Extracellular disintegration of viral proteins as an innovative strategy for developing broad-spectrum antivirals against coronavirus

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed millions of lives worldwide, not to mention innumerable losses in the global economy and disruptions in social relationships. Unfortunately, state-of-the-art treatments still lag behind the fast emergence of new variants of concern. The key to resolve this issue is to develop broad-spectrum antivirals with innovative antiviral mechanisms in which coronaviruses are deactivated regardless of their variant development. Herein, we report a new antiviral strategy involving extracellular disintegration of viral proteins that are indispensable for viral infection with hyperanion-grafted enediyne molecules. The sulfate groups ensure low cellular permeability and rather low cytotoxicity of the molecules, while the core enediyne generates reactive radical species and causes significant damage to the spike (S) protein of coronavirus. The enediyne compounds exhibit antiviral activity at micromolar to nanomolar concentrations, and the selectivity index of up to 20,000 against four kinds of human coronaviruses, including the SARS-CoV-2 omicron variant, suggesting the high potential of this new strategy in combating the COVID-19 pandemic.

Recent progress and evolution of coolant usages in conventional machining methods: a comprehensive review.

This paper reviews recent progress and applications of usage of cutting fluids in conventional machining processes. In addition to reviewing the various conventional and advanced cooling techniques during machining, the paper also discusses the use of minimum quantity lubrication (MQL) in several types on metals such as steel, aluminum, alloy, and titanium alloys. Due to the toxicity of conventional cutting fluid resulting in ecological problems, the demand for environmentally friendly cutting fluid is rising. Therefore, natural vegetable oil is chosen as potential replacement as an environmentally friendly cutting fluid which fulfills the important aspects of biodegradability and sustainability. Application of vegetable oil-based cutting fluids under MQL techniques are also discussed. Moreover, the potential of palm oil as biodegradable and environmentally friendly natural vegetable oil-based metal-working fluids in MQL are reviewed.

Diagnosis, treatment and prevention of severe acute respiratory syndrome coronavirus 2 infection in children: experts′ consensus statement (Fourth Edition) / 中华实用儿科临床杂志

Since December 2019, severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infections have raged globally for more than 2 years.China has always adopted scientific and effective prevention and control measures to achieved some success.However, with the continuous variation of SARS-CoV-2 cases and imported cases from abroad, the prevention and control work has become more difficult and complex.With the variation of the mutant strain, the number of cases in children changed, and some new special symptoms and complications were found, which proposed a new topic for the prevention and treatment of SARS-CoV-2 infection in children in China.Based on the third edition, the present consensus according to the characteristics of the new strain, expounded the etiology, pathology, pathogenesis, and according to the clinical characteristics and experience of children′s cases, and puts forward recommendations on the diagnostic criteria, laboratory examination, treatment, prevention and control of children′s cases for providing reference for further guidance of effective prevention and treatment of SARS-CoV-2 infection in children in China.

Childhood asthma outcomes during the COVID-19 pandemic: Findings from the PeARL multi-national cohort.

ImportanceImportance: The interplay between COVID-19 pandemic and asthma in children is still unclear. ObjectiveWe evaluated the impact of COVID-19 pandemic on childhood asthma outcomes. DesignThe PeARL multinational cohort included children with asthma and non-asthmatic controls recruited during the COVID-19 pandemic and compared current disease activity with data available from the previous year. SettingPediatric outpatient clinics. ParticipantsThe study included 1,054 children with asthma and 505 non-asthmatic controls, aged between 4-18 years, from 25 pediatric departments, from 15 countries globally. ExposuresCOVID-19 pandemic first wave, starting from the date of the first fatality in the respective country. Main outcomes and measuresWe assessed the pandemics impact on the frequency of respiratory infections, emergency presentations and hospital admissions in asthmatic versus non-asthmatic participants, controlling for confounding factors including the pandemics duration and the frequency of such acute events during 2019. Using paired analyses, we evaluated the impact of the pandemic on the annualized frequency of asthma attacks and the previously mentioned acute events, asthma control, and pulmonary function in children with asthma, compared to their baseline disease activity, during the preceding year. ResultsDuring the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks and hospitalizations due to asthma, in comparison to the preceding year. Sixty-six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimally clinically important difference. Pre-bronchodilatation FEV1 and peak expiratory flow rate were also improved during the pandemic. When compared to non-asthmatic controls, children with asthma were not found to be at increased risk of LRTIs, episodes of pyrexia, emergency visits or hospitalizations during the pandemic. However, an increased risk of URTIs emerged. Conclusions and relevanceChildhood asthma outcomes, including control, were improved during the first wave of the COVID-19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID-19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent. Key PointsO_ST_ABSQuestionC_ST_ABSWhat was the impact of COVID-19 pandemic on childhood asthma outcomes? FindingsDuring the first wave of the pandemic, children with asthma have experienced improved outcomes, as evidenced by fewer asthma attachks, hospitalizations, improved scores in validated asthma control measures and improved pulmonary function. MeaningThis is the first study to show a positive impact of COVID-19 pandemic on childhood asthma activity. This is probably the result of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the hypothesis that childhood asthma may be a risk factor for COVID-19.

