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Coronavirus 2019 (COVID-19) is a complex disease that affects billions of people worldwide. Currently, effective etiological treatment of COVID-19 is still lacking; COVID-19 also causes damages to various organs that affects therapeutics and mortality of the patients. Surveillance of the treatment responses and organ injury assessment of COVID-19 patients are of high clinical value. In this study, we investigated the characteristic fragmentation patterns and explored the potential in tissue injury assessment of plasma cell-free DNA in COVID-19 patients. Through recruitment of 37 COVID-19 patients, 32 controls and analysis of 208 blood samples upon diagnosis and during treatment, we report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA fragmentation characteristics reflect patient-specific physiological changes during treatment. Further analysis on cfDNA tissue-of-origin tracing reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, our work demonstrates and extends the translational merit of cfDNA fragmentation pattern as valuable analyte for effective treatment monitoring, as well as tissue injury assessment in COVID-19.

A full understanding of the inactivated COVID-19 vaccine-mediated antibody responses to SARS-CoV-2 circulating variants will inform vaccine effectiveness and vaccination development strategies. Here, we offer insights into the inactivated vaccine-induced antibody responses after prime-boost vaccination at both the polyclonal and monoclonal levels. We characterized the VDJ sequence of 118 monoclonal antibodies (mAbs) and found that 20 neutralizing mAbs showed varied potency and breadth against a range of variants including XBB.1.5, BQ.1.1, and BN.1. Bispecific antibodies (bsAbs) based on nonoverlapping mAbs exhibited enhanced neutralizing potency and breadth against the most antibody-evasive strains, such as XBB.1.5, BQ.1.1, and BN.1. The passive transfer of mAbs or their bsAb effectively protected female hACE2 transgenic mice from challenge with an infectious Delta or Omicron BA.2 variant. The neutralization mechanisms of these antibodies were determined by structural characterization. Overall, a broad spectrum of potent and distinct neutralizing antibodies can be induced in individuals immunized with the SARS-CoV-2 inactivated vaccine BBIBP-CorV, suggesting the application potential of inactivated vaccines and these antibodies for preventing infection by SARS-CoV-2 circulating variants.

As SARS-CoV-2 variants have been causing increasingly serious drug resistance problem, development of broadly effective and hard-to-escape anti-SARS-CoV-2 agents is in urgent need. Here we describe further development and characterization of two SARS-CoV-2 receptor decoy proteins, ACE2-Ig-95 and ACE2-Ig-105/106. We found that both proteins had potent and robustin vitroneutralization activities against diverse SARS-CoV-2 variants including Omicron, with an average IC50of up to 37 pM. In a stringent lethal SARS-CoV-2 infection mouse model, both proteins lowered lung viral load by up to ∼1000 fold, prevented the emergence of clinical signs in >75% animals, and increased animal survival rate from 0% (untreated) to >87.5% (treated). These results demonstrate that both proteins are good drug candidates for protecting animals from severe COVID-19. In a head-to-head comparison of these two proteins with five previously-described ACE2-Ig constructs, we found that two of these constructs, each carrying five surface mutations in the ACE2 region, had partial loss of neutralization potency against three SARS-CoV-2 variants. These data suggest that extensively mutating ACE2 residues near the RBD-binding interface should be avoided or performed with extra caution. Further, we found that both ACE2-Ig-95 and ACE2-Ig-105/106 could be produced to gram/liter level, demonstrating the developability of them as biologic drug candidates. Stress-condition stability test of them further suggests that more studies are required in the future to improve the stability of these proteins. These studies provide useful insight into critical factors for engineering and preclinical development of ACE2 decoys as broadly effective therapeutics against diverse ACE2-utilizing coronaviruses.Abstract ImportanceEngineering soluble ACE2 proteins that function as a receptor decoy to block SARS-CoV-2 infection is a very attractive approach to broadly effective and hard-to-escape anti-SARS-CoV-2 agents. This study here describes development of two antibody-like soluble ACE2 proteins that broadly block diverse SARS-CoV-2 variants including Omicron. In a stringent COVID-19 mouse model, both proteins successfully protected >87.5% animals from lethal SARS-CoV-2 infection. In addition, a head-to-head comparison of the two constructs developed in this study with five previously-described ACE2 decoy constructs were performed here. Two previously-described constructs with relatively more ACE2-surface mutations were found with less robust neutralization activities against diverse SARS-CoV-2 variants. Further, the developability of the two proteins as biologic drug candidates was also assessed here. This study provides two broadly anti-SARS-CoV-2 drug candidates and useful insight into critical factors for engineering and preclinical development of ACE2 decoy as broadly effective therapeutics against diverse ACE2-utilizing coronaviruses.TweetTwo antibody-like ACE2 decoy proteins could block diverse SARS-CoV-2 variants and prevent animals from severe COVID-19.

