Steroids Therapy in Patients With Severe COVID-19: Association With Decreasing of Pneumonia Fibrotic Tissue Volume

Background We use longitudinal chest CT images to explore the effect of steroids therapy in COVID-19 pneumonia which caused pulmonary lesion progression. Materials and Methods We retrospectively enrolled 78 patients with severe to critical COVID-19 pneumonia, among which 25 patients (32.1%) who received steroid therapy. Patients were further divided into two groups with severe and significant-severe illness based on clinical symptoms. Serial longitudinal chest CT scans were performed for each patient. Lung tissue was segmented into the five lung lobes and mapped into the five pulmonary tissue type categories based on Hounsfield unit value. The volume changes of normal tissue and pneumonia fibrotic tissue in the entire lung and each five lung lobes were the primary outcomes. In addition, this study calculated the changing percentage of tissue volume relative to baseline value to directly demonstrate the disease progress. Results Steroid therapy was associated with the decrease of pneumonia fibrotic tissue (PFT) volume proportion. For example, after four CT cycles of treatment, the volume reduction percentage of PFT in the entire lung was −59.79[±12.4]% for the steroid-treated patients with severe illness, and its p-value was 0.000 compared to that (−27.54[±85.81]%) in non-steroid-treated ones. However, for the patient with a significant-severe illness, PFT reduction in steroid-treated patients was −41.92[±52.26]%, showing a 0.275 p-value compared to −37.18[±76.49]% in non-steroid-treated ones. The PFT evolution analysis in different lung lobes indicated consistent findings as well. Conclusion Steroid therapy showed a positive effect on the COVID-19 recovery, and its effect was related to the disease severity.

Analysis and forecast of marine economy development in China

Purpose>In recent years, China's marine industry has maintained rapid growth in general, and marine-related economic activities have continued to improve. The purpose of this research is to analyze the basic situation of China's marine economy development, identify the problems therein, forecast development trends and propose policy recommendations accordingly.Design/methodology/approach>This research conducts a comprehensive and detailed analysis of the development of China's marine economy with rich data in diversified aspects. The current situation of China's marine economy development is analyzed from the perspective of scale and structure, and the external and internal development environment of China's marine economy is discussed. With the application of measurement and prediction method such as trend extrapolation, exponential smoothing, grey forecasting and neural network method, the future situation of China's marine economy development is forecasted.Findings>In a complex environment where uncertainties at home and abroad have increased significantly, China's marine economy development suffers tremendous downward pressure in recent years. As China has achieved major achievements in the prevention and control of the COVID-19 epidemic, the marine economy development will gradually return to normal. It is estimated that the gross marine production value in 2022 will exceed 10 trillion yuan. China's marine economy will continue to maintain a steady growth trend in the future, and its development prospects will remain promising.Originality/value>This research explores the current situation and trends of China's marine economy development and puts forward policy recommendations to promote the steady and health development of China's marine economy accordingly.

Plasmacytoid dendritic cells regulate megakaryocyte and platelet homeostasis (preprint)

Platelet homeostasis is essential for vascular integrity and immune defense. While the process of platelet formation by fragmenting megakaryocytes (thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of megakaryocytes by their progenitor cells (megakaryopoiesis) remains unclear. Here we use intravital 2 photon microscopy to track individual megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as crucial bone marrow niche cells that regulate megakaryopoiesis. pDCs monitor the bone marrow for platelet-producing megakaryocytes and deliver IFN-a to the megakaryocytic niche to trigger local on-demand proliferation of megakaryocyte progenitors. This fine-tuned coordination between thrombopoiesis and megakaryopoiesis is crucial for megakaryocyte and platelet homeostasis in steady state and stress. However, uncontrolled pDC function within the megakaryocytic niche is detrimental. Accordingly, we show that pDCs activated by SARS-CoV2 drive inappropriate megakaryopoiesis associated with thrombotic complications. Together, we uncover a hitherto unknown megakaryocytic bone marrow niche maintained by the constitutive delivery of pDC-derived IFN-a.

