A novel type of facultative and plasminogen independent thrombolytic enzyme from the ancient marine organism, Sipunculus nudus (preprint)

Thrombotic diseases have become a leading threat to global health, especially in the post-COVID-19 era. Current thrombolytic drugs are highly dependent on the activation of the human plasminogen. Herein we disclose a novel facultative and plasminogen independent thrombolytic enzyme (snFPITE) from Sipunculus nudus, which could completely dissolve fibrin(ogen) into ultra-small molecule fragments without leaving any undegradable D-dimer. Furthermore, it cleaves the plasminogen to form a new fibrinolytic-active agent (Flaa) rather than the conventional plasmin. Mechanistically, snFPITE activates the plasminogen and degrades fibrin(ogen) at multiple cleavage sites, and this plasminogen activation and fibrin(ogen) degradation are inhibited by plasminogen activator inhibitor 1 and α2-antiplasmin through a unique competitive inhibition mechanism. On the other hand, up to 29 snFPITE candidate sequences have been identified by mass spectroscopy, molecular cloning and genome sequencing, including 10 of which that have been functionally verified. This novel thrombolytic enzyme pool might be valuable for the rapid development of powerful and efficient thrombolytic drugs in the near future.

Rational design of multivalent biosensor surfaces to enhance viral particle capture.

Viral particles bind to receptors through multivalent protein interactions. Such high avidity interactions on sensor surfaces are less studied. In this work, three polyelectrolytes that can form biosensing surfaces with different interfacial characteristics in probe density and spatial arrangement were designed. Quartz crystal microbalance, interferometry and atomic force microscopy were used to study their surface density and binding behaviors with proteins and virus particles. A multivalent adsorption kinetic model was developed to estimate the number of bonds from the viral particles bound to the polyelectrolyte surfaces. Experimental results show that the heterogeneous 3D surface with jagged forest-like structure enhances the virus capture ability by maximizing the multivalent interactions. As a proof of concept, specific coronavirus detection was achieved in spiked swab samples. These results indicate the importance of both probe density and their spatial arrangement on the sensing performance, which could be used as a guideline for rational biosensing surface design.

Xuebijing injection inhibited neutrophil extracellular traps to reverse lung injury in sepsis mice via reducing Gasdermin D.

The mortality of sepsis and septic shock remains high worldwide. Neutrophil extracellular traps (NETs) release is a major cause of organ failure and mortality in sepsis. Targeting Gasdermin D (GSDMD) can restrain NETs formation, which is promising for sepsis management. However, no medicine is identified without severe safety concerns for this purpose. Xuebijing injection (XBJ) has been demonstrated to alleviate the clinical symptoms of COVID-19 and sepsis patients, but there are not enough animal studies to reveal its mechanisms in depth. Therefore, we wondered whether XBJ relieved pulmonary damage in sepsis by suppressing NETs formation and adopted a clinically relevant polymicrobial infection model to test this hypothesis. Firstly, XBJ effectively reversed lung injury caused by sepsis and restrained neutrophils recruitment to lung by down-regulating proinflammatory chemokines, such as CSF-3, CXCL-2, and CXCR-2. Strikingly, we found that XBJ significantly reduced the expressions of NETs component proteins, including citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE). GSDMD contributes to the production of NETs in sepsis. Notably, XBJ exhibited a reduced effect on the expressions of GSDMD and its upstream regulators. Besides, we also revealed that XBJ reversed NETs formation by inhibiting the expressions of GSDMD-related genes. Collectively, we demonstrated XBJ protected against sepsis-induced lung injury by reversing GSDMD-related pathway to inhibit NETs formation.

