Modeling the Opening SARS-CoV-2 Spike: an Investigation of its Dynamic Electro-Geometric Properties (preprint)

The recent COVID-19 pandemic has brought about a surge of crowd-sourced initiatives aimed at simulating the proteins of the SARS-CoV-2 virus. A bottleneck currently exists in translating these simulations into tangible predictions that can be leveraged for pharmacological studies. Here we report on extensive electrostatic calculations done on an exascale simulation of the opening of the SARS-CoV-2 spike protein, performed by the Folding@home initiative. We compute the electric potential as the solution of the non-linear Poisson-Boltzmann equation using a parallel sharp numerical solver. The inherent multiple length scales present in the geometry and solution are reproduced using highly adaptive Octree grids. We analyze our results focusing on the electro-geometric properties of the receptor-binding domain and its vicinity. This work paves the way for a new class of hybrid computational and data-enabled approaches, where molecular dynamics simulations are combined with continuum modeling to produce high-fidelity computational measurements serving as a basis for protein bio-mechanism investigations.

Large-scale single-cell analysis reveals critical immune characteristics of COVID-19 patients (preprint)

Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic up-regulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19.

Clinical Course and Features of Critical Patients with COVID-19: A Single- Center, Retrospective Study from Wuhan Huoshenshan Hospital (preprint)

Background: Nationally, the indicators tracking the coronavirus pandemic has remained stable. However, it’s still a public health concern and it’s worth providing more front-line data on critical illness. We aim to investigate the clinical course and features of critical patients with Corona Virus Disease 2019 (COVID-19).Methods: The data on 124 consecutive critical patients from 8th February through April 16th 2020, including demographic and clinical information, were obtained from the intensive care unit (ICU) of Wuhan Huoshenshan Hospital. A cross-sectional survey and comparisons of key biomarkers between survivors and nonsurvivors were performed.Results: Over the study period, 57 nonsurvivors and 67 survivors were included. The overall case-fatality rate for critical patients with COVID-19 was approximately 46%. The overall average age was 69.89±11.03 years, and the majority had underlying health problems such as hypertension (63[51%]) and diabetes (27[22%]). Compared with survivors, nonsurvivors were more likely to develop sepsis (57[100%] vs. 34[51%]), acute respiratory distress syndrome (52[91%] vs. 21[38%]) and organ dysfunction. Besides, the dynamic changes in some biomarkers (i.e. WBC, TLC, CRP, PLT) were significantly different between the two groups. The trajectories of temperature revealed that the group with a high temperature on admission that steadily declined had the highest percentage of deaths (84.21%).Conclusions: The elderly with many concomitant diseases were at the highest risk. Lymphocyte, platelet, C-reactive protein and temperature were revealed to have potential as prognostic factors, whereas some other biomarkers, such as hepatic enzymes, may not offer additional information. Moreover, patients with high temperatures on admission should receive extra care.

Clinical course and features of critical patients with COVID-19: a single- center, retrospective study from Wuhan Huoshenshan Hospital (preprint)

Background : The coronavirus pandemic has become a growing public health concern worldwide, and there are insufficient epidemiological data on critical illness. Objective: To investigate the clinical course and features of critical patients with Corona Virus Disease 2019 ( COVID-19 ). Methods: The data on 94 consecutive critical patients from 8 th February through 16 th March 2020, including demographic and clinical information, were obtained from the intensive care unit (ICU) of Wuhan Huoshenshan Hospital. A cross-sectional survey and comparisons of key biomarkers between survivors and nonsurvivors were performed. Results: Over the study period, 42 nonsurvivors and 52 survivors were included. The overall case fatality rate for critical patients with COVID-19 was approximately 45%. The average age was 69.17±9.55 years, and the majority had underlying health problems such as hypertension (56[60%]) and diabetes (18[19%]). The median length of ICU stay was 8 days (IQR 4, 13). Compared with survivors, nonsurvivors were more likely to develop sepsis (42[100%] vs. 34[65%]), acute respiratory distress syndrome (40[95%] vs. 28[54%]) and organ dysfunction. In addition, the dynamic changes in some biomarkers were significantly different between the two groups. The trajectories of temperature revealed that the group with a high temperature on admission that steadily declined had the highest percentage of deaths (93.33%). Conclusions: Patients aged 60 years or older with many concomitant diseases were at highest risk, and the fatality rate started to increase with age. Lymphocyte, platelet, C-reactive protein and hypersensitivity troponin I were revealed to have potential as prognostic factors, whereas some other biomarkers, such as hepatic enzymes, may not offer additional information. Moreover, patients with high temperatures on admission should receive extra care.