Uncovering Novel Viral Innate Immune Evasion Strategies: What Has SARS-CoV-2 Taught Us?

The ongoing SARS-CoV-2 pandemic has tested the capabilities of public health and scientific community. Since the dawn of the twenty-first century, viruses have caused several outbreaks, with coronaviruses being responsible for 2: SARS-CoV in 2007 and MERS-CoV in 2013. As the border between wildlife and the urban population continue to shrink, it is highly likely that zoonotic viruses may emerge more frequently. Furthermore, it has been shown repeatedly that these viruses are able to efficiently evade the innate immune system through various strategies. The strong and abundant antiviral innate immunity evasion strategies shown by SARS-CoV-2 has laid out shortcomings in our approach to quickly identify and modulate these mechanisms. It is thus imperative that there be a systematic framework for the study of the immune evasion strategies of these viruses, to guide development of therapeutics and curtail transmission. In this review, we first provide a brief overview of general viral evasion strategies against the innate immune system. Then, we utilize SARS-CoV-2 as a case study to highlight the methods used to identify the mechanisms of innate immune evasion, and pinpoint the shortcomings in the current paradigm with its focus on overexpression and protein-protein interactions. Finally, we provide a recommendation for future work to unravel viral innate immune evasion strategies and suitable methods to aid in the study of virus-host interactions. The insights provided from this review may then be applied to other viruses with outbreak potential to remain ahead in the arms race against viral diseases.

Aerosolized Ad5-nCoV booster vaccination elicited potent immune response against the SARS-CoV-2 Omicron variant after inactivated COVID-19 vaccine priming (preprint)

The SARS-CoV-2 Omicron variant has become the dominant SARS-CoV-2 variant around the world and exhibits immune escape to current COVID-19 vaccines to some extent due to its numerous spike mutations. Here, we evaluated the immune responses to booster vaccination with intramuscular adenovirus-vectored vaccine (Ad5-nCoV), aerosolized Ad5-nCoV, a recombinant protein subunit vaccine (ZF2001) or homologous inactivated vaccine (CoronaVac) in those who received two doses of inactivated COVID-19 vaccines 6 months prior. We found that the Ad5-nCoV booster induced potent neutralizing activity against the wild-type virus and Omicron variant, while aerosolized Ad5-nCoV generated the greatest neutralizing antibody responses against the Omicron variant at day 28 after booster vaccination, at 14.1-fold that of CoronaVac, 5.6-fold that of ZF2001 and 2.0-fold that of intramuscular Ad5-nCoV. Similarly, the aerosolized Ad5-nCoV booster produced the greatest IFNgamma T-cell response at day 14 after booster vaccination. The IFNgamma T-cell response to aerosolized Ad5-nCoV was 12.8-fold for CoronaVac, 16.5-fold for ZF2001, and 5.0-fold for intramuscular Ad5-nCoV. Aerosolized Ad5-nCoV booster also produced the greatest spike-specific B cell response. Our findings suggest that inactivated vaccine recipients should consider adenovirus-vectored vaccine boosters in China and that aerosolized Ad5-nCoV may provide a more efficient alternative in response to the spread of the Omicron variant.

Human Nasal Epithelial Cells Sustain Persistent SARS-CoV-2 Infection In Vitro, despite Eliciting a Prolonged Antiviral Response.

