Publications by authors named "Honglin Chen"

267 Publications

Low dose inocula of SARS-CoV-2 Alpha variant transmits more efficiently than earlier variants in hamsters.

Commun Biol 2021 09 20;4(1):1102. Epub 2021 Sep 20.

Department of Microbiology and State Key Laboratory for Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Emerging variants of SARS-CoV-2 have been shown to rapidly replace original circulating strains in humans soon after they emerged. There is a lack of experimental evidence to explain how these natural occurring variants spread more efficiently than existing strains of SARS-CoV-2 in transmission. We found that the Alpha variant (B.1.1.7) increased competitive fitness over earlier parental D614G lineages in in-vitro and in-vivo systems. Using hamster transmission model, we further demonstrated that the Alpha variant is able to replicate and shed more efficiently in the nasal cavity of hamsters than other variants with low dose and short duration of exposure. The capability to initiate effective infection with low inocula may be one of the key factors leading to the rapid transmission of emerging variants of SARS-CoV-2.
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http://dx.doi.org/10.1038/s42003-021-02640-xDOI Listing
September 2021

Multiple basic amino acids in the cleavage site of H7N9 hemagglutinin contribute to high virulence in mice.

J Thorac Dis 2021 Aug;13(8):4650-4660

State Key Laboratory of Respiratory Disease, Institute of Integration of Traditional and Western Medicine, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: Avian influenza A (H7N9) virus has caused more than 1,500 cases of human infection since its emergence in early 2013. Displaying little or no pathogenicity in poultry, but a 40% case-fatality rate in humans, five waves of H7N9 human infections occurred in China during 2013-2017, caused solely by a low pathogenicity strain. However, avian isolates possessing a polybasic connecting peptide in the hemagglutinin (HA) protein were detected in mid-2016, indicating that a highly pathogenic virus had emerged and was co-circulating with the low pathogenicity strains.

Methods: Here we characterize the pathogenicity of a newly emerged human H7N9 variant with a PEVPKRKRTAR/GLF insertion motif at the cleavage site of the HA protein and .

Results: This variant replicates in MDCK cells independently of TPCK-trypsin, which is indicative of high pathogenicity in chickens. The 50% mouse lethal dose (MLD) of this novel isolate was less than 10 plaque forming units (PFU), compared with 3.16×10 for an identical virus lacking the polybasic insertion, indicating a high virulence phenotype.

Conclusions: Our results demonstrate that the multiple basic amino acid insertion in the HA protein of the H7N9 variant confers high virulence in mammals, highlighting a potential risk to humans. Continuous viral surveillance is therefore necessary in the China region to improve pandemic preparedness.
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http://dx.doi.org/10.21037/jtd-21-226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411188PMC
August 2021

The combination of dextran sulphate and polyvinyl alcohol prevents excess aggregation and promotes proliferation of pluripotent stem cells in suspension culture.

Cell Prolif 2021 Sep 13;54(9):e13112. Epub 2021 Aug 13.

Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China.

Objectives: For clinical applications of cell-based therapies, a large quantity of human pluripotent stem cells (hPSCs) produced in standardized and scalable culture processes is required. Currently, microcarrier-free suspension culture shows potential for large-scale expansion of hPSCs; however, hPSCs tend to aggregate during culturing leading to a negative effect on cell yield. To overcome this problem, we developed a novel protocol to effectively control the sizes of cell aggregates and enhance the cell proliferation during the expansion of hPSCs in suspension.

Materials And Methods: hPSCs were expanded in suspension culture supplemented with polyvinyl alcohol (PVA) and dextran sulphate (DS), and 3D suspension culture of hPSCs formed cell aggregates under static or dynamic conditions. The sizes of cell aggregates and the cell proliferation as well as the pluripotency of hPSCs after expansion were assessed using cell counting, size analysis, real-time quantitative polymerase chain reaction, flow cytometry analysis, immunofluorescence staining, embryoid body formation, teratoma formation and transcriptome sequencing.

Results: Our results demonstrated that the addition of DS alone effectively prevented hPSC aggregation, while the addition of PVA significantly enhanced hPSC proliferation. The combination of PVA and DS not only promoted cell proliferation of hPSCs but also produced uniform and size-controlled cell aggregates. Moreover, hPSCs treated with PVA, or DS or a combination, maintained the pluripotency and were capable of differentiating into all three germ layers. mRNA-seq analysis demonstrated that the combination of PVA and DS significantly promoted hPSC proliferation and prevented cell aggregation through improving energy metabolism-related processes, regulating cell growth, cell proliferation and cell division, as well as reducing the adhesion among hPSC aggregates by affecting expression of genes related to cell adhesion.

