Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction.

Remdesivir is an antiviral drug used for COVID-19 treatment worldwide. Cardiovascular side effects have been associated with remdesivir; however, the underlying molecular mechanism remains unknown. Here, we performed a large-scale G-protein-coupled receptor screening in combination with structural modeling and found that remdesivir is a selective, partial agonist for urotensin-II receptor (UTS2R) through the Gαi/o-dependent AKT/ERK axis. Functionally, remdesivir treatment induced prolonged field potential and APD90 in human induced pluripotent stem cell (iPS)-derived cardiomyocytes and impaired contractility in both neonatal and adult cardiomyocytes, all of which mirror the clinical pathology. Importantly, remdesivir-mediated cardiac malfunctions were effectively attenuated by antagonizing UTS2R signaling. Finally, we characterized the effect of 110 single-nucleotide variants in UTS2R gene reported in genome database and found four missense variants that show gain-of-function effects in the receptor sensitivity to remdesivir. Collectively, our study illuminates a previously unknown mechanism underlying remdesivir-related cardiovascular events and that genetic variations of UTS2R gene can be a potential risk factor for cardiovascular events during remdesivir treatment, which collectively paves the way for a therapeutic opportunity to prevent such events in the future.

t6A and ms2t6A Modified Nucleosides in Serum and Urine as Strong Candidate Biomarkers of COVID-19 Infection and Severity.

SARS-CoV-2 infection alters cellular RNA content. Cellular RNAs are chemically modified and eventually degraded, depositing modified nucleosides into extracellular fluids such as serum and urine. Here we searched for COVID-19-specific changes in modified nucleoside levels contained in serum and urine of 308 COVID-19 patients using liquid chromatography-mass spectrometry (LC-MS). We found that two modified nucleosides, N6-threonylcarbamoyladenosine (t6A) and 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A), were elevated in serum and urine of COVID-19 patients. Moreover, these levels were associated with symptom severity and decreased upon recovery from COVID-19. In addition, the elevation of similarly modified nucleosides was observed regardless of COVID-19 variants. These findings illuminate specific modified RNA nucleosides in the extracellular fluids as biomarkers for COVID-19 infection and severity.

Activation of the urotensin-II receptor by anti-COVID-19 drug remdesivir induces cardiomyocyte dysfunction (preprint)

Remdesivir is an antiviral drug used for COVID-19 treatment worldwide. Cardiovascular (CV) side effects have been associated with remdesivir; however, the underlying molecular mechanism remains unknown. Here, we performed a large-scale G-protein-coupled receptor (GPCR) screening in combination with structural modeling and found that remdesivir is a selective agonist for urotensin-II receptor (UTS2R). Functionally, remdesivir treatment induced prolonged field potential in human induced pluripotent stem cell (iPS)-derived cardiomyocytes and reduced contractility in neonatal rat cardiomyocytes, both of which mirror the clinical pathology. Importantly, remdesivir-mediated cardiac malfunctions were effectively attenuated by antagonizing UTS2R signaling. Finally, we characterized the effect of 110 single-nucleotide variants (SNVs) in UTS2R gene reported in genome database and found four missense variants that show gain-of-function effects in the receptor sensitivity to remdesivir. Collectively, our study illuminates a previously unknown mechanism underlying remdesivir-related CV events and that genetic variations of UTS2R gene can be a potential risk factor for CV events during remdesivir treatment, which collectively paves the way for a therapeutic opportunity to prevent such events in the future.

Exhausting T Cells During HIV Infection May Improve the Prognosis of Patients with COVID-19.

