Virtually the Same? Evaluating the Effectiveness of Remote Undergraduate Research Experiences.

In-person undergraduate research experiences (UREs) promote students' integration into careers in life science research. In 2020, the COVID-19 pandemic prompted institutions hosting summer URE programs to offer them remotely, raising questions about whether undergraduates who participate in remote research can experience scientific integration and whether they might perceive doing research less favorably (i.e., not beneficial or too costly). To address these questions, we examined indicators of scientific integration and perceptions of the benefits and costs of doing research among students who participated in remote life science URE programs in Summer 2020. We found that students experienced gains in scientific self-efficacy pre- to post-URE, similar to results reported for in-person UREs. We also found that students experienced gains in scientific identity, graduate and career intentions, and perceptions of the benefits of doing research only if they started their remote UREs at lower levels on these variables. Collectively, students did not change in their perceptions of the costs of doing research despite the challenges of working remotely. Yet students who started with low cost perceptions increased in these perceptions. These findings indicate that remote UREs can support students' self-efficacy development, but may otherwise be limited in their potential to promote scientific integration.

Interaction Context-Aware Network Behavior Anomaly Detection for Discovering Unknown Attacks

Network behavior anomaly detection is an effective approach to discover unknown attacks, where generating high-efficacy network behavior representation is one of the most crucial parts. Nowadays, complicated network environments and advancing attack techniques make it more challenging. Existing methods cannot yield satisfied representations that express the semantics of network behaviors comprehensively. To tackle this problem, we propose XNBAD, a novel unsupervised network behavior anomaly detection framework, in this work. It integrates the timely high-order host states under the dynamic interaction context with the conversation patterns between hosts for behavior representation. High-order states can better summarize latent interaction patterns, but they are hard to be obtained directly. Therefore, XNBAD utilizes a graph neural network (GNN) to automatically generate high-order features from series of extracted base ones. We evaluated the detection performance of XNBAD in a publicly available benchmark dataset ISCX-2012. To report detailed and precise experimental results, we carefully refined the dataset before evaluation. The results show that XNBAD discovered various attack behaviors more effectively, and it significantly outperformed the existing representative methods by at least 3.8% relative improvement in terms of the overall weighted AUC.

"How Do We Do This at a Distance?!" A Descriptive Study of Remote Undergraduate Research Programs during COVID-19.

The COVID-19 pandemic shut down undergraduate research programs across the United States. A group of 23 colleges, universities, and research institutes hosted remote undergraduate research programs in the life sciences during Summer 2020. Given the unprecedented offering of remote programs, we carried out a study to describe and evaluate them. Using structured templates, we documented how programs were designed and implemented, including who participated. Through focus groups and surveys, we identified programmatic strengths and shortcomings as well as recommendations for improvements from students' perspectives. Strengths included the quality of mentorship, opportunities for learning and professional development, and a feeling of connection with a larger community. Weaknesses included limited cohort building, challenges with insufficient structure, and issues with technology. Although all programs had one or more activities related to diversity, equity, inclusion, and justice, these topics were largely absent from student reports even though programs coincided with a peak in national consciousness about racial inequities and structural racism. Our results provide evidence for designing remote Research Experiences for Undergraduates (REUs) that are experienced favorably by students. Our results also indicate that remote REUs are sufficiently positive to further investigate their affordances and constraints, including the potential to scale up offerings, with minimal concern about disenfranchising students.

Molecular basis of SARS-CoV-2 Omicron variant receptor engagement and antibody evasion and neutralization (preprint)

The SARS-CoV-2 Omicron variant exhibits striking immune evasion and is spreading globally at an unprecedented speed. Understanding the underlying structural basis of the high transmissibility and greatly enhanced immune evasion of Omicron is of high importance. Here through cryo-EM analysis, we present both the closed and open states of the Omicron spike, which appear more compact than the counterparts of the G614 strain, potentially related to the Omicron substitution induced enhanced protomer-protomer and S1-S2 interactions. The closed state showing dominant population may indicate a conformational masking mechanism of immune evasion for Omicron spike. Moreover, we capture two states for the Omicron S/ACE2 complex with S binding one or two ACE2s, revealing that the substitutions on the Omicron RBM result in new salt bridges/H-bonds and more favorable electrostatic surface properties, together strengthened interaction with ACE2, in line with the higher ACE2 affinity of the Omicron relative to the G614 strain. Furthermore, we determine cryo-EM structures of the Omicron S/S3H3 Fab, an antibody able to cross-neutralize major variants of concern including Omicron, elucidating the structural basis for S3H3-mediated broad-spectrum neutralization. Our findings shed new lights on the high transmissibility and immune evasion of the Omicron variant and may also inform design of broadly effective vaccines against emerging variants.

Establishment of a quantitative RT-PCR detection of SARS-CoV-2 virus.