Conclusions: Our results represent a significant step towards developing a simple and robust approach for the expansion of hPSCs in large scale.
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http://dx.doi.org/10.1111/cpr.13112DOI Listing
September 2021

Intradermal vaccination of live attenuated influenza vaccine protects mice against homologous and heterologous influenza challenges.

NPJ Vaccines 2021 Aug 4;6(1):95. Epub 2021 Aug 4.

Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

We previously developed a temperature-sensitive, and NS1 gene deleted live attenuated influenza vaccine (DelNS1-LAIV) and demonstrated its potent protective efficacy in intranasally vaccinated mice. Here we investigated whether intradermal (i.d.) vaccination induces protective immunity. Our results showed that DelNS1-LAIV intradermal vaccination conferred effective and long-lasting protection against lethal virus challenge in mice. A single intradermal injection of DelNS1-LAIV conferred 100% survival with no weight loss in mice after A(H1N1)09 influenza virus (H1N1/415742Md) challenge. DelNS1-LAIV injection resulted in a significant reduction of lung viral load and reduced airway epithelial cell death and lung inflammatory cytokine responses at day 2 and 4 post challenge. Full protections of mice lasted for 6 months after immunization. In vitro infection of DelNS1-LAIV in monocyte-derived dendritic cells (MoDCs) demonstrated activation of antigen-presenting cells at 33 °C, together with the results of abortive replication of DelNS1-LAIV in skin tissue and strong upregulation of inflammatory cytokines/chemokines expression, our results suggested the strong immunogenicity of this vaccine. Further, we demonstrate that the underlying protection mechanism induced by intradermal DelNS1-LAIV is mainly attributed to antibody responses. Together, this study opens up an alternative route for the administration of LAIV, which may benefit individuals not suitable for intranasal LAIV immunization.
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http://dx.doi.org/10.1038/s41541-021-00359-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339132PMC
August 2021

Cellular 5'-3' mRNA Exoribonuclease XRN1 Inhibits Interferon Beta Activation and Facilitates Influenza A Virus Replication.

mBio 2021 Aug 27;12(4):e0094521. Epub 2021 Jul 27.

Research Center for Emerging Viral Infection, College of Medicine, Chang Gung Universitygrid.145695.a, Taoyuan, Taiwan.

Cellular 5'-3' exoribonuclease 1 (XRN1) is best known for its role as a decay factor, which by degrading 5' monophosphate RNA after the decapping of DCP2 in P-bodies (PBs) in , yeast, and mammals. XRN1 has been shown to degrade host antiviral mRNAs following the influenza A virus (IAV) PA-X-mediated exonucleolytic cleavage processes. However, the mechanistic details of how XRN1 facilitates influenza A virus replication remain unclear. In this study, we discovered that XRN1 and nonstructural protein 1 (NS1) of IAV are directly associated and colocalize in the PBs. Moreover, XRN1 downregulation impaired viral replication while the viral titers were significantly increased in cells overexpressing XRN1, which suggest that XRN1 is a positive regulator in IAV life cycle. We further demonstrated that the IAV growth curve could be suppressed by adenosine 3',5'-bisphosphate (pAp) treatment, an inhibitor of XRN1. In virus-infected knockout cells, the phosphorylated interferon regulatory factor 3 (p-IRF3) protein, interferon beta () mRNA, and interferon-stimulated genes (ISGs) were significantly increased, resulting in the enhancement of the host innate immune response and suppression of viral protein production. Our data suggest a novel mechanism by which the IAV hijacks the cellular XRN1 to suppress the host innate immune response and to facilitate viral replication. A novel mechanistic discovery reveals that the host decay factor XRN1 contributes to influenza A virus replication, which exploits XRN1 activity to inhibit RIG-I-mediated innate immune response. Here, we identified a novel interaction between viral NS1 and host XRN1. Knockdown and knockout of XRN1 expression in human cell lines significantly decreased virus replication while boosting RIG-I-mediated interferon immune response, suggesting that XRN1 facilitates influenza A virus replication. The pAp effect as XRN1 inhibitor was evaluated; we found that pAp was capable of suppressing viral growth. To our knowledge, this study shows for the first time that a negative-strand and nucleus-replicating RNA virus, as influenza A virus, can hijack cellular XRN1 to suppress the host RIG-I-dependent innate immune response. These findings provide new insights suggesting that host XRN1 plays a positive role in influenza A virus replication and that the inhibitor pAp may be used in novel antiviral drug development.
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http://dx.doi.org/10.1128/mBio.00945-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406323PMC
August 2021

Single-Dose Immunization With a Chimpanzee Adenovirus-Based Vaccine Induces Sustained and Protective Immunity Against SARS-CoV-2 Infection.

Front Immunol 2021 28;12:697074. Epub 2021 Jun 28.

Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

The development of a safe and effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we aim to develop novel SARS-CoV-2 vaccines based on a derivative of less commonly used rare adenovirus serotype AdC68 vector. Three vaccine candidates were constructed expressing either the full-length spike (AdC68-19S) or receptor-binding domain (RBD) with two different signal sequences (AdC68-19RBD and AdC68-19RBDs). Single-dose intramuscular immunization induced robust and sustained binding and neutralizing antibody responses in BALB/c mice up to 40 weeks after immunization, with AdC68-19S being superior to AdC68-19RBD and AdC68-19RBDs. Importantly, immunization with AdC68-19S induced protective immunity against high-dose challenge with live SARS-CoV-2 in a golden Syrian hamster model of SARS-CoV-2 infection. Vaccinated animals demonstrated dramatic decreases in viral RNA copies and infectious virus in the lungs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in rhesus macaques. Taken together, these results confirm that AdC68-19S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.
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http://dx.doi.org/10.3389/fimmu.2021.697074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273614PMC
July 2021

Evaluation of the short-term efficacy of local analgesic (lidocaine) and opioid analgesic (sufentanil) on patients with centrally mediated abdominal pain syndrome: a randomized controlled trial.

Therap Adv Gastroenterol 2021 24;14:17562848211021783. Epub 2021 Jun 24.

Department of Gastroenterology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Wu Hou District, Chengdu, Sichuan 610041, China.

Background: Centrally mediated abdominal pain syndrome (CAPS) is characterized by continuous or frequently recurring abdominal pain and can result in functional loss across several life domains. The efficacy of the present management methods has not been established yet. We performed a prospective randomized controlled trial to explore the short-term efficacy of local analgesic (lidocaine) and opioid analgesic (sufentanil) in patients with CAPS.

Methods: We consecutively enrolled 130 patients who met the Rome IV CAPS criteria and divided them into the sufentanil + lidocaine (S + L) group and sufentanil (S) group. Patients completed the pain rating scales, including the numeric rating scale (NRS) and verbal rating scale (VRS), 60 min before colonoscopy. All the patients were initially administered sufentanil. In the S + L group, we sprayed a 5 ml solution of lidocaine on the surface of ascending, transverse, descending, and sigmoid colon during colonoscope withdrawal, while 5 ml saline was sprayed in the S group. Follow up was performed 1 day, 3 days, 1 week, 2 weeks, 1 month, and 3 months after colonoscopy, to complete the pain scaling.

Results: A comparison of the NRS and VRS showed that there were no significant differences between the S + L and S groups and within each group ( > 0.05).

Conclusions: Local analgesic lidocaine and opioid analgesic sufentanil showed negative efficacy during short-term observation. The opioid receptor blocker sufentanil did not worsen symptoms in patients with CAPS after colonoscopy under general anesthesia in the short term.[chictr.org.cn, Chinese Clinical Trial Identifier, ChiCTR-IOR-16008187].
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http://dx.doi.org/10.1177/17562848211021783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237217PMC
June 2021

Correction to: Transmission of H7N9 influenza virus in mice by different infective routes.

Virol J 2021 Jul 6;18(1):140. Epub 2021 Jul 6.

Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical Collage (PUMC); Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, No. 5 Pan Jia Yuan Nan Li, Chaoyang District, Beijing, 100021, China.

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http://dx.doi.org/10.1186/s12985-021-01603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261966PMC
July 2021

Establishment of a 3D model of tumor-driven angiogenesis to study the effects of anti-angiogenic drugs on pericyte recruitment.

Biomater Sci 2021 Sep 14;9(18):6064-6085. Epub 2021 Sep 14.

Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China.

Hepatocellular carcinoma (HCC), as a well-vascularized tumor, has attracted increasing attention in antiangiogenic therapies. Notably, emerging studies reveal that the long-term administration of antiangiogenic drugs induces hypoxia in tumors. Pericytes, which play a vital role in vascular stabilization and maturation, have been documented to be associated with antiangiogenic drug-induced tumor hypoxia. However, the role of antiangiogenic agents in regulating pericyte behavior still remains elusive. In this study, by using immunostaining analysis, we first demonstrated that tumors obtained from HCC patients were highly angiogenic, in which vessels were irregularly covered by pericytes. Therefore, we established a new 3D model of tumor-driven angiogenesis by culturing endothelial cells, pericytes, cancer stem cells (CSCs) and mesenchymal stem cells (MSCs) with microcarriers in order to investigate the effects and mechanisms exerted by antiangiogenic agents on pericyte recruitment during tumor angiogenesis. Interestingly, microcarriers, as supporting matrices, enhanced the interactions between tumor cells and the extracellular matrix (ECM), promoted malignancy of tumor cells and increased tumor angiogenesis within the 3D model, as determined by qRT-PCR and immunostaining. More importantly, we showed that zoledronic acid (ZA) reversed the inhibited pericyte recruitment, which was induced by sorafenib (Sora) treatment, through fostering the expression and activation of ErbB1/ErbB2 and PDGFR-β in pericytes, in both an 3D model and an xenograft HCC mouse model. Hence, our model provides a more pathophysiologically relevant platform for the assessment of therapeutic effects of antiangiogenic compounds and identification of novel pharmacological targets, which might efficiently improve the benefits of antiangiogenic treatment for HCC patients.
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http://dx.doi.org/10.1039/d0bm02107eDOI Listing
September 2021

