Evolution-guided large language model is a predictor of virus mutation trends (preprint)

Emerging viral infections, especially the global pandemic COVID-19, have had catastrophic impacts on public health worldwide. The culprit of this pandemic, SARS-CoV-2, continues to evolve, giving rise to numerous sublineages with distinct characteristics. The traditional post-hoc wet-lab approach is lagging behind, and it cannot quickly predict the evolutionary trends of the virus while consuming high costs. Capturing the evolutionary drivers of virus and predicting potential high-risk mutations has become an urgent and critical problem to address. To tackle this challenge, we introduce ProtFound-V, an evolution-inspired deeplearning framework designed to explore the mutational trajectory of virus. Take SARS-CoV-2 as an example, ProtFound-V accurately identifies the evolutionary advantage of Omicron and proposes evolutionary trends consistent with wetlab experiments through in silico deep mutational scanning. This showcases the potential of deep learning predictions to replace traditional wet-lab experimental measurements. With the evolution-guided large language model, ProtFound-V presents a new state-of-the-art performance in key property predictions. Despite the challenge posed by epistasis to model generalization, ProtFound-V remains robust when extrapolating to lineages with different genetic backgrounds. Overall, this work paves the way for rapid responses to emerging viral infections, allowing for a plug-and-play approach to understanding and predicting virus evolution.

SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia (preprint)

Age is a major risk factor for coronavirus disease (COVID-19)-associated severe pneumonia and mortality; however, the underlying mechanism remains unclear. Herein, we investigated whether age-related deregulation of RNAi components and RNA splicing factors affects COVID-19 severity. Decreased expression of RNAi components (Dicer and XPO5) and splicing factors (SRSF3 and hnRNPA3) correlated with increased severity of COVID-19 and SARS-CoV-2 nucleocapsid (N) protein-induced pneumonia. N protein induced autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, repressing miRNA biogenesis and RNA splicing and inducing DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 were downregulated with age in mouse lung tissues. Older mice experienced more severe N protein-induced pneumonia than younger mice. However, treatment with a poly(ADP-ribose) polymerase inhibitor (PJ34) or aromatase inhibitor (anastrozole) relieved N protein-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.

Deep spatial proteomic exploration of severe COVID-19-related pulmonary injury in post-mortem specimens (preprint)

The lung, as a primary target of SARS-CoV-2, exhibits heterogeneous microenvironment accompanied by various histopathological changes following virus infection. However, comprehensive insight into the protein basis of COVID-19-related pulmonary injury with spatial resolution is currently deficient. Here, we generated a region-resolved quantitative proteomic atlas of seven major pathological structures within the lungs of COVID-19 victims by integrating histological examination, laser microdissection, and ultrasensitive proteomic technologies. Over 10,000 proteins were quantified across 71 dissected FFPE post-mortem specimens. By comparison with control samples, we identified a spectrum of COVID-19-induced protein and pathway dysregulations in alveolar epithelium, bronchial epithelium, and pulmonary blood vessels, providing evidence for the proliferation of transitional-state pneumocytes. Additionally, we profiled the region-specific proteomes of hallmark COVID-19 pulmonary injuries, including bronchiole mucus plug, pulmonary fibrosis, airspace inflammation, and hyperplastic alveolar type 2 cells. Bioinformatic analysis revealed the enrichment of cell-type and functional markers in these regions (e.g. enriched TGFBI in fibrotic region). Furthermore, we identified the up-regulation of proteins associated with viral entry, host restriction, and inflammatory response in COVID-19 lungs, such as FURIN and HGF. Collectively, this study provides spatial proteomic insights for understanding COVID-19-caused pulmonary injury, and may serve as a valuable reference for improving therapeutic intervention for severe pneumonia.

Angiotensin II-pretreated hucMSCs attenuate inflammation and reverse pulmonary fibrosis in SD rat lung (preprint)

Background: Pulmonary fibrosis (PF) is an irreversible disease with a poor prognosis and a serious impact on patients' health. PF is also associated with COVID-19, especially in immunocompromised people. Herein, efforts have been made to treat PF using pretreatment of human umbilical cord mesenchymal stem cells (hucMSCs) with angiotensin II (Ang II) as a novel therapeutic method. Methods: PF model of Sprague Dawley (SD) rats were established by tracheal injection of bleomycin (BLM) (5U/Kg). On day 15 after modeling, PBS, hucMSCs or hucMSCs-Ang II were injected into tail vein. On the 23rd day after modeling, samples were taken and corresponding indexes were tested.Results: Our results first showed that Ang II pretreatment induced more hucMSCs to reach the injured lung and alleviated pulmonary fibrosis. Transplantation of hucMSCs-Ang II reduced inflammatory infiltration, increased IL-10 expression and enhanced macrophage matrix-metallopeptidase-9 (MMP-9) expression for collagen degradation. Moreover, the Ang II-treated hucMSCs decreased hydroxyproline (HYP) and alpha-smooth muscle actin (α-SMA) expression in SD rats and promoted collagen and collagen fiber degradation.Conclusions: Ang II pretreatment enhanced the homing ability of hucMSCs, and hucMSCs-Ang II transplantation reversed PF by inhibiting inflammation and promoting collagen and collagen fiber degradation, promising its clinical application in the treatment of post-inflammatory PF caused by various disorders, including COVID-19 and related pneumonia. 