BACKGROUND: The outbreak of novel coronavirus disease 2019 (COVID-19) has become a public health emergency of international concern. Quantitative testing of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus is demanded in evaluating the efficacy of antiviral drugs and vaccines and RT-PCR can be widely deployed in the clinical assay of viral loads. Here, we developed a quantitative RT-PCR method for SARS-CoV-2 virus detection in this study. METHODS: RT-PCR kits targeting E (envelope) gene, N (nucleocapsid) gene and RdRP (RNA-dependent RNA polymerase) gene of SARS-CoV-2 from Roche Diagnostics were evaluated and E gene kit was employed for quantitative detection of COVID-19 virus using Cobas Z480. Viral load was calculated according to the standard curve established by series dilution of an E-gene RNA standard provided by Tib-Molbiol (a division of Roche Diagnostics). Assay performance was evaluated. RESULTS: The performance of the assay is acceptable with limit of detection (LOD) below 10E1 copies/µL and lower limit of quantification (LLOQ) as 10E2 copies/µL. CONCLUSION: A quantitative detection of the COVID-19 virus based on RT-PCR was established.

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. FINDINGS: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. INTERPRETATION: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. FUNDING: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.

Clinical Characteristics and Immune Injury Mechanisms in 71 Patients with COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19), caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a threat to global health. The mortality rate of severely ill patients in the early stage is 32.5%. The exacerbation of the condition and death of patients are closely associated with inflammatory cytokine storms, which are caused by excessive activation of the immune and complement systems as well as the coinfection of other pathogens. However, the immunological characteristics and the mechanisms underlying inflammatory storms have not been well elucidated. Here, we analyzed the clinical and immunological characteristics of 71 confirmed COVID-19 patients. Based on the National Health Commission of China (NHCC) guidelines, patients were stratified into mild and severe types. We compared the clinical and laboratory data obtained from electronic medical records between the two types. In regard to the hematological parameters, COVID-19 patients showed decreased erythrocyte count, hemoglobin, hematocrit, lymphocyte count, eosinophil count, and complement C1q, whereas neutrophils, C-reactive protein, and procalcitonin were significantly increased, especially in severe cases. We also found that CD3+ CD4+ T lymphocytes, CD3+ CD8+ T lymphocytes, CD19+ B lymphocytes, and CD16+ CD56+ NK cells in the peripheral blood of all patients were decreased. In addition, CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, and complement C1q in severely ill patients decreased more significantly. Additionally, interleukin 6 (IL-6) elevation was particularly prominent in all patients, especially in severe cases. These results suggest that CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, C1q as well as IL-6 may play critical roles in the inflammatory cytokine storm. The dysregulation of these aforementioned immune parameters, along with bacterial coinfection, were the important causes of exacerbation of the patients' condition and death. This study improves our understanding of the immune dysregulation of COVID-19 and provides potential immunotherapeutic strategies.IMPORTANCE The dysregulation of CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, C1q as well as IL-6, along with bacterial coinfection, were important causes of exacerbation of the patients' condition and death.

Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM (preprint)

The recent outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid international spread pose a global health emergency. The trimeric spike (S) glycoprotein interacts with its receptor human ACE2 to mediate viral entry into host-cells. Here we present cryo-EM structures of an uncharacterized tightly closed SARS-CoV-2 S-trimer and the ACE2-bound-S-trimer at 2.7-Å and 3.8-Å-resolution, respectively. The tightly closed S-trimer with inactivated fusion peptide may represent the ground prefusion state. ACE2 binding to the up receptor-binding domain (RBD) within S-trimer triggers continuous swing-motions of ACE2-RBD, resulting in conformational dynamics of S1 subunits. Noteworthy, SARS-CoV-2 S-trimer appears much more sensitive to ACE2-receptor than SARS-CoV S-trimer in terms of receptor-triggered transformation from the closed prefusion state to the fusion-prone open state, potentially contributing to the superior infectivity of SARS-CoV-2. We defined the RBD T470-T478 loop and residue Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2, and provided structural basis of the spike D614G-mutation induced enhanced infectivity. Our findings offer a thorough picture on the mechanism of ACE2-induced conformational transitions of S-trimer from ground prefusion state towards postfusion state, thereby providing important information for development of vaccines and therapeutics aimed to block receptor binding.Competing Interest StatementThe authors have declared no competing interest.View Full Text

A follow-up study of children infected with SARS-CoV-2 from western China.

BACKGROUND: To clarify the characteristic and the duration of positive nucleic acid in children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including asymptomatic children. METHODS: A total of 32 children confirmed with SARS-CoV-2 infection between January 24 and February 12, 2020 from four provinces in western China were enrolled in this study and followed up until discharge and quarantine 14 days later. RESULTS: Eleven children (34%) were asymptomatic, among whom six children had normal computed tomographic (CT) scan images. Age and gender were not associated with clinical symptoms or the results of CT scan in children infected with SARS-CoV-2. The concentrations of white blood cells and neutrophils were higher in children with asymptomatic infection than in children with clinical symptoms or CT abnormalities. Patients who presented with CT abnormalities had lower D-dimer or lower total bilirubin than those who had normal CT scan but clinical symptoms. All children recovered and no one died or was admitted to the pediatric intensive care unit (PICU). The mean duration of positive SARS-CoV-2 nucleic acid was 15.4 (SD =7.2) days and similar for both asymptomatic children and children with symptoms or CT abnormalities. We found a significant negative correlation between the lymphocyte count and the duration of positive nucleic acid test. CONCLUSIONS: Children with asymptomatic infection should be quarantined for the same duration as symptomatic patients infected with SARS-CoV-2. The clinical significance and mechanism behind the negative correlation between the number of lymphocytes and the duration of positive SARS-CoV-2 needs further study.