s)
COVID-19
2.
researchsquare; 2021.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-195760.v1

ABSTRACT

Novel Coronavirus (COVID-19) has spread worldwide, causing continued casualties and economic losses. To characterize the pandemic dynamics, we propose fractional order generalized SEIR epidemic models for COVID-19, considering real-world Facebook symptom data and state-level Google mobility. Fractional order models based on noninteger order calculus can better characterize inhomogeneity in human interactions and infection rates. Our models can describe psychological effect factors within the nonlinear incidence functions. Therefore, we can deliver better fitting and prediction performances. Comparative analysis of model predictions with different mitigation and intervention scenarios, which are affected by mobilities in California, are made. Now, vaccination is becoming a critical response so that the COVID-19 pandemic can become endemic in optimal possible ways.We propose the modified fractional order GSEIR model for near real-time COVID- 19 Receding Horizon vaccine policy study. The proposed Receding Horizon Control (RHC) optimal vaccine strategy can not only explicitly consider the constraints on vaccine availability, speed of replenishing, vaccine application rate, etc., but also can make the whole management in a closedloop manner with an optimization performance index. Additionally, our model can accommodate the age structure of the population, mobility level, community mitigation measures, the willingness to be vaccinated, etc. The closedloop vaccine system can achieve good tracking performance given a future desired and feasible trend. Specifically, our forecast trends of infections and death cases in different immunization scenarios can guide individual and policy decision-making processes in developing mitigation measures and monitoring community risk levels. Numerical simulations using Simulink Design Optimization (SLDO) are given to support our analysis.


Subject(s)
Death , COVID-19
3.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.11.03.20225409

ABSTRACT

Policymakers make decisions about COVID-19 management in the face of considerable uncertainty. We convened multiple modeling teams to evaluate reopening strategies for a mid-sized county in the United States, in a novel process designed to fully express scientific uncertainty while reducing linguistic uncertainty and cognitive biases. For the scenarios considered, the consensus from 17 distinct models was that a second outbreak will occur within 6 months of reopening, unless schools and non-essential workplaces remain closed. Up to half the population could be infected with full workplace reopening; non-essential business closures reduced median cumulative infections by 82%. Intermediate reopening interventions identified no win-win situations; there was a trade-off between public health outcomes and duration of workplace closures. Aggregate results captured twice the uncertainty of individual models, providing a more complete expression of risk for decision-making purposes.


Subject(s)
Cognition Disorders , COVID-19
4.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.11.05.369264

ABSTRACT

The widespread occurrence of SARS-CoV-2 has had a profound effect on society and a vaccine is currently being developed. Angiotensin-converting enzyme 2 (ACE2) is the primary host cell receptor that interacts with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Although pneumonia is the main symptom in severe cases of SARS-CoV-2 infection, the expression levels of ACE2 in the lung is low, suggesting the presence of another receptor for the spike protein. In order to identify the additional receptors for the spike protein, we screened a receptor for the SARS-CoV-2 spike protein from the lung cDNA library. We cloned L-SIGN as a specific receptor for the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. The RBD of the spike protein did not bind to L-SIGN. In addition, not only L-SIGN but also DC-SIGN, a closely related C-type lectin receptor to L-SIGN, bound to the NTD of the SARS-CoV-2 spike protein. Importantly, cells expressing L-SIGN and DC-SIGN were both infected by SARS-CoV-2. Furthermore, L-SIGN and DC-SIGN induced membrane fusion by associating with the SARS-CoV-2 spike protein. Serum antibodies from infected patients and a patient-derived monoclonal antibody against NTD inhibited SARS-CoV-2 infection of L-SIGN or DC-SIGN expressing cells. Our results highlight the important role of NTD in SARS-CoV-2 dissemination through L-SIGN and DC-SIGN and the significance of having anti-NTD neutralizing antibodies in antibody-based therapeutics.