Effect of physical frailty on elder mistreatment in a national survey: examining psychological vulnerability, housework involvement, and financial independence as mediators.

Int Psychogeriatr 2021 Jun 15:1-11. Epub 2021 Jun 15.

School of Social Development and Public Policy, Fudan University, Shanghai, China.

Objectives: To explore the prevalence of EM in an older Chinese population and examine the mediating role of three psychosocial variables - psychological vulnerability, housework involvement, and financial independence - in the relationship between physical frailty and EM.

Design: Cross-sectional analysis.

Setting: The data source was the Third Survey on Chinese Women's Social Status (SCSSW), which is a nationwide decennial survey conducted in 2010.

Participants: Community-dwelling adults aged 60 and older who participated in SCSSW (N = 3516).

Measurements: The past-year prevalence of EM and its seven subtypes, physical frailty, psychological vulnerability, housework involvement, financial independence, and demographic characteristics.

Results: The past-year prevalence of EM was 4% among Chinese older adults, with psychological abuse being the most common subtype (3.9%). A higher level of physical frailty had a direct influence on EM. Older adults with higher levels of physical frailty were more likely to have higher levels of psychological vulnerability (anxiety, loneliness, and uselessness) and lower levels of housework involvement, which further correlated with increased risk of EM. Frail Chinese older adults were less likely to have financial independence, which in turn, surprisingly predicted a lower probability of EM.

Conclusions: In this nationally representative sample, we provided the first evidence of the prevalence of EM among Chinese older adults and expanded the global understanding of EM by examining the mediating role of three psychosocial variables. Future studies are warranted to corroborate our findings and identify factors contributing to the complex mechanism of EM.
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http://dx.doi.org/10.1017/S1041610221000739DOI Listing
June 2021

A novel C-type lectin from Crassostrea gigas involved in the innate defense against Vibrio alginolyticus.

Biochem Biophys Res Commun 2021 Aug 11;566:155-163. Epub 2021 Jun 11.

Guangxi Key Laboratory of Beibu Gulf Marine Biodiversity Conservation, Ocean College, Beibu Gulf University, Qinzhou, 535011, China; College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address:

C-type lectins (CTLs) are important immune molecules that participate in invertebrate defense response. In the present work, a novel structural CTL (CgLec-4E) was identified from Crassostrea gigas, which encodes 237 amino acids (aa) with an extra long chain of aa and in the C-type CRD domain with EPA, QPG and WHD mutated motifs respectively. rCgLec-4E could agglutinate and inhibit the growth of Vibrio alginolyticus, except Chlorella, which might be relevant to three mutated motifs. CgLec-4E was mainly expressed in digestive gland, and its expression level was significantly up-regulated post V. alginolyticus challenge, indicating that the high expression of CgLec-4E could provide necessary mucosal immune protections and might involve in food particle recognition for C. gigas. Moreover, the subcellular locations indicated that CgLec-4E might play different roles in the immune response. Taken together, our results enrich our understanding of the structures and function of CTLs in invertebrates.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.092DOI Listing
August 2021

Widowhood and depression among Chinese older adults: examining coping styles and perceptions of aging as mediators and moderators.

Aging Ment Health 2021 Jun 12:1-9. Epub 2021 Jun 12.

Department of Social Work and Social Administration, The University of Hong Kong, Hong Kong, Hong Kong.

Based on the stress-coping framework, this study examined the role of coping styles and perceptions of aging in the relationship between widowhood and depression through two alternative pathways-mediation and moderation-with a national probability sample of older adults in China.Method: The data came from the baseline wave of the China Longitudinal Aging Social Survey of 2014. Our final sample featured 8,404 older adults. The results of structural equation modeling showed a good fit for the total sample (NFI = .909, IFI = .916, GFI = .963, RMSEA = .038) and indicated the significant direct impact of widowhood on depression among Chinese older adults. Moreover, the findings of mediating effects found compared with a married group, widowed older adults used less problem-focused coping and had more negative perceptions of aging, which in turn, predicted higher depression; they were also more likely to use emotion-focused coping, which in turn, predicted lower depression. The results of moderation analysis demonstrated that a higher level of negative perceptions of aging significantly worsened the adverse effects of widowhood on depression. Overall, our findings highlight the importance of a cognitive approach to targeting programs for widowed older adults in China, with a focus on strengthening their abilities to alter maladaptive copings styles and reauthor their life narratives.
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http://dx.doi.org/10.1080/13607863.2021.1935455DOI Listing
June 2021

Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection.