Ultra-fast bacterial inactivation of Cu2O@Halloysite nanotubes hybrids with charge adsorption and physical piercing ability for medical protective fabrics

Metals have been used for wound treatment and toxicity testing since ancient times. With the development of nanotechnology, metal oxides have been proven to have excellent sterilization and disinfection functions. However, the rapid bacterial inactivation efficiency and trapping physicochemical killing ability remain simultaneously undemonstrated in antibacterial nanohybrids. Here, we demonstrate a method for in-situ reduction of small-sized Cu2O particles on one-dimensional inorganic halloysite nanotubes (HNTs). The resultant Cu2O@HNTs hybrids not only give Cu2O excellent dispersibility, but also exert the synergistic effect of the charge adsorption of metal oxides and the physical piercing effect of the small-sized nanotubes. Furthermore, the release of Cu2+ from hybrids damages cell membranes and denatures proteins and DNA. Through this sterilization mechanism, Cu2O@HNTs allow for the inactivation rate of Escherichia coli to reach 94.5% within 2 min and complete inactivation within 10 min. This excellent sterilization mode makes Cu2O@HNTs exhibit excellent broad-spectrum antibacterial activity and inactivation efficiency, while shows weak cytotoxicity. These hybrids were further applied in the processing of functional antibacterial fibers and fabrics. Thus, we believe that this excellent antibacterial hybrid is practically attractive in this critical time of the COVID-19 pandemic.

Study on the Light Field Regulation of UVC-LED Disinfection for Cold Chain Transportation

In this paper, the pain point that cold chain transportation urgently needs for an efficient disinfection method is pointed out. Thus, this work aims at solving the problems and improving the disinfection efficiency in cold chain transportation. While Ultraviolet-C (UVC) irradiation is an effective method by which to kill viruses, it is difficult to apply the commonly used UVC-LED disinfection light source to ice-covered cold chain transportation due to its uneven light field distribution. Thus, the light field regulation of UVC-LED disinfection for cold chain transportation is studied. A UVC-LED chip with a wavelength of 275 nm was used as a light source, and parallel light was obtained by collimating lenses. Then, microlens array homogenization technology was used to shape the UVC light into a uniform light spot, with an energy space uniformity rate of 96.4%. Moreover, a simulation was conducted to compare the effects of the ice layer on the absorption of UVC light. Finally, an experiment was carried out to verify that the disinfection efficiency can be increased nearly by 30% with the proposed system by disinfecting E. coli (Escherichia coli), and the results indicate that the proposed system is an effective disinfection solution during cold chain transportation.

Identification of a novel lineage bat SARS-related coronaviruses that use bat ACE2 receptor (preprint)

Severe respiratory disease coronavirus-2 (SARS-CoV-2) causes the most devastating disease, COVID-19, of the recent century. One of the unsolved scientific questions around SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbor the highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). Here, we report the identification of a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities to SARS-CoV-2 in the conserved ORF1b region, but only show less than 77.6% to all known SARSr-CoVs in genome level, thus forms a distinct lineage in the Sarbecovirus phylogenetic tree. We then found that RaTG15 receptor binding domain (RBD) can bind to and use Rhinolophus affinis bat ACE2 (RaACE2) but not human ACE2 as entry receptor, although which contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we show that none of the known viruses in bat SARSr-CoV-2 lineage or the novel lineage discovered so far use human ACE2 efficiently compared to SARSr-CoV-2 from pangolin or some of the SARSr-CoV-1 lineage viruses. Collectively, we suggest more systematic and longitudinal work in bats to prevent future spillover events caused by SARSr-CoVs or to better understand the origin of SARS-CoV-2.

Promoting mental wellbeing through internet during COVID-19: A case report in Yunnan, China

People's lives were significantly impacted when China underwent a self-quarantine period, spanning multiple weeks to months, due to COVID-19. The impacts of this quarantine included disruption of daily occupational habits and balance, having resulted in compromised physical and mental health. During this physical distancing period, occupational therapists in Yunnan Province of China delivered a health promotion programme using WeChat, an online platform. The main purpose of the programme was to support the redesigning of a person's lifestyle in the face of the pandemic, as well as to enable participation in occupations that foster their self-efficacy and mental wellbeing. During the self-quarantine period, the programme was accessed frequently, with viewers spanning from practicing therapists to the general public. Findings from WeChat analytics and follow up interviews with programme viewers suggested that internet-based health promotion programme can be effective in places where internet is commonly used by the general public.