Rapid development and mass production of SARS-CoV-2 neutralizing Chicken egg yolk antibodies with protective efficacy in hamsters (preprint)

Despite the record speed of developing vaccines and therapeutics against the SARS-CoV-2 virus, it is not a given that such success can be secured in future pandemics. In addition, COVID-19 vaccination and application of therapeutics remain low in developing countries. Rapid and low cost mass production of antiviral IgY antibodies could be an attractive alternative or complementary option for vaccine and therapeutic development. In this article, we rapidly produced SARS-CoV-2 antigens, immunized hens and purified IgY antibodies in 2 months after the SARS-CoV-2 gene sequence became public. We further demonstrated that the IgY antibodies competitively block RBD binding to ACE2, neutralize authentic SARS-CoV-2 virus and effectively protect hamsters from SARS-CoV-2 challenge by preventing weight loss and lung pathology, representing the first comprehensive study with IgY antibodies. The process of mass production can be easily implemented in most developing countries and hence could become a new vital option in our toolbox for combating viral pandemics. This study could stimulate further studies, optimization and potential applications of IgY antibodies as therapeutics and prophylactics for human and animals.

Xuebijing injection inhibited neutrophil extracellular traps to reverse lung injury in sepsis mice via reducing Gasdermin D

The mortality of sepsis and septic shock remains high worldwide. Neutrophil extracellular traps (NETs) release is a major cause of organ failure and mortality in sepsis. Targeting Gasdermin D (GSDMD) can restrain NETs formation, which is promising for sepsis management. However, no medicine is identified without severe safety concerns for this purpose. Xuebijing injection (XBJ) has been demonstrated to alleviate the clinical symptoms of COVID-19 and sepsis patients, but there are not enough animal studies to reveal its mechanisms in depth. Therefore, we wondered whether XBJ relieved pulmonary damage in sepsis by suppressing NETs formation and adopted a clinically relevant polymicrobial infection model to test this hypothesis. Firstly, XBJ effectively reversed lung injury caused by sepsis and restrained neutrophils recruitment to lung by down-regulating proinflammatory chemokines, such as CSF-3, CXCL-2, and CXCR-2. Strikingly, we found that XBJ significantly reduced the expressions of NETs component proteins, including citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE). GSDMD contributes to the production of NETs in sepsis. Notably, XBJ exhibited a reduced effect on the expressions of GSDMD and its upstream regulators. Besides, we also revealed that XBJ reversed NETs formation by inhibiting the expressions of GSDMD-related genes. Collectively, we demonstrated XBJ protected against sepsis-induced lung injury by reversing GSDMD-related pathway to inhibit NETs formation. Graphical

PF-D-Trimer, a broadly protective SARS-CoV-2 subunit vaccine: immunogenicity and application (preprint)

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had and still has a considerable impact on global public health. One of the characteristics of SARS-CoV-2 is a surface homotrimeric spike protein, the primary responsible for the host immune response upon infection. Here we show the preclinical studies of a broad protective SARS-CoV-2 subunit vaccine developed from our Trimer Domain platform using the Delta spike protein, from antigen design to purification, vaccine evaluation and manufacturability. The prefusion trimerized Delta spike protein, PF-D-Trimer, was highly expressed in Chinese hamster ovary (CHO) cells, purified by a rapid one-step anti-Trimer Domain monoclonal antibody immunoaffinity process and prepared as a vaccine formulation with an adjuvant. The immunogenicity studies demonstrated that this vaccine candidate induces robust immune responses in mouse, rat and Syrian hamster models. It also protects K18-hACE2 transgenic mice in a homologous virus challenge. The neutralizing antibodies induced by this vaccine display a cross-reactive capacity against the ancestral WA1 and Delta variants as well as different Omicron, including BA.5.2. The Trimer Domain platform was proven to be a key technology in the rapid production of the PF-D-Trimer vaccine and may be crucial to accelerate the development of updated versions of SARS-CoV-2 vaccines.

Highly Efficient Red/NIR-Emissive Fluorescent Probe with Polarity-Sensitive Character for Visualizing Cellular Lipid Droplets and Determining Their Polarity.