The dynamics of SARS-CoV-2 infection in COVID-19 patients are highly variable, with a subset of patients demonstrating prolonged virus shedding, which poses a significant challenge for disease management and transmission control. In this study, the long-term dynamics of SARS-CoV-2 infection were investigated using a human well-differentiated nasal epithelial cell (NEC) model of infection. NECs were observed to release SARS-CoV-2 virus onto the apical surface for up to 28 days postinfection (dpi), further corroborated by viral antigen staining. Single-cell transcriptome sequencing (sc-seq) was utilized to explore the host response from infected NECs after short-term (3-dpi) and long-term (28-dpi) infection. We identified a unique population of cells harboring high viral loads present at both 3 and 28 dpi, characterized by expression of cell stress-related genes DDIT3 and ATF3 and enriched for genes involved in tumor necrosis factor alpha (TNF-α) signaling and apoptosis. Remarkably, this sc-seq analysis revealed an antiviral gene signature within all NEC cell types even at 28 dpi. We demonstrate increased replication of basal cells, absence of widespread cell death within the epithelial monolayer, and the ability of SARS-CoV-2 to replicate despite a continuous interferon response as factors likely contributing to SARS-CoV-2 persistence. This study provides a model system for development of therapeutics aimed at improving viral clearance in immunocompromised patients and implies a crucial role for immune cells in mediating viral clearance from infected epithelia. IMPORTANCE Increasing medical attention has been drawn to the persistence of symptoms (long-COVID syndrome) or live virus shedding from subsets of COVID-19 patients weeks to months after the initial onset of symptoms. In vitro approaches to model viral or symptom persistence are needed to fully dissect the complex and likely varied mechanisms underlying these clinical observations. We show that in vitro differentiated human NECs are persistently infected with SARS-CoV-2 for up to 28 dpi. This viral replication occurred despite the presence of an antiviral gene signature across all NEC cell types even at 28 dpi. This indicates that epithelial cell intrinsic antiviral responses are insufficient for the clearance of SARS-CoV-2, implying an essential role for tissue-resident and infiltrating immune cells for eventual viral clearance from infected airway tissue in COVID-19 patients.

The China Carbon Watch (CCW) system: A rapid accounting of household carbon emissions in China at the provincial level

A large proportion of carbon emissions emitted by human activities is from the household sector. Efforts to control such carbon emissions need a timely accounting. We attempt to establish a rapid accounting China Carbon Watch (CCW) system, through which we use an alternative solution for accounting household carbon emissions in China by applying monthly nighttime light (NTL) data. The compiled carbon emission accounting method is considered as timely with high accuracy by employing a 1-km grid dataset built from point-emission sources. The heterogeneities of carbon emissions in both urban and rural sectors are presented. Furthermore, this research calculates monthly data of urban and rural household carbon emissions at the provincial level from January to May 2020. Results show that the overall household carbon emissions slightly increased during the COVID-19 forced confinement due to the closure of international borders and the confinement of urbanists with significant heterogeneity between provinces.

Quantifying Air Pollutant Variations during COVID-19 Lockdown in a Capital City in Northwest China

In the context of the outbreak of coronavirus disease 2019 (COVID-19), strict lockdown policies were implemented to control nonessential human activities in Xi’an, northwest China, which greatly limited the spread of the pandemic and affected air quality. Compared with pre-lockdown, the air quality index and concentrations of PM2.5, PM10, SO2, and CO during the lockdown reduced, but the reductions were not very significant. NO2 levels exhibited the largest decrease (52%) during lockdown, owing to the remarkable decreased motor vehicle emissions. The highest K+ and lowest Ca2+ concentrations in PM2.5 samples could be attributed to the increase in household biomass fuel consumption in suburbs and rural areas around Xi’an and the decrease in human physical activities in Xi’an (e.g., human travel, vehicle emissions, construction activities), respectively, during the lockdown period. Secondary chemical reactions in the atmosphere increased in the lockdown period, as evidenced by the increased O3 level (increased by 160%) and OC/EC ratios in PM2.5 (increased by 26%), compared with pre-lockdown levels. The results, based on a natural experiment in this study, can be used as a reference for studying the formation and source of air pollution in Xi’an and provide evidence for establishing future long-term air pollution control policies.