Mol Cell 2021 07 24;81(13):2851-2867.e7. Epub 2021 May 24.

MRC-University of Glasgow Centre for Virus Research, G61 1QH Glasgow, Scotland, UK; Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control its life cycle remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively the cellular and viral RBPs that are involved in SARS-CoV-2 infection. We reveal that SARS-CoV-2 infection profoundly remodels the cellular RNA-bound proteome, which includes wide-ranging effects on RNA metabolic pathways, non-canonical RBPs, and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Among them are several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.
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http://dx.doi.org/10.1016/j.molcel.2021.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142890PMC
July 2021

Mammalian cells use the autophagy process to restrict avian influenza virus replication.

Cell Rep 2021 Jun;35(10):109213

State Key Laboratory for Emerging Infectious Diseases, InnoHK Centre for Virology, Vaccinology, and Therapeutics, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address:

Host adaptive mutations in the influenza A virus (IAV) PB2 protein are critical for human infection, but their molecular action is not well understood. We observe that when IAV containing avian PB2 infects mammalian cells, viral ribonucleoprotein (vRNP) aggregates that localize to the microtubule-organizing center (MTOC) are formed. These vRNP aggregates resemble LC3B-associated autophagosome structures, with aggresome-like properties, in that they cause the re-distribution of vimentin. However, electron microscopy reveals that these aggregates represent an accumulation of autophagic vacuoles. Compared to mammalian-PB2 virus, avian-PB2 virus induces higher autophagic flux in infected cells, indicating an increased rate of autophagosomes containing avian vRNPs fusing with lysosomes. We found that p62 is essential for the formation of vRNP aggregates and that the Raptor-interacting region of p62 is required for interaction with vRNPs through the PB2 polymerase subunit. Selective autophagic sequestration during late-stage virus replication is thus an additional strategy for host restriction of avian-PB2 IAV.
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http://dx.doi.org/10.1016/j.celrep.2021.109213DOI Listing
June 2021

Antigenic Drift of the Hemagglutinin from an Influenza A (H1N1) pdm09 Clinical Isolate Increases its Pathogenicity In Vitro.

Virol Sin 2021 Jun 9. Epub 2021 Jun 9.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510180, China.

The influenza A (H1N1) pdm09 virus emerged in 2009 and has been continuously circulating in humans for over ten years. Here, we analyzed a clinical influenza A (H1N1) pdm09-infected patient case hospitalized for two months in Guangdong (from December 14, 2019 to February 15, 2020). This isolate, named A/Guangdong/LCF/2019 (LCF/19), was genetically sequenced, rescued by reverse genetics, and phylogenetically analyzed in the context of other relevant pdm09 isolates. Compared with earlier isolates, this pdm09 virus's genetic sequence contains four substitutions, S186P, T188I, D190A, and Q192E, of the hemagglutinin (HA) segment at position 186-192 (H3 numbering) in the epitope Sb, and two of which are located at the 190-helix. Phylogenetic analysis indicated that the epitope Sb started undergoing a rapid antigenic change in 2018. To characterize the pathogenicity of this novel substitution motif, a panel of reassortant viruses containing the LCF/2019 HA segment or the chimeric HA segment with the four substitutions were rescued. Kinetic growth data revealed that the reassortant viruses, including the LCF/2019 with the PTIAAQE substitution, propagated faster than those rescued ones having the STTADQQ motif in the epitope Sb in Madin-Darby Canine Kidney (MDCK) cells. The HI test showed that the binding activity of escape mutant to 2018 pdm09 sera was weaker than GLW/2018, suggesting that old vaccines might not effectively protect people from infection. Due to the difference in the selection of vaccine strains, people vaccinated in the southern hemisphere could still suffer a severe infection if infected with this antigenic drift pdm09 virus.
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http://dx.doi.org/10.1007/s12250-021-00401-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188537PMC
June 2021

Characterization of an attenuated SARS-CoV-2 variant with a deletion at the S1/S2 junction of the spike protein.

Nat Commun 2021 05 13;12(1):2790. Epub 2021 May 13.

Department of Microbiology and State Key Laboratory for Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.