Clinical course and features of critical patients with COVID-19: a single-center, retrospective study from Wuhan Huoshenshan Hospital (preprint)

Background and Aims: The coronavirus pandemic has become a growing public health concern worldwide, and there are insufficient epidemiological data on critical illness. We sought to investigate the clinical course and features of critical patients with Corona Virus Disease 2019 (COVID-19).Method: The data on 94 critical patients from 8th February through 16th March 2020, including demographic and clinical information, were obtained from the intensive care unit (ICU) of Wuhan Huoshenshan Hospital. A cross-sectional survey and comparisons of key biomarkers between survivors and nonsurvivors were performed.Results: Over the study period, 42 nonsurvivors and 52 survivors were included. The overall case fatality rate for critical patients with COVID-19 was approximately 45%. The average age was 69.17±9.55 years, and the majority had underlying health problems such as hypertension (56[60%]) and diabetes (18[19%]). The median length of ICU stay was 8 days (IQR 4, 13). Compared with survivors, nonsurvivors were more likely to develop sepsis (42[100%] vs. 34[65%]), acute respiratory distress syndrome (40[95%] vs. 28[54%]) and organ dysfunction. In addition, the dynamic changes in some biomarkers were significantly different between the two groups. The trajectories of temperature revealed that the group with a high temperature on admission that steadily declined had the highest percentage of deaths (93.33%).Conclusion: Patients aged 60 years or older with many concomitant diseases were at highest risk, and the fatality rate started to increase with age. Lymphocyte, platelet, C-reactive protein and hypersensitivity troponin I were revealed to have potential as prognostic factors, whereas some other biomarkers, such as hepatic enzymes, may not offer additional information. Moreover, patients with high temperatures on admission should receive extra care.

Immune Cell Profiling of COVID-19 Patients in the Recovery Stage by Single-Cell Sequencing (preprint)

COVID-19 caused by SARS-CoV-2 has recently affected over 200,000 people and killed more than 8000. Immune system dysregulation such as lymphopenia and inflammatory cytokine storm has been observed in COVID-19 patients, but it remains unclear for the change of key immune cell subsets and their states during COVID-19. Here, we applied single-cell technology to comprehensively characterize transcriptional changes of peripheral blood mononuclear cells in ten patients recovered from COVID-19. Compared with healthy control, COVID-19 induced a unique signature of immune cells in humans, especially in the early recovery stage (ERS). In ERS patients, T cells were decreased remarkably, while monocytes were increased. A detailed analysis of monocytes showed that there was an increased ratio of classical CD14++ monocytes with highly inflammatory genes expression, as well as a greater abundance of CD14++IL1B+ monocytes. For nature killer (NK) cells and T cells, CD4+ T cells were significantly decreased and expressed high level of inflammatory markers, while NK cells were increased. In addition, T cells were highly expanded clone, especially in CD4+ T memory cells and CD8+ T cells. Among B cells, plasma cells were increased remarkably, and naive B cells were reduced. Our study also identified several novel B cell receptor (BCR) changes (such as IGHV1-8 and IGHV3-7), and confirmed isotypes (IGKV3-11 and IGHV3-21) previously used for virus vaccine development. The strongest pairing frequencies, IGHV3-23+IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity. Furthermore, integrated analysis predicated that IL-1B and M-CSF may be novel candidate target gene for inflammatory storm, and TNFSF13, IL-18 and IL-4 may be benefit for the recovery of COVID-19 patients. Our study provides the first evidence of inflammatory immune signature in early recovery stage, suggesting that the COVID-19 patients are still vulnerable after hospital discharge. Our identification of novel BCR signaling may lead to the development of vaccine and antibodies for the treatment of COVID-19.