DNA damage contributes to age-associated differences in SARS-CoV-2 infection (preprint)

Coronavirus disease 2019 (COVID-19), caused by coronavirus SARS-CoV-2, is known to disproportionately affect older individuals1,2. How aging processes affect the disease progression remains largely unknown. Here we found that DNA damage, one of the major causes of aging3, promoted susceptibility to SARS-CoV-2 infection in cells and intestinal organoids. SARS-CoV-2 entry was facilitated by DNA damage caused by telomere attrition or extrinsic genotoxic stress and hampered by inhibition of DNA damage response (DDR). Mechanistic analysis revealed that DDR increased expression of ACE2, the receptor of SARS-CoV-2, by activation of transcription factor c-Jun in vitro and in vivo. Expression of ACE2 was elevated in the older tissues and positively correlated with γH2Ax and phosphorylated c-Jun (p-c-Jun). Finally, targeting DNA damage by increasing the DNA repair capacity, alleviated cell susceptibility to SARS-CoV-2. Our data provide insights into the age-associated differences in SARS-CoV-2 infection and a novel target for anti-viral intervention.

A novel viral protein translation mechanism reveals mitochondria as a target for antiviral drug development (preprint)

The ongoing Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic has acutely highlighted the need to identify new treatment strategies for viral infections. Here we present a pivotal molecular mechanism of viral protein translation that relies on the mitochondrial translation machinery. We found that rare codons such as Leu-TTA are highly enriched in many viruses, including SARS-CoV-2, and these codons are essential for the regulation of viral protein expression. SARS-CoV-2 controls the translation of its spike gene by hijacking host mitochondria through 5' leader and 3'UTR sequences that contain mitochondrial localization signals and activate the EGR1 pathway. Mitochondrial-targeted drugs such as lonidamine and polydatin significantly repress rare codon-driven gene expression and viral replication. This study identifies an unreported viral protein translation mechanism and opens up a novel avenue for developing antiviral drugs.

Germicidal Ultraviolet Light Does Not Damage or Impede Performance of N95 Masks Upon Multiple Uses

The COVID-19 pandemic is increasing the need for personal protective equipment (PPE) worldwide, including the demand for facial mask used by healthcare workers. Disinfecting and reusing these masks may off benefits in the short term to meet urgent demand. Germicidal ultraviolet light provides a nonchemical, easily deployable technology capable of achieving inactivation of H1N1 virus on masks. Working with N95-rated masks and nonrated surgical masks, we demonstrated that neither 254 nor 265 nm UV-C irradiation at 1 and 10 J/cm(2) had adverse effects on the masks' ability to remove aerosolized virus-sized particles. Additional testing showed no change in polymer structure, morphology, or surface hydrophobicity for multiple layers in the masks and no change in pressure drop or tensile strength of the mask materials. Results were similar when applying 254 nm low-pressure UV lamps and 265 nm light-emitting diodes. On the basis of the input from healthcare workers and our findings, a treatment system and operational manual were prepared to enable treatment and reuse of N95 facial masks. Knowledge gained during this study can inform techno-economic analyses for treating and reusing masks or lifecycle assessments of options to reduce the enormous waste production of single-use PPE used in the healthcare system, especially during pandemics.

An effective, safe and cost-effective cell-based chimeric vaccine against SARS-CoV2 (preprint)

More than one hundred vaccines against SARS-CoV-2 have been developed and some of them have entered clinical trials, but the latest results revealed that these vaccines still face great challenges. Here, we developed a novel cell-based gp96-Ig-secreting chimeric vaccine which is composed of two viral antigens, the RBD of spike protein, and a truncated nucleocapsid protein that could induce epitope-specific cytotoxic T lymphocytes but low antibody response. Syrian hamsters immunized with the cell-based vaccine produced high level of SARS-CoV-2 specific NAbs and specific T cell immunity which could eliminate RBD-truncated N-expressing cells, without the induction of antibody against N protein and other observed toxicity. This study provides a proof of concept for clinical testing of this safe, effective and cost-effective vaccine against SARS-CoV2 infection.