Human coronavirus 229E (HCoV-229E) and NL63 (HCoV-NL63) are endemic causes of upper respiratory infections such as the “common cold” but may occasionally cause severe lower respiratory tract disease in the elderly and immunocompromised patients. There are no approved antiviral drugs or vaccines for these common cold coronaviruses (CCCoV). The recent emergence of COVID-19 and the possible cross-reactive antibody and T cell responses between these CCCoV and SARS-CoV-2 emphasize the need to develop experimental animal models for CCCoV. Mice are an ideal experimental animal model for such studies, but are resistant to HCoV-229E and HCoV-NL63 infections. Here, we generated 229E and NL63 mouse models by exogenous delivery of their receptors, human hAPN and hACE2 using replication-deficient adenoviruses (Ad5-hAPN and Ad5-hACE2), respectively. Ad5-hAPN- and Ad5-hACE2-sensitized IFNAR −/− and STAT1 −/− mice developed pneumonia characterized by inflammatory cell infiltration with virus clearance occurring 7 d post infection. Ad5-hAPN- and Ad5-hACE2-sensitized mice generated virus-specific T cells and neutralizing antibodies after 229E or NL63 infection, respectively. Remdesivir and a vaccine candidate targeting spike protein of 229E and NL63 accelerated viral clearance of virus in these mice. 229E- and NL63-infected mice were partially protected from SARS-CoV-2 infection, likely mediated by cross-reactive T cell responses. Ad5-hAPN- and Ad5-hACE2-transduced mice are useful for studying pathogenesis and immune responses induced by HCoV-229E and HCoV-NL63 infections and for validation of broadly protective vaccines, antibodies, and therapeutics against human respiratory coronaviruses including SARS-CoV-2.

Lipopolysaccharide (LPS)‐induced sepsis‐associated acute kidney injury (SA‐AKI) is a model of clinical serious care syndrome, with high morbidity and mortality. Tacrolimus (TAC), a novel immunosuppressant that inhibits inflammatory response, plays a pivotal role in kidney diseases. In this study, LPS treated mice and cultured podocytes were used as the models of SA‐AKI in vivo and in vitro, respectively. Medium‐ and high‐dose TAC administration significantly attenuated renal function and renal pathological manifestations at 12, 24 and 48 h after LPS treatment in mice. Moreover, the Toll‐like receptor 4 (TLR4)/myeloid differential protein‐88 (MyD88)/nuclear factor‐kappa (NF‐κB) signalling pathway was also dramatically inhibited by medium‐ and high‐dose TAC administration at 12, 24 and 48 h of LPS treatment mice. In addition, TAC reversed LPS‐induced podocyte cytoskeletal injury and podocyte migratory capability. Our findings indicate that TAC has protective effects against LPS‐induced AKI by inhibiting TLR4/MyD88/NF‐κB signalling pathway and podocyte dysfunction, providing another potential therapeutic effects for the LPS‐induced SA‐AKI.

Dengue fever is a mosquito-borne viral disease spread in tropical and subtropical regions caused by the dengue virus (DENV). DENV causes a febrile illness, severe forms including hemorrhagic fevers and shock with fatalities in humans. DENV-2 is frequently associated with severe dengue infections and epidemics. DENV-2 strains from Guangdong, China, have not been characterized to compare the phylogenetics and pathogenicity of different DENV-2 subgenotype strains in both vitro and vivo. A total of 22 patients tested to be DENV-2 positive and were enrolled in this study, 22 complete genomes were obtained by virus isolation and high-throughput sequencing. Phylogenetic and single amino polymorphism (SAP) analysis indicated that two major subgenotypes (A and C) of DENV-2 Cosmopolitan were prevalent in Guangdong in 2018. The apparent change of major subgenotypes of DENV-2 circulating in Guangdong indicated the diversity of DENV-2 strains, including endemic genotype and imported genotype. It alerted the risk of cross-border transmission of DENV. A significant difference in replication rate was observed in C6/36 between different DENV-2 strains, although growth kinetics comparison of different DENV-2 Cosmopolitan subgenotypes showed similar profiles. DENV-2 subgenotypes (A and C) replicated efficiently in IFNAR−/− C57BL/6 mice, and subgenotype A of Cosmopolitan infected mice showed increased weight loss and delayed viral clearance compared with the subgenotype C group. DENV-2 prevalent in Guangdong in 2018 showed apparent genetic and pathogenicity diversity in both vitro and vivo, indicating the necessity of molecular surveillance and exploration of the relationship between its pathogenicity and clinical characteristics.

This paper investigates the timing of Chinese ODI under exchange rate uncertainty by employing the Cox proportional hazards model. Using matched data this paper finds both exchange rate level and volatility are the important determinants, and RMB depreciation and greater volatility will deter ODI. Such adverse effect is found more striking for non-SOEs, firms in the eastern region, and non-exporting firms. With China’s recent exchange rate formation mechanism reform, the impact of exchange rate uncertainty is expected to be stronger. These findings have important implications for China’s exchange rate regime reform and its “Going Global” strategy.

Despite the claims that China has been implementing mercantilism policies to support its exports, recent studies argue that the dominant factor affecting China’s foreign exchange reserves is the precautionary motives. Apart from the economic uncertainty, political instability may be another risk source to consider by those motives. This study intends to empirically investigate how a particular factor originated in the US such as partisan conflict or economic uncertainty explains the foreign exchange reserves hoarding in China. Using SVAR models we find strong evidence suggesting that partisan conflict is positively associated with China’s reserve level, and has a primarily dominant role in predicting the surge in China’s foreign exchange reserves. In contrast, the impact of the US economic uncertainty is found negative and less persistent. The Forecast-error-variance decomposition (FEVD) analysis confirms partisan conflict’s dominant role in explaining the variations in China’s reserve accumulation, in comparison with other variables such as US exports to China and US economic policy uncertainty. The results are robust and consistent under different scenarios and robustness checks. The findings have important policy implications and contribute to the existing literature on the global impacts of US political instability.