Subject(s)
Severe Acute Respiratory Syndrome , Pneumonia , COVID-19
5.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.11.05.369413

ABSTRACT

SARS-CoV-2 is a coronavirus that sparked the current COVID-19 pandemic. To stop the shattering effect of COVID-19, effective and safe vaccines, and antiviral therapies are urgently needed. To facilitate the preclinical evaluation of intervention approaches, relevant animal models need to be developed and validated. Rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) are widely used in biomedical research and serve as models for SARS-CoV-2 infection. However, differences in study design make it difficult to compare and understand potential species-related differences. Here, we directly compared the course of SARS-CoV-2 infection in the two genetically closely-related macaque species. After inoculation with a low passage SARS-CoV-2 isolate, clinical, virological, and immunological characteristics were monitored. Both species showed slightly elevated body temperatures in the first days after exposure while a decrease in physical activity was only observed in the rhesus macaques and not in cynomolgus macaques. The virus was quantified in tracheal, nasal, and anal swabs, and in blood samples by qRT-PCR, and showed high similarity between the two species. Immunoglobulins were detected by various enzyme-linked immunosorbent assays (ELISAs) and showed seroconversion in all animals by day 10 post-infection. The cytokine responses were highly comparable between species and computed tomography (CT) imaging revealed pulmonary lesions in all animals. Consequently, we concluded that both rhesus and cynomolgus macaques represent valid models for evaluation of COVID-19 vaccine and antiviral candidates in a preclinical setting.


Subject(s)
Lung Diseases , COVID-19
6.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.11.04.361576

ABSTRACT

The COVID-19 pandemic is a widespread and deadly public health crisis. The pathogen SARS-CoV-2 replicates in the lower respiratory tract and causes fatal pneumonia. Although tremendous efforts have been put into investigating the pathogeny of SARS-CoV-2, the underlying mechanism of how SARS-CoV-2 interacts with its host is largely unexplored. Here, by comparing the genomic sequences of SARS-CoV-2 and human, we identified five fully conserved elements in SARS-CoV-2 genome, which were termed as "human identical sequences (HIS)". HIS are also recognized in both SARS-CoV and MERS-CoV genome. Meanwhile, HIS-SARS-CoV-2 are highly conserved in the primate. Mechanically, HIS-SARS-CoV-2 RNA directly binds to the targeted loci in human genome and further interacts with host enhancers to activate the expression of adjacent and distant genes, including cytokines gene and angiotensin converting enzyme II (ACE2), a well-known cell entry receptor of SARS-CoV-2, and hyaluronan synthase 2 (HAS2), which further increases hyaluronan formation. Noteworthily, hyaluronan level in plasma of COVID-19 patients is tightly correlated with severity and high risk for acute respiratory distress syndrome (ARDS) and may act as a predictor for the progression of COVID-19. HIS antagomirs, which downregulate hyaluronan level effectively, and 4-Methylumbelliferone (MU), an inhibitor of hyaluronan synthesis, are potential drugs to relieve the ARDS related ground-glass pattern in lung for COVID-19 treatment. Our results revealed that unprecedented HIS elements of SARS-CoV-2 contribute to the cytokine storm and ARDS in COVID-19 patients. Thus, blocking HIS-involved activating processes or hyaluronan synthesis directly by 4-MU may be effective strategies to alleviate COVID-19 progression.


Subject(s)
Severe Acute Respiratory Syndrome , Respiratory Distress Syndrome , Dissociative Identity Disorder , Pneumonia , COVID-19
7.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.11.04.369041

ABSTRACT

Motivation: In the event of an outbreak due to an emerging pathogen, time is of the essence to contain or to mitigate the spread of the disease. Drug repositioning is one of the strategies that has the potential to deliver therapeutics relatively quickly. The SARS-CoV-2 pandemic has shown that integrating critical data resources to drive drug-repositioning studies, involving host-host, host-pathogen and drug-target interactions, remains a time-consuming effort that translates to a delay in the development and delivery of a life-saving therapy. Results: Here, we describe a workflow we designed for a semi-automated integration of rapidly emerging datasets that can be generally adopted in a broad network pharmacology research setting. The workflow was used to construct a COVID-19 focused multimodal network that integrates 487 host-pathogen, 74,805 host-host protein and 1,265 drug-target interactions. The resultant Neo4j graph database named "Neo4COVID19" is accessible via a web interface and via API calls based on the Bolt protocol. We believe that our Neo4COVID19 database will be a valuable asset to the research community and will catalyze the discovery of therapeutics to fight COVID-19. Availability: https://neo4covid19.ncats.io . Keywords: SARS-CoV-2, COVID-19, network pharmacology, graph database, Neo4j, data integration, drug repositioning


Subject(s)
COVID-19
8.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.06.18.20134916

ABSTRACT

In this project, we study a class of fractional order generalized SEIR epidemic models. Based on the public data from Jan. 22th to May 15th, 2020, we reliably estimate key epidemic parameters and make predictions on the peak point and possible ending time for the target region. We analyze the current management strategy and predict the future implementation of different management strategies. Numerical simulations which support our analysis are also given.


Subject(s)
COVID-19
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