Lipid droplets (LDs), which are ubiquitous organelles existing in almost all eukaryotic cells, have attracted a lot of attention in the field of cell biology over the last decade. For the biological study of LDs via fluorescence imaging, the superior LD fluorescent probes with environmental polarity-sensitive character are highly desired and powerful but are very scarce. Herein, we have newly developed such a kind of fluorescent probe named LDs-Red which enables us to visualize LDs and to further reveal their polarity information. This fluorescent probe displays the advantages of intense red/near-infrared emission, high LD staining specificity, and good photostability; thus, it would be very useful for LD fluorescence imaging application. As a result, the three-dimensional confocal imaging to visualize spatial distribution of LDs and the multicolor confocal imaging to simultaneously observe LDs and other cellular organelles have been realized using this new LD fluorescent probe. Furthermore, the polarity-sensitive emission character of this probe enables us to quantitatively determine the LD polarity via spectral scan imaging. Consequently, the cancer cells (HepG2, HeLa, and Panc02) displaying lower polarity of LDs than the normal cells (L929, U251, and HT22) have been systematically demonstrated. In addition, this polarity-sensitive probe displaying shorter fluorescence wavelengths in cancer cells than in normal cells has an important and potential ability to distinguish them.

Customer sovereignty, algorithmic management, economic precarity and networked support: A Job Demands-Resources analysis of stress and response among Chinese couriers (preprint)

The COVID-19 pandemic has given the global e-commerce market a strong boost, of which China has the largest share and is growing rapidly. Concerns have been raised about intensified work stress and its consequences on health and safety among Chinese couriers. Sociological research of work and occupations has offered important insights into the labour process and politics of the gig economy, although how exactly the workers perceive and respond to technology-driven structural changes remains less clear. We conducted 14 semi-structured interviews with frontline couriers in May-June 2021 in China and interpreted the emerged themes following the Job Demands-Resources (JD-R) model. Four major work-stressor themes were identified: customer sovereignty, algorithmic management, economic precarity and networked support. These work conditions rarely worked alone. Technological, managerial and customer controlling mechanisms reinforced each other and increased work stress. In the absence of adequate organizational support, workers found support and resources through personal networks.

Development and application of an uncapped mRNA platform (preprint)

A novel uncapped mRNA platform was developed. Five lipid nanoparticle (LNP)-encapsulated mRNA constructs were made to evaluate several aspects of our platform, including transfection efficiency and durability in vitro and in vivo and the activation of humoral and cellular immunity in several animal models. The constructs were eGFP-mRNA-LNP (for enhanced green fluorescence mRNA), Fluc-mRNA-LNP (for firefly luciferase mRNA), S{delta}T-mRNA-LNP (for Delta strain SARS-CoV-2 spike protein trimer mRNA), gDED-mRNA-LNP (for truncated glycoprotein D mRNA coding ectodomain from herpes simplex virus type 2 (HSV2)) and gDFR-mRNA-LNP (for truncated HSV2 glycoprotein D mRNA coding amino acids 1~400). Quantifiable target protein expression was achieved in vitro and in vivo with eGFP- and Fluc-mRNA-LNP. S{delta}T-mRNA-LNP, gDED-mRNA-LNP and gDFR-mRNA-LNP induced both humoral and cellular immune responses comparable to those obtained by previously reported capped mRNA-LNP constructs. Notably, 25, 50 and 100 g of S{delta}T-mRNA-LNP all elicited neutralizing antibodies in hamsters against the Omicron and Delta strains. Additionally, gDED-mRNA-LNP and gDFR-mRNA-LNP induced potent neutralizing antibodies in rabbits and mice. The mRNA constructs with uridine triphosphate (UTP) outperformed those with N1-methylpseudouridine triphosphate (N1m{psi}TP) in the in vivo expression of luciferase and the induction of antibodies via S{delta}T-mRNA-LNP. Our uncapped, process-simplified, and economical mRNA platform may have broad utility in vaccines and protein replacement drugs.