SARS-CoV-2 has caused a global pandemic of COVID-19, posing a huge threat to public health. The SARS-CoV-2 papain-like cysteine protease (PLpro) plays a significant role in virus replication and host immune regulation, which is a promising antiviral drug target. Several potential inhibitors have been identified in vitro. However, the detailed mechanism of action and structure-activity relationship require further studies. Here, we investigated the structure-activity relationships of the series of derivatives of tanshinone IIA sulfonate sodium (TSS) and chloroxine based on biochemical analysis and molecular dynamics simulation. We found that compound

In order to explore the effect of accounting computer information processing technology on enterprise internal control, this paper puts forward the method of simultaneous equation of panel data. This paper constructs an accounting computer index to measure the accounting computer level of manufacturing enterprises in Shanghai stock market, and studies the relationship between enterprise accounting computer and internal control by using panel data simultaneous equations model. The empirical results show that: first, although the average accounting computer level of manufacturing industry increases year by year, the overall level is low, and there are great differences among sub industries, even within the same industry; Second, the level of accounting computer has a negative impact on the internal control of enterprises, and the internal control of enterprises has a positive impact on the level of accounting computer; Third, enterprise scale and operating years have a significant positive impact on the level of accounting computer. The experimental results show that: from the estimation results of accounting computer equation, firstly, ROA has a significant positive impact on the level of accounting computer; Secondly, the scale and operating age of enterprises positively affect the level of accounting computer, while the nature of ownership and listing age are not related to the level of accounting computer; Finally, document disclosure has a high level of accounting computer, which is consistent with the conclusion of the above descriptive statistics of EMI, which may be related to the mandatory provisions of national laws and regulations on the industry of document disclosure.

This paper examines how news flow affects cross-market volatility spillovers and price discovery process in China’s stock market and index futures market. We find robust evidence confirming dominant predicting power of the stock market in the price discovery process, and presence of asymmetric and persistent volatility effects. The results show that volatility spillovers are bidirectional between stock index futures and spot prices, and news release has significant and positive association with the dynamic conditional correlation between the index spot and the index futures markets. These have important implications for effective hedging and portfolio management decision in emerging markets.

Two outbreaks of severe respiratory infection caused by severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) caused global pandemics and highlighted the importance of preparedness for respiratory CoVs Recently, a third highly pathogenic CoV, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan, Hubei, China and posed a public health crisis worldwide Here, we focus on the recent advances of the novel CoV, and discuss its genomic similarity with other CoVs, transmission, animal model and clinical treatment of coronavirus disease 2019 (COVID-19) induced by SARS-CoV-2, which help epidemic prevention and control, and guide treatment strategies © Journal of Thoracic Disease All rights reserved

Using the comprehensive RavenPack Dow Jones News Analytics (DJNA) database that captures firm-specific news releases and their sentiment scores at high frequencies, we examine the contemporaneous correlation as well as the lead-lag relation between news and return volatility of major commercial banks listed on the Chinese stock market. Contrary to the Sequential Information Arrival Hypothesis (SIAH), most of the Chinese bank stocks do not exhibit significant lead-lag relations between news and volatility. However, there is substantial evidence that news is strongly correlated with return volatility in all the stocks, consistent with the Mixture of Distributions Hypothesis (MDH). Further analysis based on news sentiment scores suggests that positive news arrivals influence return volatility more strongly, compared with negative news. In addition, there is some evidence indicating that news arrivals contribute to the persistence in return volatility.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR–confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20–40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti–SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients’ plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.

Heavy metals are the most important indicator for farmland soil; however, in China, few provincial and national scales of studies have been done on heavy metals. Herein, by retrieving published studies, we calculated the spatial distribution characters and evaluated the health risks of Cu, Zn, Cd, Ni, Pb, Cr, As, and Hg in the farmland soil of 146 cities in China. Results showed that (1) the range (mean) values of eight (metalloid) heavy metals were as follows in mg/kg: Cu 0.236–251.015 (44.604), Zn 0.151–1547.060 (154.203), Cd 0.014–39.100 (1.497), Ni 0.709–554.420 (41.968), Pb 0.327–495.400 (55.143), Cr 0.078–333.510 (70.093), As 0.836–60.000 (12.207), and Hg 0.008–12.190 (0.371). The coefficient of variation values of Cu, Cr, and As displayed moderate variation, and Zn, Cd, Ni, Pb, and Hg displayed high variation (142.148–364.960%). (2) the Igeo values of As, Cu, Cd, Ni, Zn, Cr, Pb, and Hg were − 4.329 to 1.837, − 7.166 to 2.888, − 3.378 to 8.070, − 5.831 to 3.780, − 9.527 to 3.797, − 10.120 to 1.866, − 6.899 to 3.667, and − 3.681 to 6.966, respectively; in many cities, there was some degree of heavy metal pollution of the farmland soil such as Zn in Pingdu, Pb in Huludao, and Hg in Tongguan, Funshun, Huludao, and Qinglong (Igeo > 3); there were no obvious spatial patterns of Cr, Ni, and As, and Zn, Cu, but Cd, Ni, Pb, and Hg mainly located in some cities in the southwest, central or eastern parts of China. (3) Health risk assessment showed that with the exception of Cd, Cr, and As by the respiration route and Ni, Cr, and As through skin exposure, the average amount of daily exposure of the eight (metalloid) heavy metals all showed values for children > adults, and the HQ and HI values were all lower than 1.0, indicating noncarcinogenic risks; calculation of carcinogenic risks showed there were no carcinogenic risks for As, Cr, Ni, and Cd; however, the value for Cr was the maximum and contributed 98.505% of the total.