SARS-CoV-2 is of zoonotic origin and contains a PRRA polybasic cleavage motif which is considered critical for efficient infection and transmission in humans. We previously reported on a panel of attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction of the spike protein. Here, we characterize pathogenicity, immunogenicity, and protective ability of a further cell-adapted SARS-CoV-2 variant, Ca-DelMut, in in vitro and in vivo systems. Ca-DelMut replicates more efficiently than wild type or parental virus in Vero E6 cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut causes no obvious pathological changes and does not induce elevation of proinflammatory cytokines, but still triggers a strong neutralizing antibody and T cell response in hamsters and mice. Ca-DelMut immunized hamsters challenged with wild type SARS-CoV-2 are fully protected, with little sign of virus replication in the upper or lower respiratory tract, demonstrating sterilizing immunity.
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http://dx.doi.org/10.1038/s41467-021-23166-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119425PMC
May 2021

Network pharmacology integrated with experimental validation reveals the regulatory mechanism of plastrum testudinis in treating senile osteoporosis.

J Ethnopharmacol 2021 Aug 11;276:114198. Epub 2021 May 11.

The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. Electronic address:

Ethnopharmacological Relevance: Plastrum testudinis (PT) has been used in traditional Chinese medicine to treat bone diseases such as senile osteoporosis (SOP) for thousands of years. However, the underlying mechanisms remain largely unknown.

Aim Of The Study: This study aims to investigate the possible molecular mechanism of PT in the treatment of SOP using an integrated strategy of network pharmacology and experimental validation.

Materials And Methods: The compounds of PT and its targets were identified through the BATMAN-TCM database. The SOP-related targets were retrieved from the GeneCards database. Protein-protein interaction information was obtained by inputting the intersection targets into the STRING database. Cytoscape software was used to construct a protein-protein interaction network and a PT-compound-target-SOP network. Using Cytoscape and R software, we conducted GO function and KEGG pathway enrichment analyses. We also conducted in vivo and in vitro experiments to verify the network pharmacology findings.

Results: In total, 6 active compounds and 342 targets of PT were screened, of which 57 common targets were related to SOP. The GO biological process enrichment analysis identified 880 entries, mainly relating to the regulation of hormone response, the cell apoptotic process, the apoptotic signaling pathway, NF-kappaB transcription factor activity, fatty acid transportation, osteoclast differentiation, macrophage activation, and inflammatory response. The KEGG pathway enrichment analysis identified 52 entries, including 14 related signaling pathways, which mainly involved the TNF, MAPK, IL-17, AGE-RAGE, estrogen, relaxin, and other signaling pathways. Our in vivo experiments confirmed that PT alleviates SOP, while the in vitro experiments demonstrated that PT exerts a suppressive effect on osteoclast differentiation and bone resorption in a concentration-dependent manner. Furthermore, we observed that PT downregulates the expression of osteoclast-specific genes, including C-FOS, TNF, and BDNF, in the MAPK signaling pathway.

Conclusion: Through network pharmacology and experimental validation, this study is the first to report that PT downregulates the expression of osteoclast-specific genes, including C-FOS, TNF, and BDNF, in the MAPK signaling pathway, thus exerting a suppressive effect on osteoclast differentiation and bone resorption, which may be the molecular mechanism for PT treatment of SOP.
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http://dx.doi.org/10.1016/j.jep.2021.114198DOI Listing
August 2021

Plastrum testudinis extract suppresses osteoclast differentiation via the NF-κB signaling pathway and ameliorates senile osteoporosis.

J Ethnopharmacol 2021 Aug 8;276:114195. Epub 2021 May 8.

The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. Electronic address:

Ethnopharmacological Relevance: Plastrum testudinis (PT) is a kind of single traditional Chinese medicine that can tonify kidney and strengthen bone. Plastrum testudinis extract (PTE) has been approved to promote the osteogenic differentiation of bone marrow-derived mesenchymal stem cells in vitro. However, the mechanism by which PTE reduces osteoclast differentiation has not yet been reported.

Aim Of The Study: To explore the potential of PTE as a therapeutic treatment for bone loss caused by senile osteoporosis (SOP).

Materials And Methods: We evaluated whether PTE could inhibit RANKL-induced osteoclast differentiation both in vitro and in vivo, and investigated PTE-induced phenotypes of human peripheral blood monocytes.

Results: We found that PTE inhibited osteoclast differentiation and bone resorption in vitro in a concentration-dependent manner and that PTE treatment is most effective during the early stages of osteoclastogenesis. Moreover, we found that PTE could block the NF-κB signaling pathway in vitro, leading to the down-regulation of osteoclast-specific genes including C-FOS and NFATC1. The results from our in vivo mouse study suggest that PTE treatment suppresses osteoclast formation and mitigates bone loss caused by SOP. Notably, we also found that PTE inhibited RANKL-induced osteoclast differentiation in human peripheral blood monocytes.