A New Precise High Flow Oxygen Therapy System Based on Sliding Mode Control Strategy

In recent years, precise high flow oxygen therapy as a new type of oxygen therapy machine has gradually attracted people’s attention and has been widely used in hospital emergency and clinical treatment of respiratory diseases;especially in recent years, severe coronavirus disease (COVID-19) has played an important role in the treatment of patients. This paper presents a new type of precise high flow oxygen therapy machine with electromagnetic pneumatic flow valve as the core control element. A sliding mode control strategy based on the system is proposed to realize the accurate control of oxygen concentration and output flow of oxygen therapy mixture. The physical equipment of the precision high flow system is established, and its working performance is verified through the test platform. The optimization design goal of the precision high flow equipment is achieved.

Severe novel coronavirus pneumonia: a case report and literature review

Objective To describe the diagnosis and treatment of a patient with severe novel coronavirus pneumonia, and to improve the understanding and management of clinicians on novel coronavirus pneumonia. Methods The onset, development, treatment and outcome of a patient with severe 2019 novel coronavirus pneumonia were retrospectively analyzed and relevant literatures were reviewed. Results At the beginning of the disease, the patient presented fever and dry cough, and later the disease progressed to dyspnea. Chest CT showed bilateral exudation of the lung. Lopinavir/ritonavir, IFN-a and immunoglobulin were given to the patient according to the expert group's opinion. The pneumonia was cured and the patient was discharged two weeks later. Conclusion Appropriate management strategies are effective on diagnosis and treatment of new coronavirus pneumonia.

Integrated bioinformatics analysis to determine the impact of SARS-CoV-2 infections to Heart Failure patients (preprint)

Background: COVID-19, the highly contagious respiratory disease, has become a major threat to humanity, and its extrapulmonary effects were also evident. Heart failure (HF) may be the result of myocardial damage associated with COVID-19. Methods: : To understand the relationship between SARS-COV-2 and HF, we used bioinformatics analysis to identify common pathways and molecular biomarkers for HF and COVID-19. In this study, two datasets (GSE152418, GSE57338) from Gene Expression Omnibus (GEO) were used to identify differentially expressed genes (DEGs) of SARS-COV-2 infection in HF patients to find common pathways and drug candidates. Results: : A total of 123 common DEGs were identified in the two datasets. Using a variety of bioinformatics tools, we first constructed protein-protein interactions (PPI) and then identified hub genes that could be served as potential biomarkers or novel therapeutic strategies. In addition, some common associations between HF and the progression of COVID-19 infection were found by using functional under ontological terms and pathway analysis. Through the datasets, we also identified transcription factor-gene interactions, protein-drug interactions, and co-regulatory network of DEGs-miRNAs with common DEGs. We built gene-disease association network to represent diseases associated with mutual DEGs. Conclusions: : Our study has identified the candidate hub genes and drugs that might become a new therapeutic target for novel coronavirus vaccine development and treatment in COVID-19 and HF.

Investigation and influencing factors about well-being level of elderly chronic patients during COVID-19 postpandemic period in Beijing.