Human coronavirus NL63 (HCoV-NL63) is primarily associated with common cold in children, elderly and immunocompromised individuals. Outbreaks caused by HCoV-NL63 are rare. Here we report a cluster of HCoV-NL63 cases with severe lower respiratory tract infection that arose in Guangzhou, China, in 2018. Twenty-three hospitalized children were confirmed to be HCoV-NL63 positive, and most of whom were hospitalized with severe pneumonia or acute bronchitis. Whole genomes of HCoV-NL63 were obtained using next-generation sequencing. Phylogenetic and single amino acid polymorphism analyses showed that this outbreak was associated with two subgenotypes (C3 and B) of HCoV-NL63. Half of patients were identified to be related to a new subgenotype C3. One unique amino acid mutation at I507 L in spike protein receptor binding domain (RBD) was detected, which segregated this subgenotype C3 from other known subgenotypes. Pseudotyped virus bearing the I507 L mutation in RBD showed enhanced entry into host cells as compared to the prototype virus. This study proved that HCoV-NL63 was undergoing continuous mutation and has the potential to cause severe lower respiratory disease in humans.

Currently, there is a lack of studies on microplastic pollution in mountain terrains and foothills areas in Northwest China and Central Asia. Here, we collected monthly dusts samples for one year and we studied the distribution, pollution levels, and sources of microplastics in atmospheric dust fall in the Ebinur Lake Basin in Northwest China. Results showed that the average content of dust microplastic on construction land was 28.61 ± 1.13 mg/kg, followed by farmland (20.25 ± 1.56 mg/kg), forest (19.52 ± 1.06 mg/kg), and deserts (8.08 ± 0.56 mg/kg). Regarding different land use types, atmospheric dust reduction dominated on farmland (58.64%), followed by urban area (26.65%), forest (9.76%), and desert (4.95%). Regarding the shape of microplastics, the order of occurrence in dust was film (46.85%) fiber (35.15%) foam(12.35%) fragment (5.65%). In this study, four colors of microplastics were found in dust, and white accounted for the largest proportion (52.15%), followed by transparent (18.65%), black (19.45%), and green (9.75%). The main components of film microplastics in atmospheric dustfall in the Ebinur Lake Basin were PE and PP, and their sources were mainly plastic products in daily life, plastic industrial packaging materials from urban enterprises, broken plastic woven bags, and PET mostly from fabric fragment emissions. The abundance of microplastics in dust was correlated with atmospheric dust pH, EC, and total salt content. The contents of seven heavy metals (Cu, Ni, Cd, Pb, Cr, Mn, and Co) adsorbed by microplastics were also correlated with pH, EC, and total salt content. Our results represent a reference for microplastics pollution prevention in mountain terrains and foothills areas in northwest China and Central Asia.

Objective: Our study aimed to report the clinical features of ATTR-PN with TTR p.Ala117Ser mutation in mainland China. Methods: Thirteen patients from 13 different families diagnosed with p.Ala117Ser ATTR-PN were identified from three centres. Clinical and laboratory data were retrospectively retrieved for analysis. Results: The male/female ratio was 11:2. All patients showed late onset, with the age of onset at 57.8 ± 5.8 years. The initial symptom was numbness of the lower or upper extremities in 9 patients (69.2%). Paraesthesia was present in all patients. Eleven patients (84.6%) had autonomic dysfunction. Cardiac, renal, hepatic, and ocular dysfunctions were noted in 8 (61.5%), 1 (7.7%), 2 (15.4%), and 3 (23.1%) patients, respectively. Nerve conduction studies have shown axonal-type sensorimotor polyneuropathy. The decline in sensory nerve action potentials was more noticeable than in compound muscle action potentials. The nerve damage present in the lower limbs was more severe than that in the upper limbs. Nerve biopsy revealed positive Congo red staining in 7/10 patients (70%). Conclusion: Our study is the largest population report on this rare p.Ala117Ser mutation in mainland China.