Safety of reopening universities and colleges using a combined strategy during coronavirus disease 2019 in China: a cross-sectional study (preprint)

Background There is no consensus as to when and how to reopen schools during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to evaluate the safety of reopening universities and colleges using a combined strategy in China.Methods This cross-sectional study included 13,116 staffs and postgraduate students who have returned to the four campuses of the University of Science and Technology of China from 17 February (students returned from 12 May) to 2 July 2020. The returning to school was guided by a combined strategy including use of personal protective equipment, management of transportation, serological and nucleic acid tests for COVID-19, quarantine, and restrictions in and out of campus. Epidemiology history and COVID-19 related symptoms (fever, cough, and dyspnoea) were recorded in a subset of participants using an online questionnaire.Results Among 13,116 participants, 4067 tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid and no positive results were identified. Of 9049 participants who chose to conduct antibody tests, 28 (0.3%) tested positive but no one was confirmed by the additional viral nucleic acid tests. Online questionnaires were collected from 5741 participants (mean 25.1 years, 35% female). High-risk exposures and COVID-19 related symptoms were reported in 8.3% and 7.4% of participants, respectively. Comorbidities (hypertension, diabetes, chronic pulmonary disease, and chronic kidney disease) were rare (0.2%-1.5%). Conclusions Using a combined strategy for COVID-19 prevention and control, safely reopening of universities and colleges in low-risk regions is possible and laboratory screening for SARS-CoV-2 infection may not be necessary. Further studies need to cautiously evaluate the safety of reopening schools, if any, in the middle- and high-risk regions.

Investigation on the influencing factors of mental health of healthcare workers for aid in Hubei during the outbreak of the COVID-19 (preprint)

Background The objective of this study is to understand the psychological health status and analyze the related factors of healthcare workers for aid in Hubei during the epidemic. 220 subjects were investigated by Self-Rating Scale of Sleep(SRSS), Generalized Anxiety Scale (GAD-7), and 9-item patient health questionnaire (PHQ-9).Results The average SRSS score of all subjects was significantly higher than the national norm (p < 0.001)and the influencing factors were gender, whether the patients died under the charge of nursing/treatment, the history of psychosis and whether their family members were infected with the COVID-19. The average GAD-7 score of all subjects was in a moderate anxiety level, and the main influencing factors were gender, years of work, history of psychosis, self-perceived health statues and whether their family members were infected with the COVID-19. The average PHQ-9 score of all subjects was in mild depression level. The primary influencing factors were whether they nursed/treated severely ill patients during aid in Hubei and whether they had a history of psychosis.Conclusions During the outbreak of COVID-19, the symptoms of insomnia and anxiety of the healthcare workers for aid in Hubei were prominent. Moreover, male workers, those whose patients have died during their treatment, with previous anxiety disorders and whose family members infected with COVID-19 were facing more serious problems. Therefore, this special group needs to be strengthened follow-up psychological support individually.

Early Awake Prone and Lateral Position in Non-intubated Severe and Critical Patients with COVID-19 in Wuhan: A Respective Cohort Study (preprint)

Background Previous studies suggest applying prone position (PP) and lateral position (LP) in patients with severe acute respiratory distress syndrome (ARDS) for their efficacy in improving oxygenation and lung recruitment.This paper aims to share clinical experiences and outcome of using PP and LP in combination with oxygen therapy (OT) and Non-invasive ventilation (NIV) in severe and critical patients with COVID-19. Methods Clinical data of 48 severe and critical patients have been retrieved from medical records and reviewed. The primary outcome is the survival rate. Secondary outcome is the rate of patients requiring intubation. Results In total, 25 patients were finally included in the study.The mean respiratory rate of all 25 patients decreased from 28.4 breaths/min to 21.3 breaths/min. CT results showed increase in lung recruitment. All patients tolerated PP and LP well. No deterioration or severe adverse events associated with PP and LP occurred. All patients recovered and survived without intubation. Follow-up to date showed that all patients have been discharged except one with mild symptoms and positive RNA test. Conclusion: Clinical outcomes of early application of PP and LP in combination with OT and NIV in severe and critical patients with COVID-19 indicated well tolerance of the therapy and resulted in improving patients' oxygenation in a safe and effective manner. Therefore, this strategy can be explored as an early intervention in managing patients in early stage of disease development under the context of pandemic and limited medical resources.

Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin (preprint)

Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats1-4. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a novel coronavirus (nCoV-2019) which caused an epidemic of acute respiratory syndrome in humans, in Wuhan, China. The epidemic, started from December 12th, 2019, has caused 198 laboratory confirmed infections with three fatal cases by January 20th, 2020. Full-length genome sequences were obtained from five patients at the early stage of the outbreak. They are almost identical to each other and share 79.5% sequence identify to SARS-CoV. Furthermore, it was found that nCoV-2019 is 96% identical at the whole genome level to a bat coronavirus. The pairwise protein sequence analysis of seven conserved non-structural proteins show that this virus belongs to the species of SARSr-CoV. The nCoV-2019 virus was then isolated from the bronchoalveolar lavage fluid of a critically ill patient, which can be neutralized by sera from several patients. Importantly, we have confirmed that this novel CoV uses the same cell entry receptor, ACE2, as SARS-CoV.