Conclusion: Our results suggest that PTE treatment suppresses osteoclastogenesis and ameliorates bone loss caused by SOP by selectively blocking the nuclear translocation of NF-κB/p50.
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http://dx.doi.org/10.1016/j.jep.2021.114195DOI Listing
August 2021

Effect of photoperiod on vitamin E and carotenoid biosynthesis in mung bean (Vigna radiata) sprouts.

Food Chem 2021 Oct 21;358:129915. Epub 2021 Apr 21.

Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China. Electronic address:

Light affects the accumulation of vitamin E and carotenoids in many crops. This study investigated the impact of photoperiods on the metabolic regulation of vitamin E and carotenoids in mung bean sprouts considering their dietary health benefits. Mung beans were germinated under three different photoperiods: constant light, semilight and constant dark. Results revealed that the semilight photoperiod was optimum for vitamin E and carotenoid accumulation in mung bean sprouts. DXS was activated in the constant dark and was inhibited by constant light. GGPPS and HPT were sensitive to semilight photoperiod in the vitamin E biosynthetic pathway, playing dominant roles in vitamin E accumulation. The PSY, LCYE, LUT5, LUT1 and ZE genes, which are associated with carotenoid biosynthesis, were activated under semilight treatment and significantly regulated the accumulation of carotenoids. This knowledge improves knowledge on light-mediated regulation of vitamin E and carotenoids in mung bean sprouts.
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http://dx.doi.org/10.1016/j.foodchem.2021.129915DOI Listing
October 2021

Association between primary caregiver type and mortality among Chinese older adults with disability: a prospective cohort study.

BMC Geriatr 2021 04 21;21(1):268. Epub 2021 Apr 21.

Global Health Research Center, Duke Kunshan University, Academic Building 3038, No. 8 Duke Avenue, Kunshan, 215316, Jiangsu, China.

Background: Socio-demographic transitions have dramatically changed the traditional family care settings in China, caused unmet care needs among older adults. However, whether different primary caregiver types have different influences on disabled older adults' health outcomes remain poorly understood. We aimed to examine the association between the type of primary caregiver (e.g., spouse and children) and death among community-dwelling Chinese older adults disabled in activities of daily living.

Methods: We used data from Chinese Longitudinal Healthy Longevity Survey. The analytic sample comprised 4278 eligible adults aged ≥ 80 years. We classified primary caregiver type into five categories: spouse, son/daughter-in-law, daughter/son-in-law, grandchildren, and domestic helper. We used Cox regression model to examine the association between primary caregiver type and all-cause mortality. Covariates included age, sex, residence, years of education, co-residence status, financial independence, whether living with children, number of ADL disability, number of chronic conditions, and self-reported health, cognitive impairment, and caregiving quality.

Results: Married older adults whose primary caregivers were son/daughter-in-law had a 38% higher hazard of death than those who had spouse as the primary caregiver. Married men who received care primarily from son/daughter-in-law or daughter/son-in-law had a 64 and 68% higher hazard of death, respectively, than those whose primary caregiver was spouse. The association between primary caregiver type and mortality among widowed older adults differed between urban and rural areas. Urban residents who had domestic helpers as the primary caregiver had an 16% lower hazard of death, while those living in rural areas had a 50% higher hazard of death, than those having son/daughter-in-law as the primary caregiver.

Conclusions: The quality of care of the primary caregiver may be a risk factor for mortality of disabled older adults in China. Interventions are necessary for reducing unmet needs and managing care burden.
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http://dx.doi.org/10.1186/s12877-021-02219-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061058PMC
April 2021

Multimodal investigation of rat hepatitis E virus antigenicity: Implications for infection, diagnostics, and vaccine efficacy.

J Hepatol 2021 Jun 9;74(6):1315-1324. Epub 2021 Apr 9.

Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong. Electronic address:

Background & Aims: Rat hepatitis E virus (Orthohepevirus species C; HEV-C1) is an emerging cause of viral hepatitis in humans. HEV-C1 is divergent from other HEV variants infecting humans that belong to Orthohepevirus species A (HEV-A). This study assessed HEV-C1 antigenic divergence from HEV-A and investigated the impact of this divergence on infection susceptibility, serological test sensitivity, and vaccine efficacy.

Methods: Immunodominant E2s peptide sequences of HEV-A and HEV-C1 were aligned. Interactions of HEV-C1 E2s and anti-HEV-A monoclonal antibodies (mAbs) were modeled. Recombinant peptides incorporating E2s of HEV-A (HEV-A4 p239) and HEV-C1 (HEV-C1 p241) were expressed. HEV-A and HEV-C1 patient sera were tested using antibody enzymatic immunoassays (EIA), antigen EIAs, and HEV-A4 p239/HEV-C1 p241 immunoblots. Rats immunized with HEV-A1 p239 vaccine (Hecolin), HEV-A4 p239 or HEV-C1 p241 peptides were challenged with a HEV-C1 strain.