The pathogenesis of COVID-19 is still elusive, which impedes disease progression prediction, differential diagnosis, and targeted therapy. Plasma cell-free RNAs (cfRNAs) carry unique information from human tissue and thus could point to resourceful solutions for pathogenesis and host-pathogen interactions. Here, we performed a comparative analysis of cfRNA profiles between COVID-19 patients and healthy donors using serial plasma. Analyses of the cfRNA landscape, potential gene regulatory mechanisms, dynamic changes in tRNA pools upon infection, and microbial communities were performed. A total of 380 cfRNA molecules were up-regulated in all COVID-19 patients, of which seven could serve as potential biomarkers (AUC > 0.85) with great sensitivity and specificity. Antiviral (NFKB1A,IFITM3, andIFI27) and neutrophil activation (S100A8,CD68, andCD63)–related genes exhibited decreased expression levels during treatment in COVID-19 patients, which is in accordance with the dynamically enhanced inflammatory response in COVID-19 patients. Noncoding RNAs, including some microRNAs (let 7 family) and long noncoding RNAs (GJA9-MYCBP) targeting interleukin (IL6/IL6R), were differentially expressed between COVID-19 patients and healthy donors, which accounts for the potential core mechanism of cytokine storm syndromes; the tRNA pools change significantly between the COVID-19 and healthy group, leading to the accumulation of SARS-CoV-2 biased codons, which facilitate SARS-CoV-2 replication. Finally, several pneumonia-related microorganisms were detected in the plasma of COVID-19 patients, raising the possibility of simultaneously monitoring immune response regulation and microbial communities using cfRNA analysis. This study fills the knowledge gap in the plasma cfRNA landscape of COVID-19 patients and offers insight into the potential mechanisms of cfRNAs to explain COVID-19 pathogenesis.

COVID-19 is a huge threat to global health. Due to the lack of definitive etiological therapeutics currently, effective disease monitoring is of high clinical value for better healthcare and management of the large number of COVID-19 patients. In this study, we recruited 37 COVID-19 patients, collected 176 blood samples upon diagnosis and during treatment, and analyzed cell-free DNA (cfDNA) in these samples. We report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA characteristics reflect patient-specific physiological conditions during treatment. Further analysis on tissue origin tracing of cfDNA reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, we demonstrate the translational merit of cfDNA as valuable analyte for effective disease monitoring, as well as tissue injury assessment in COVID-19 patients.

Cardiovascular diseases (CVD) are common in maintenance hemodialysis (MHD) patients, and vascular calcification is associated with the incidence of CVD. Malnourished MHD patients are particularly prone to CVD events. Thus far, there is no clear explanation for the relationship of nutrition status with vascular calcification; therefore, we investigated the relationship between malnutrition and vascular calcification. One hundred thirty-one patients underwent laboratory testing, assessment of vascular calcification, modified quantitative subjective global assessment (MQSGA), bioelectrical impedance analysis (BIA), and anthropometric measurements. The patients were divided into two groups based on the presence or absence of coronary artery calcification (CAC), and nutritional statuses were compared between the two groups. The MQSGA score was higher in the CAC group (mean 10.9 ± 1.81) than in the no-CAC group (mean 10.2 ± 1.51); in addition, the mean phase angle (PA) value was significantly lower in the CAC group than in the no-CAC group. Stratification according to CAC score showed that age, Kt/V, incidence of valve calcification, incidence of abdominal aortic calcification, MQSGA score, and blood cell mass were related to the severity of CAC. In addition, quartile analysis revealed that MQSGA score and PA value were related to the incidence and severity of vascular calcification. Binary regression analysis showed that MQSGA score, age, hemoglobin level, and high-density lipoprotein level were independent risk factors for dialysis-related CAC. Patients on MHD who exhibited malnutrition were more likely to have vascular calcification, especially CAC. Namely, the higher the MQSGA score, the lower the PA, and the more likely the occurrence of CAC.

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus disease 2019 (COVID-19). However, the microbial composition of the respiratory tract and other infected tissues as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19 patients remain unclear. Between 27 January and 26 February 2020, serial clinical specimens (sputum, nasal and throat swab, anal swab and feces) were collected from a cohort of hospitalized COVID-19 patients, including 8 mildly and 15 severely ill patients in Guangdong province, China. Total RNA was extracted and ultra-deep metatranscriptomic sequencing was performed in combination with laboratory diagnostic assays. We identified distinct signatures of microbial dysbiosis among severely ill COVID-19 patients on broad spectrum antimicrobial therapy. Co-detection of other human respiratory viruses (including human alphaherpesvirus 1, rhinovirus B, and human orthopneumovirus) was demonstrated in 30.8% (4/13) of the severely ill patients, but not in any of the mildly affected patients. Notably, the predominant respiratory microbial taxa of severely ill patients were Burkholderia cepacia complex (BCC), Staphylococcus epidermidis, or Mycoplasma spp. (including M. hominis and M. orale). The presence of the former two bacterial taxa was also confirmed by clinical cultures of respiratory specimens (expectorated sputum or nasal secretions) in 23.1% (3/13) of the severe cases. Finally, a time-dependent, secondary infection of B. cenocepacia with expressions of multiple virulence genes was demonstrated in one severely ill patient, which might accelerate his disease deterioration and death occurring one month after ICU admission. Our findings point to SARS-CoV-2-related microbial dysbiosis and various antibiotic-resistant respiratory microbes/pathogens in hospitalized COVID-19 patients in relation to disease severity. Detection and tracking strategies are needed to prevent the spread of antimicrobial resistance, improve the treatment regimen and clinical outcomes of hospitalized, severely ill COVID-19 patients.