ABSTRACT: The Corona Virus Disease 2019 (COVID-19) pandemic has huge impacts on the world, including human health and economic decline. The COVID-19 has severe infectivity, especially the elderly with chronic diseases will cause various complications after infection and accelerate the disease process. In addition, COVID-19 will also affect their mental health. Therefore, the mental health of elderly patients with chronic diseases cannot be ignored. The aim of this study was to investigate the well-being level of elderly people with chronic disease during COVID-19 postpandemic period in Beijing and analysis related influencing factors, so as to provide a basis for improving the well-being level of elderly chronic patients during the postpandemic period.Elderly patients with chronic diseases who met the inclusion criteria in 5 different administrative regions in Beijing were selected to carry out a questionnaire survey. The contents of the questionnaire included general data, the Memorial University of Newfoundland Happiness scale and the awareness situation of the COVID-19 pandemic. A total of 500 questionnaires were distributed by WeChat and 486 valid questionnaires were collected. The t test and one-way analysis of variance were used to compare Memorial University of Newfoundland Happiness scores between 2 or more groups, multiple linear regression analysis was used to conduct multiple factor analysis to explore the related factors about well-being level of elderly chronic patients.A total of 109 cases (22.43%) were evaluated high well-being level, 319 cases (65.64%) were evaluated moderate well-being level and 58 cases (11.93%) were evaluated low well-being according to the Memorial University of Newfoundland Happiness (MUNSH) scores rating. The multiple linear regression indicated that the education level, number of chronic diseases, medical expenses, frequency of children's visits, taking care of grandchildren or not, and group activity frequency significantly affected the well-being of patients with chronic diseases during COVID-19 postpandemic period in Beijing (P < .05).Most elderly patients with chronic diseases had moderate or above sense of well-being during postpandemic period, but we should still pay attention to the mental health of those elderly chronic patients with low education level, much comorbidity, more medical expenses, less visits by children, not take care of grandchildren and never participate in group activities.

Biodegradable and Reusable Cellulose-Based Nanofiber Membrane Preparation for Mask Filter by Electrospinning.

Environmentally friendly face masks with high filtration efficiency are in urgent need to fight against the COVID-19 pandemic, as well as other airborne viruses, bacteria and particulate matters. In this study, coaxial electrospinning was employed to fabricate a lithium chloride enhanced cellulose acetate/thermoplastic polyurethanes (CA/TPU-LiCl) face mask nanofiber filtration membrane, which was biodegradable and reusable. The analysis results show that the CA/TPU-LiCl membrane had an excellent filtration performance: when the filtration efficiency reached 99.8%, the pressure drop was only 52 Pa. The membrane also had an outstanding reusability. The filtration performance maintained at 98.2% after 10 test cycles, and an alcohol immersion disinfection treatment showed no effect on its filtration performance. In summary, the CA/TPU-LiCl nanofiber membrane made in this work is a promising biodegradable and reusable filtration material with a wide range of potential applications, including high-performance face mask.

A Real-World Study on Myopia Control 6 Months After Withdrawal of 1% Atropine Eye Gel (preprint)

Purpose: This study aimed to observe the changes in spherical equivalent and ocular axial length 6 months after withdrawal of 1% atropine eye gel. Methods: Due to COVID-19, the follow-up of patients in our optometric clinic who were undergoing myopia control treatment with a dropwise 1% atropine “5+3” regimen was interrupted. No return visit was made after the 3 months of at-home treatment, and follow-ups resumed 6 months after treatment withdrawal. The contralateral eye was not treated over the 9-month period. A total of 16 patients aged 11.5 years (average) were enrolled from November 2019 to March 2021 during the COVID-19 pandemic. The treated eyes formed a treatment group (16 eyes) and the contralateral eyes formed a control group (16 eyes). The changes in spherical equivalent, ocular axial length, and intraocular pressure (IOP) were compared between groups. Results: After 9 months, the changes in spherical equivalent were significantly less in the treatment group (0.00 ± 0.20 [D]) compared to the control group (-0.67 ± 0.25 [D]) (P<0.05). The ocular axial length changes were significantly less in the treatment group (0.00 ± 0.06 mm) compared to the control group (0.25 ± 0.11 mm) (P<0.05). There was no significant difference between the two groups for changes in IOP. Conclusions: Despite treatment withdrawal after 3 months, treatment with 1% atropine eye gel successfully controlled myopia progression in the 6 months after withdrawal, as evidence by no rebound increase in myopic spherical equivalent after the withdrawal.

Identification of key factors shaping integrated levels of ACE2 and TMPRSS2 expression in head and neck squamous cell carcinoma.