Potent synthetic nanobodies against SARS-CoV-2 and molecular basis for neutralization

SARS-CoV-2, the causative agent of COVID-191, recognizes host cells by attaching its receptor-binding domain (RBD) to the host receptor ACE22-7. Neutralizing antibodies that block RBD-ACE2 interaction have been a major focus for therapeutic development8-18. Llama-derived single-domain antibodies (nanobodies, [~]15 kDa) offer advantages including ease of production and possibility for direct delivery to the lungs by nebulization19, which are attractive features for bio-drugs against the global respiratory disease. Here, we generated 99 synthetic nanobodies (sybodies) by in vitro selection using three libraries. The best sybody, MR3 bound to RBD with high affinity (KD = 1.0 nM) and showed high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.40 g mL-1). Structural, biochemical, and biological characterization of sybodies suggest a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency were generated by structure-based design, biparatopic construction, and divalent engineering. Among these, a divalent MR3 conjugated with the albumin-binding domain for prolonged half-life displayed highest potency (IC50 = 12 ng mL-1) and protected mice from live SARS-CoV-2 challenge. Our results pave the way to the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid responses for future outbreaks.

Laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections

BackgroundThe outbreak of novel coronavirus pneumonia (NCP) caused by 2019-nCoV spread rapidly, and elucidating the diagnostic accuracy of different respiratory specimens is crucial for the control and treatment of this disease. MethodsRespiratory samples including nasal swabs, throat swabs, sputum and bronchoalveolar lavage fluid (BALF) were collected from Guangdong CDC confirmed NCP patients, and viral RNAs were detected using a CFDA approved detection kit. Results were analyzed in combination with sample collection date and clinical information. FindingsExcept for BALF, the sputum possessed the highest positive rate (74.4%[~]88.9%), followed by nasal swabs (53.6%[~]73.3%) for both severe and mild cases during the first 14 days after illness onset (d.a.o). For samples collected [≥] 15 d.a.o, sputum and nasal swabs still possessed a high positive rate ranging from 42.9%[~]61.1%. The positive rate of throat swabs collected [≥] 8 d.a.o was low, especially in samples from mild cases. Viral RNAs could be detected in all the lower respiratory tract of severe cases, but not the mild cases. CT scan of cases 02, 07 and 13 showed typical viral pneumonia with ground-glass opacity, while no viral RNAs were detected in first three or all the upper respiratory samples. InterpretationSputum is most accurate for laboratory diagnosis of NCP, followed by nasal swabs. Detection of viral RNAs in BLAF is necessary for diagnosis and monitoring of viruses in severe cases. CT scan could serve as an important make up for the diagnosis of NCP. FundingNational Science and Technology Major Project, Sanming Project of Medicine and China Postdoctoral Science Foundation.

Marburg virus-like particles produced in insect cells induce neutralizing antibodies in rhesus macaques.

Marburg virus (MARV), which is one of the most virulent agents in the world, causes lethal haemorrhagic fever in humans and nonhuman primates (NHPs) with a mortality rate of up to 90%. Currently, there is no effective treatment or approved vaccine for MARV for human use to control disease outbreak and spread. Virus-like particles (VLPs), which are morphologically identical to the native infectious virus particle, are efficacious as vaccines against many viruses, including human papilloma virus (HPV), porcine circovirus (PCV) type 2 and hepatitis B virus (HBV). In this study, we generated MARV virus-like particles (VLPs) by co-expressing a glycoprotein (GP) and matrix protein (VP40) using the baculovirus expression system. Rhesus macaques vaccinated with MARV VLPs mixed with adjuvant Poria cocos polysaccharides (PCP-II) produced a GP-specific IgG titer of up to 1:1280 and virus-neutralizing antibody titers that reached 1:320. MARV VLPs also elicited interferon-γ (IFN-γ) and interleukin-4 (IL-4) secretion associated with T-helper 1 cell (Th1)- and T-helper 2 cell (Th2)-mediated immunity, as detected using enzyme-linked immunospot (ELISpot) assays. These data indicate that MARV VLPs mixed with adjuvant PCP-II have excellent immunogenicity in rhesus macaques and may be a promising candidate vaccine against MARV.