Additional file 2: Fig. S1. Correlation of estimated alternative allele frequencies between metatranscriptomic and hybrid capture data. Fig. S2. Correlation of estimated minor alternative allele frequencies between biological replicates. Fig. S3. Correlation between sequencing depth and detected iSNVs. Fig. S4. Number of iSNV among three codon positions. Fig. S5. Haplotype frequency of proximal iSNVs within the gastrointestinal tract of patient P01.

BackgroundSince early February 2021, the causative agent of COVID-19, SARS-CoV-2, has infected over 104 million people with more than 2 million deaths according to official reports. The key to understanding the biology and virus-host interactions of SARS-CoV-2 requires the knowledge of mutation and evolution of this virus at both inter- and intra-host levels. However, despite quite a few polymorphic sites identified among SARS-CoV-2 populations, intra-host variant spectra and their evolutionary dynamics remain mostly unknown.MethodsUsing high-throughput sequencing of metatranscriptomic and hybrid captured libraries, we characterized consensus genomes and intra-host single nucleotide variations (iSNVs) of serial samples collected from eight patients with COVID-19. The distribution of iSNVs along the SARS-CoV-2 genome was analyzed and co-occurring iSNVs among COVID-19 patients were identified. We also compared the evolutionary dynamics of SARS-CoV-2 population in the respiratory tract (RT) and gastrointestinal tract (GIT).ResultsThe 32 consensus genomes revealed the co-existence of different genotypes within the same patient. We further identified 40 intra-host single nucleotide variants (iSNVs). Most (30/40) iSNVs presented in a single patient, while ten iSNVs were found in at least two patients or identical to consensus variants. Comparing allele frequencies of the iSNVs revealed a clear genetic differentiation between intra-host populations from the respiratory tract (RT) and gastrointestinal tract (GIT), mostly driven by bottleneck events during intra-host migrations. Compared to RT populations, the GIT populations showed a better maintenance and rapid development of viral genetic diversity following the suspected intra-host bottlenecks.ConclusionsOur findings here illustrate the intra-host bottlenecks and evolutionary dynamics of SARS-CoV-2 in different anatomic sites and may provide new insights to understand the virus-host interactions of coronaviruses and other RNA viruses.

As of middle May 2020, the causative agent of COVID-19, SARS-CoV-2, has infected over 4 million people with more than 300 thousand death as official reports1,2. The key to understanding the biology and virus-host interactions of SARS-CoV-2 requires the knowledge of mutation and evolution of this virus at both inter- and intra-host levels. However, despite quite a few polymorphic sites identified among SARS-CoV-2 populations, intra-host variant spectra and their evolutionary dynamics remain mostly unknown. Here, using deep sequencing data, we achieved and characterized consensus genomes and intra-host genomic variants from 32 serial samples collected from eight patients with COVID-19. The 32 consensus genomes revealed the coexistence of different genotypes within the same patient. We further identified 40 intra-host single nucleotide variants (iSNVs). Most (30/40) iSNVs presented in single patient, while ten iSNVs were found in at least two patients or identical to consensus variants. Comparison of allele frequencies of the iSNVs revealed genetic divergence between intra-host populations of the respiratory tract (RT) and gastrointestinal tract (GIT), mostly driven by bottleneck events among intra-host transmissions. Nonetheless, we observed a maintained viral genetic diversity within GIT, showing an increased population with accumulated mutations developed in the tissue-specific environments. The iSNVs identified here not only show spatial divergence of intra-host viral populations, but also provide new insights into the complex virus-host interactions.

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory disease in humans. MERS-CoV strains from early epidemic clade A and contemporary epidemic clade B have not been phenotypically characterized to compare their abilities to infect cells and mice. We isolated the clade B MERS-CoV ChinaGD01 strain from a patient infected during the South Korean MERS outbreak in 2015 and compared the phylogenetics and pathogenicity of MERS-CoV EMC/2012 (clade A) and ChinaGD01 (clade B) in vitro and in vivo. Genome alignment analysis showed that most clade-specific mutations occurred in the orf1ab gene, including mutations that were predicted to be potential glycosylation sites. Minor differences in viral growth but no significant differences in plaque size or sensitivity to beta interferon (IFN-β) were detected between these two viruses in vitro. ChinaGD01 virus infection induced more weight loss and inflammatory cytokine production in human DPP4-transduced mice. Viral titers were higher in the lungs of ChinaGD01-infected mice than with EMC/2012 infection. Decreased virus-specific CD4(+) and CD8(+) T cell numbers were detected in the lungs of ChinaGD01-infected mice. In conclusion, MERS-CoV evolution induced changes to reshape its pathogenicity and virulence in vitro and in vivo and to evade adaptive immune response to hinder viral clearance. IMPORTANCE MERS-CoV is an important emerging pathogen and causes severe respiratory infection in humans. MERS-CoV strains from early epidemic clade A and contemporary epidemic clade B have not been phenotypically characterized to compare their abilities to infect cells and mice. In this study, we showed that a clade B virus ChinaGD01 strain caused more severe disease in mice, with delayed viral clearance, increased inflammatory cytokines, and decreased antiviral T cell responses, than the early clade A virus EMC/2012. Given the differences in pathogenicity of different clades of MERS-CoV, periodic assessment of currently circulating MERS-CoV is needed to monitor potential severity of zoonotic disease.