T-cell reduction is an important characteristic of coronavirus disease 2019 (COVID-19), and its immunopathology is a subject of debate. It may be due to the direct effect of the virus on T-cell exhaustion or indirectly due to T cells redistributing to the lungs. HIV/AIDS naturally served as a T-cell exhaustion disease model for recognizing how the immune system works in the course of COVID-19. In this study, we collected the clinical charts, T-lymphocyte analysis, and chest CT of HIV patients with laboratory-confirmed COVID-19 infection who were admitted to Jin Yin-tan Hospital (Wuhan, China). The median age of the 21 patients was 47 years [interquartile range (IQR) = 40-50 years] and the median CD4 T-cell count was 183 cells/µl (IQR = 96-289 cells/µl). Eleven HIV patients were in the non-AIDS stage and 10 were in the AIDS stage. Nine patients received antiretroviral treatment (ART) and 12 patients did not receive any treatment. Compared to the reported mortality rate (nearly 4%-10%) and severity rate (up to 20%-40%) among COVID-19 patients in hospital, a benign duration with 0% severity and mortality rates was shown by 21 HIV/AIDS patients. The severity rates of COVID-19 were comparable between non-AIDS (median CD4 = 287 cells/µl) and AIDS (median CD4 = 97 cells/µl) patients, despite some of the AIDS patients having baseline lung injury stimulated by HIV: 7 patients (33%) were mild (five in the non-AIDS group and two in the AIDS group) and 14 patients (67%) were moderate (six in the non-AIDS group and eight in the AIDS group). More importantly, we found that a reduction in T-cell number positively correlates with the serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP), which is contrary to the reported findings on the immune response of COVID-19 patients (lower CD4 T-cell counts with higher levels of IL-6 and CRP). In HIV/AIDS, a compromised immune system with lower CD4 T-cell counts might waive the clinical symptoms and inflammatory responses, which suggests lymphocyte redistribution as an immunopathology leading to lymphopenia in COVID-19.

Having to Work from Home: Basic Needs, Well-Being, and Motivation.

During the COVID-19 pandemic, many employees were asked to start working from home for an extended time. The current study investigated how well employees worked and felt in this novel situation by following n = 199 German employees-56% of them female, 24% with childcare duties-over the course of two working weeks in which they reported once daily on their well-being (PANAS-20, detachment) and motivation (work engagement, flow). Participants reported on organizational and personal resources (emotional exhaustion, emotion regulation, segmentation preference, role clarity, job control, social support). Importantly, they indicated how well their work-related basic needs, i.e., autonomy, competence, and relatedness, were met when working from home and how these needs had been met in the office. Multilevel models of growth showed that work engagement, flow, affect and detachment were on average positive and improving over the two weeks in study. Higher competence need satisfaction predicted better daily work engagement, flow, and affect. In a network model, we explored associations and dynamics between daily variables. Overall, the results suggest that people adapted well to the novel situation, with their motivation and well-being indicators showing adequate levels and increasing trajectories. Avenues for improving work from home are job control and social support.

Holmes: An Efficient and Lightweight Semantic Based Anomalous Email Detector (preprint)

Email threat is a serious issue for enterprise security, which consists of various malicious scenarios, such as phishing, fraud, blackmail and malvertisement. Traditional anti-spam gateway commonly requires to maintain a greylist to filter out unexpected emails based on suspicious vocabularies existed in the mail subject and content. However, the signature-based approach cannot effectively discover novel and unknown suspicious emails that utilize various hot topics at present, such as COVID-19 and US election. To address the problem, in this paper, we present Holmes, an efficient and lightweight semantic based engine for anomalous email detection. Holmes can convert each event log of email to a sentence through word embedding then extract interesting items among them by novelty detection. Based on our observations, we claim that, in an enterprise environment, there is a stable relation between senders and receivers, but suspicious emails are commonly from unusual sources, which can be detected through the rareness selection. We evaluate the performance of Holmes in a real-world enterprise environment, in which it sends and receives around 5,000 emails each day. As a result, Holmes can achieve a high detection rate (output around 200 suspicious emails per day) and maintain a low false alarm rate for anomaly detection.

Estimation of infection density and epidemic size of COVID-19 using the back-calculation algorithm.

The novel coronavirus (COVID-19) is continuing its spread across the world, claiming more than 160,000 lives and sickening more than 2,400,000 people as of April 21, 2020. Early research has reported a basic reproduction number (R0) between 2.2 to 3.6, implying that the majority of the population is at risk of infection if no intervention measures were undertaken. The true size of the COVID-19 epidemic remains unknown, as a significant proportion of infected individuals only exhibit mild symptoms or are even asymptomatic. A timely assessment of the evolving epidemic size is crucial for resource allocation and triage decisions. In this article, we modify the back-calculation algorithm to obtain a lower bound estimate of the number of COVID-19 infected persons in China in and outside the Hubei province. We estimate the infection density among infected and show that the drastic control measures enforced throughout China following the lockdown of Wuhan City effectively slowed down the spread of the disease in two weeks. We also investigate the COVID-19 epidemic size in South Korea and find a similar effect of its "test, trace, isolate, and treat" strategy. Our findings are expected to provide guidelines and enlightenment for surveillance and control activities of COVID-19 in other countries around the world.