Development of a high-throughput homogeneous AlphaLISA drug screening assay for the detection of SARS-CoV-2 Nucleocapsid (preprint)

The coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is in urgent need of therapeutic options. High-throughput screening (HTS) offers the research field an opportunity to rapidly identify such compounds. In this work, we have developed a homogeneous cell-based HTS system using AlphaLISA detection technology for the SARS-CoV-2 nucleocapsid protein (NP). Our assay measures both recombinant NP and endogenous NP from viral lysates and tissue culture supernatants (TCS) in a sandwich-based format using two monoclonal antibodies against the NP analyte. Viral NP was detected and quantified in both tissue culture supernatants and cell lysates, with large differences observed between 24 hours and 48 hours of infection. We simulated the viral infection by spiking in recombinant NP into 384-well plates with live Vero-E6 cells and were able to detect the NP with high sensitivity and a large dynamic range. Anti-viral agents that inhibit either viral cell entry or replication will decrease the AlphaLISA NP signal. Thus, this assay can be used for high-throughput screening of small molecules and biologics in the fight against the COVID-19 pandemic.

SARS-CoV-2 manipulates the SR-B1-mediated HDL uptake pathway for its entry (preprint)

The recently emerged pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global COVID-19 pandemic. Binding of the viral spike protein (SARS-2-S) to cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediates host cell infection. In the present study, we demonstrate that in addition to ACE2, the S1 subunit of SARS-2-S binds to HDL and that SARS-CoV-2 hijacks the SR-B1-mediated HDL uptake pathway to facilitate its entry. SR-B1 facilitates SARS-CoV-2 entry into permissive cells by augmenting virus attachment. MAb (monoclonal antibody)-mediated blocking of SARS-2-S-HDL binding and SR-B1 antagonists strongly inhibit HDL-enhanced SARS-CoV-2 infection. Notably, SR-B1 is co-expressed with ACE2 in human pulmonary and extrapulmonary tissues. These findings revealed a novel mechanism for SARS-CoV-2 entry and could provide a new target to treat SARS-CoV-2 infection.

Cohort Profile: Chinese Color Nest Project (preprint)

The ongoing CCNP was established to plot normative growth curves for brain structure and function across the human lifespan, and link age-related changes in brain imaging measures with psycho-behavioral functions at the behavioral, cognitive and emotional levels using an accelerated longitudinal design. It comprises three phases: developmental CCNP (devCCNP: 6-20 years), standardizing CCNP (stdCCNP: 20-60 years) and aging CCNP (ageCCNP: 60-90 years). The devCCNP started in 2013 and has successfully acquired CCNP-SWU data with three repeated measurements ( the trial stage of devCCNP), and accumulated CCNP-CAS baseline data (the second stage of devCCNP). CCNP-SWU consists of 201 age-sex stratified schoolchildren at enrollment (100 children followed up for 2.5 years at 1.25-year intervals) while CCNP-CAS has been recruiting participants since July 2018, and has collected data from 133 eligible children so far. A T1-weighted MRI and two resting functional MRI scans were acquired across three waves in CCNP-SWU with the same imaging protocols on a Siemens Trio 3T scanner at Southwest University in Chongqing, China. CCNP-SWU obtained longitudinal biophysical, social, behavioral and cognitive data via parent-reported questionnaires, self-reported questionnaires, behavioral assessment, as well as E-Prime computer tasks. Data were collected on the impact of COVID-19 on children’s learning and daily life from 46 children between March and May 2020. Children’s emotional states during COVID-19 pandemic were also measured. Data are accessed by researchers and collaborators of CCNP upon agreement with the principal investigator.

A single dose of an adenovirus-vectored vaccine provides complete protection of the upper and lower respiratory tracts against SARS-CoV-2 challenge (preprint)

The unprecedented coronavirus disease 2019 (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective vaccine to control this severe infectious disease. Here, we found that a single vaccination with a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV) protected mice completely against SARS-CoV-2 infection in the upper and lower respiratory tracts. Additionally, a single vaccination with Ad5-nCoV protected ferrets from SARS-CoV-2 infection in the upper respiratory tract. This study suggested that a combination of intramuscular and mucosal vaccination maybe provide a desirable protective efficacy and different Ad5-nCoV delivery modes are worth further investigation in human clinical trials.

A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability (preprint)

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.