Background The immunogenicity and safety of the sequential schedule of Sabin strain-based inactivated poliovirus vaccine (sIPV) and bivalent oral poliovirus vaccine (bOPV) remains poorly understood in Chinese population. Methods A multi-center, open-label, randomized controlled trial was performed involving 648 healthy infants aged 2 months from Inner Mongolia, Shanxi, and Hebei provinces. These participants were divided into three groups: sIPV-bOPV-bOPV, sIPV-sIPV-bOPV, and sIPV-sIPV-sIPV. Doses were administered sequentially at age 2, 3, and 4 months. Neutralisation assays were tested using sera collected at 2 months and 5 months. Results A total of 569 were included in the per-protocol analysis. The seroconversion rates of poliovirus type 1 and 3 were 100% in all three groups, the seroconversion rate of poliovirus type 2 was 91.53% (173/189) (95% CI: 86.62–95.08) in the sIPV-bOPV-bOPV group, 98.38% (182/185) (95% CI: 95.33–99.66) in the sIPV-sIPV-bOPV group, and 99.49% (194/195) (95% CI: 97.18–99.99) in the sIPV-sIPV-sIPV group. For the seroconversion rate of poliovirus types 1 and 3, the sIPV-bOPV-bOPV and sIPV-sIPV-bOPV groups were non-inferior to the sIPV-sIPV-sIPV group. For the seroconversion rate of poliovirus type 2, the sIPV-sIPV-bOPV group was non-inferior to the sIPV-sIPV-sIPV group, and the sIPV-bOPV-bOPV group was inferior to the sIPV-sIPV-sIPV group. All three groups exhibited good safety, with two serious adverse events reported, that were unrelated to vaccine. Conclusions In china, a new vaccination schedule that including 2 doses of IPV in the national immunization programs is essential. Trial registration ClinicalTrials.govNCT04054492.

We report the complete genome sequences of five human coronavirus NL63 (HCoV-NL63) strains obtained using next-generation sequencing. The five HCoV-NL63 strains were obtained from hospitalized children with severe acute respiratory infection detected in Guangdong, China. This study provides several complete genomes of HCoV-NL63 and improves our understanding of HCoV-NL63 evolution in China.

SARS-CoV-2 caused a major outbreak of severe pneumonia (COVID-19) in humans. Viral RNA was detected in multiple organs in COVID-19 patients. However, infectious SARS-CoV-2 was only isolated from respiratory specimens. Here, infectious SARS-CoV-2 was successfully isolated from urine of a COVID-19 patient. The virus isolated could infect new susceptible cells and was recognized by its’ own patient sera. Appropriate precautions should be taken to avoid transmission from urine.

The Chinese renminbi (RMB) currency system has undergone several major developments in the past two decades, including the adoption of a managed floating system since July 2005, the expansion of an offshore RMB non-deliverable forward (NDF) market, and the relaxation of certain regulatory controls to promote the increased use of the RMB in the region. These developments have sparked intense debate on the potential of RMB internationalization and its pros and cons. In view of these developments, this paper provides a comprehensive analysis of the dynamics of the RMB in both the spot and NDF markets since 2005 by examining the role and significance of the RMB NDF in the price discovery process and in predicting the volatility dynamics of the RMB markets. The results indicate that asymmetric volatility effects are significant for several NDF contract maturities and the spot-NDF correlations are significantly time-varying. Moreover, shocks to the volatility levels are highly persistent. Causality tests on the spot and NDF volatilities further suggest that the NDF markets impact the future fluctuations of the spot market, but the spot market does not have predictive power for the volatility of the NDF markets. Public information flows are found to have a significantly positive impact on the spot-forward conditional correlations. These findings have important implications for market linkages and effective hedging strategies.

This paper studies the role and impact of credit constraints on firm’s export behavior. By using firm-level data from big data matching out of China’s Customs Database and Chinese Industrial Enterprise Database, we study the foreign market entry order strategy of the Chinese exporters and assess the role of credit constraints in the process of internationalization. The results confirm the negative effect of credit constraints on firms’ exporting behavior and entry-time decision. Firms with less credit constraints are more likely to be a pioneer in the foreign market, and those severely credit constrained firms are prevented from doing so because they lack sufficient liquidity. Our robustness tests with different product categories and ownership confirm the evidence. It is also found that a firm’s choice decision for being a pioneer or a follower in exporting each new product-market combination is jointly determined by the firm-level and host-country-level characteristics, and that firms with larger scale, higher productivity, lower production costs and more intense competition are more likely to be pioneers. We also find that the entry timing decision of the followers is influenced by the pioneers’ performance and product category. The results further confirm the existence of crowding out effect and spillover effect between pioneers and followers, and have important policy implications for China’s further financial (credit) market reform and for internationalizing Chinese MNEs.