Objectives: To quantify the integrated levels of ACE2 and TMPRSS2, the two well-recognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry-related genes, and to further identify key factors contributing to SARS-CoV-2 susceptibility in head and neck squamous cell carcinoma (HNSC). Methods: We developed a metric of the potential for tissue infected with SARS-CoV-2 ("TPSI") based on ACE2 and TMPRSS2 transcript levels and compared TPSI levels between tumor and matched normal tissues across 11 tumor types. For further analysis of HNSC, weighted gene co-expression network analysis (WGCNA), functional analysis, and single sample gene set enrichment analysis (ssGSEA) were conducted to investigate TPSI-relevant biological processes and their relationship with the immune landscape. TPSI-related factors were identified from clinical and mutational domains, followed by lasso regression to determine their relative effects on TPSI levels. Results: TPSI levels in tumors were generally lower than in the normal tissues. In HNSC, the genes highly associated with TPSI were enriched in viral entry-related processes, and TPSI levels were positively correlated with both eosinophils and T helper 17 (Th17) cell infiltration. Furthermore, the site of onset, human papillomaviruses (HPV) status, and nuclear receptor binding SET domain protein 1 (NSD1) mutations were identified as the most important factors shaping TPSI levels. Conclusions: This study identified the infection risk of SARS-CoV-2 between tumor and normal tissues, and provided evidence for the risk stratification of HNSC.

Prevalence of and risk factors for burnout and occupational stress among couriers: A systematic review (preprint)

Objective To estimate the prevalence of burnout and occupational stress (OS) among couriers and to identify the main risk factors. Method We followed PRISMA guidelines to search studies published in English and Chinese databases before February 2022. Results The search yielded 15 (7 English and 8 Chinese) papers, 12 of which studied Chinese couriers, and three studied French, Israeli and Malaysian couriers. Twelve studies reported OS using various validated measurement tools, and six reported burnout using adapted versions of Maslach Burnout Inventory. Only four included studies suggested cut-off points to define the condition, hence we used the midpoint of the scales to estimate the prevalence (the proportion of the cases that were above the midpoint). The estimated prevalence of burnout (or a dimension of burnout) among couriers ranged from 20% to 73% (median=33%). The prevalence of OS (or a dimension of OS) ranged from 7% to 90% (median=40%). Twelve studies reported risk factors for burnout or OS; the main ones were physical demands, customer behaviour and a range of working and employment conditions, such as employment precarity and financial insecurity. Job resources (i.e. social support and decision latitude) and organizational support had mitigating effects. Conclusions Burnout and OS are relatively high among couriers. Interventions to prevent or reduce burnout in this occupation are currently limited. The use of platform technology to shift risks, intensify work and tighten managerial controls could be a potential work-related stressor for app-based couriers but remains a knowledge gap.

Combining economic recovery with climate change mitigation: A global evaluation of financial instruments

Although some countries are gradually returning to production and life, the COVID-19 pandemic continues to affect the world, further motivating recovery policies. Using a global computable general equilibrium (CGE) model, this study evaluates the environmental and economic impacts of COVID-19 on the world, both today and in the longer term. This study explores the post-pandemic impacts conditional on varied fiscal policies (including forgone revenue and additional spending) and their combination with a carbon tax. This study finds that the pandemic shocks in 2020 slowed regional economies worldwide, and a continued pandemic in 2021 will further stymie economic activity. Among the government’s recovery policies, indirect tax reduction has the best positive stimulus to regional economies;however, it is not conducive to low-carbon energy development and will also lead to an increase in CO2 and pollutant emissions. A post-pandemic green recovery plan could prioritize replacing indirect production taxes with taxes on GHG emissions, which would both improve economic turnover metrics and reduce environmental emissions in 2021. In the long run, this tax shift will not only minimize the economic damage to the global economy but also help governments around the world to get back on track in meeting the goals of the Paris Agreement.