In this paper we investigate the current tensions for pedagogic change in the Chinese higher education system, and explore how the intricate interplay between the stakeholder relationships drives and mediates the system, and impacts on potential pedagogy. To achieve these goals, this study takes an inductive theory-building approach to gather the unique perceptions of 66 Chinese academics, and critically analyses the findings based through an Activity Theory framework. The findings indicate that institutional pedagogy is driven generally by regulated knowledge sources, knowledge dissemination, student compliance, parental expectations, examination achievement and pastoral care. The academics were enthusiastic about introducing more interactive, self-paced, authentic and web-based pedagogy, but continually indicated how traditional practice, social expectations, local regulations and economic restraints would frustrate reforming practices. The findings also show how pedagogic reform confronts existing subjectivity, and emphasise the importance of building and disseminating a rationale for changing prior to any pedagogic innovation. The Activity Theory framework demonstrates how potential pedagogic change has to be preceded by changing the understanding of stakeholders about the new goals and practices of learning. This study and the results have important implications for restructuring and reforming Chinese higher education system to meet future global and societal demands.

The aim of this study was to forecast the Singapore gross domestic product (GDP) growth rate by employing the mixed‐data sampling (MIDAS) approach using mixed and high‐frequency financial market data from Singapore, and to examine whether the high‐frequency financial variables could better predict the macroeconomic variables. We adopt different time‐aggregating methods to handle the high‐frequency data in order to match the sampling rate of lower‐frequency data in our regression models. Our results showed that MIDAS regression using high‐frequency stock return data produced a better forecast of GDP growth rate than the other models, and the best forecasting performance was achieved by using weekly stock returns. The forecasting result was further improved by performing intra‐period forecasting.

We test the impact of stock split rule changes on liquidity behavior in Bursa Malaysia during 2004–2020. Using event study methodology, this study examines stock liquidity on and around stock split days through three subperiods of study, including the first (2004–2006), second (2007–2009), and third (2010–2020) period. We find that liquidity improvement is short-lived in the first and second periods, while it is a long-lived phenomenon in the third period. Firms in the first and second period experienced liquidity improvement only on the split announcement day, while it lasts up to a year after the Ex-date for firms in the third period. Our findings also show a liquidity improvement after the Ex-date only in the third period for the groups of firms categorized based on the liquidity, split factor, and other simultaneous announcements. The findings suggest a positive effect of stock split rule changes implemented by the Securities Commission.

Systemic risk contagion is a key issue in the banking sector in maintaining financial system stability. This study is among the first few to use three different distance-to-risk measures to empirically assess the domestic interbank linkages and systemic contagion risk of the Chinese banking industry, by using bivariate dynamic conditional correlation GARCH model on data collected from eight prominent Chinese banks for the period 2006–2018. The results show a relatively high correlation among almost all the banks, suggesting an interconnectedness among the banks. We found evidence that the banking system is exposed to significant domestic contagion risks arising from systemic defaults. Given that Chinese markets deliver weak signals of forthcoming stress in banking sectors, new policy intervention is crucial to resolve the hidden stress in the system. The results have important policy implications and will provide scholars and policymakers further insight into the risk contagion originating from interbank networks.

This paper examines the dynamic relationship among stock illiquidity, corporate social responsibility (CSR) news release and media tone. Using news from 93 news publishers, we investigate the circumstance in which public news release is related to illiquidity by employing the EGARCH-M and the FIGARCH models. The results indicate that CSR news release has a negative and significant impact on stock illiquidity, and media tone effect is asymmetric. Both CSR news and other firm specific general news reduce the volatility persistence and long memory property of stock illiquidity. The sources of news releases matter in impacting stock illiquidity.

This paper examines the impact of public information flows on the volatility of the bilateral Chinese Renminbi–US dollar (RMB–USD) exchange rates in the spot, non-deliverable forward (NDF) and futures markets. By using the comprehensive RavenPack Dow Jones News Analytics database that captures Chinese and US macroeconomic news releases and their sentiment scores at high frequencies, we investigate the circumstances in which public news sentiment is related to the volatility of the above exchange rates. To account for the possibility of different volatility regimes in the RMB–USD volatility, a two-state Regime-Switching EGARCH-in-mean (RS-EGARCH-M) model that incorporates the effects of news sentiment is proposed. Our model suggests that news sentiment has a greater impact on reducing volatility persistence in the low-volatility regime (calm state) for all the NDF and futures exchange rates; in contrast, the impact is greater in the high-volatility regime (turbulent state) for the spot rate. Furthermore, depending on the news sources and sentiment, the marginal effects of news on these exchange rates can vary significantly. In particular, compared with the USD news releases, the RMB news releases have a stronger influence on the RMB–USD volatility. Moreover, the impact of negative news sentiment is greater than that of positive news sentiment. However, the effects of RMB–USD volatility on contemporaneous returns are mostly insignificant. Our RS-EGARCH-M model indicates that the estimated smoothing probability of the RMB–USD spot rate can produce consistent identification of the different economic states arising from changes in the macroeconomic and exchange rate policies of the Chinese government. These findings have important implications for China’s exchange rate regime and the process of RMB internationalization.

This paper examines the democracy-growth nexus and its interactive effect on human development by using cross-national panel data spanning over 20 years incorporating the effect of democratization process. We find evidence that the effect from democracy to human development is nonlinear and varies depending on the levels of growth and democracy. The results confirm that the interaction effect of democracy-growth nexus has a positive impact on human development but the effect is sensitive to democratization process and the level of a country's economic development. It is established that democracy is more crucial in developed countries, whereas economic growth is vital in developing countries. The findings imply that the role of democracy in enhancing human development should not be overemphasized as economic growth is vital in the developing countries.