Results: E2s sequence identity between HEV-A and HEV-C1 was only 48%. There was low conservation at E2s residues (23/53; 43.4%) involved in mAb binding. Anti-HEV-A mAbs bound HEV-C1 poorly in homology modeling and antigen EIAs. Divergence resulted in low sensitivity of commercial antigen (0%) and antibody EIAs (10-70%) for HEV-C1 diagnosis. Species-specific HEV-A4 p239/HEV-C1 p241 immunoblots accurately differentiated HEV-A and HEV-C1 serological profiles in immunized rats (18/18; 100%) and infected-patient sera (32/36; 88.9%). Immunization with Hecolin and HEV-A4 p239 was partially protective while HEV-C1 p241 was fully protective against HEV-C1 infection in rats.

Conclusions: Antigenic divergence significantly decreases sensitivity of hepatitis E serodiagnostic assays for HEV-C1 infection. Species-specific immunoblots are useful for diagnosing HEV-C1 and for differentiating the serological profiles of HEV-A and HEV-C1. Prior HEV-A exposure is not protective against HEV-C1. HEV-C1 p241 is an immunogenic vaccine candidate against HEV-C1.

Lay Summary: Rat hepatitis E virus (HEV-C1) is a new cause of hepatitis in humans. Using a combination of methods, we showed that HEV-C1 is highly divergent from the usual cause of human hepatitis (HEV-A). This divergence reduces the capacity of existing tests to diagnose HEV-C1 and also indicates that prior exposure to HEV-A (via infection or vaccination) is not protective against HEV-C1.
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http://dx.doi.org/10.1016/j.jhep.2020.12.028DOI Listing
June 2021

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation.

Cell 2021 05 30;184(10):2618-2632.e17. Epub 2021 Mar 30.

Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.
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http://dx.doi.org/10.1016/j.cell.2021.03.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008343PMC
May 2021

Effect of different factors on treatment of oily wastewater by TiO/AlO-PVDF ultrafiltration membrane.

Environ Technol 2021 Apr 18:1-9. Epub 2021 Apr 18.

School of Environmental Science and Engineering, Hainan University, Haikou, People's Republic of China.

An ultrafiltration membrane developed by our research group was applied to treat simulated emulsified oil wastewater. ATR-FTIR, SEM, TEM, and Zeta potential analyzes demonstrated that the modified ultrafiltration membrane (MM) has excellent stability and anti-fouling capacity than origin membrane (OM), which possesses a pure water flux of 260 L·m·h and oil/water (o/w) rejection of 98.5 ± 0.33%. Inorganic salt CaCl has more considerable influence than MgSO and NaCl under the same mass concentration in the two membranes UF process. Along with concentration increasing, flux sharply reduces; meanwhile, the rejection has an opposite trend. Moreover, permeation flux has a maximum value, and the rejection also gets its optimal state under neutral conditions during the pH value of 2-12. The membrane also exhibits excellent anti-fouling performance and anti- o/w adsorption properties with an adsorption rate below 0.8% compared with OM, which has an adsorption rate of nearly 2.1%, respectively. A kind of new UF membrane developed by our research group was applied to treat simulated o/w. ATR-FTIR, SEM, TEM, and Zeta potential analyzes demonstrated that PVDF-AlO/TiO material has excellent stability and anti-fouling capacity. CaCl has the greatest influence than MgSO and NaCl under the same mass concentration. Moreover, permeation flux has maximum value and the rejection also gets its optimal state under neutral conditions during pH 2-12. The membrane also exhibits excellent anti-fouling performance and anti-O/W adsorption properties with adsorption rate below 0.8% compared with OM which has an adsorption rate nearly 2.1%, respectively.
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http://dx.doi.org/10.1080/09593330.2021.1912832DOI Listing
April 2021

Gender associates with both susceptibility to infection and pathogenesis of SARS-CoV-2 in Syrian hamster.

Signal Transduct Target Ther 2021 03 31;6(1):136. Epub 2021 Mar 31.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, P. R. China.

Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness. To experimentally demonstrate the epidemiological results, we performed animal studies to infect male and female Syrian hamsters with SARS-CoV-2. Remarkably, high viral titer in nasal washings was detectable in male hamsters who presented symptoms of weight loss, weakness, piloerection, hunched back and abdominal respiration, as well as severe pneumonia, pulmonary edema, consolidation, and fibrosis. In contrast with the males, the female hamsters showed much lower shedding viral titers, moderate symptoms, and relatively mild lung pathogenesis. The obvious differences in the susceptibility to SARS-CoV-2 and severity of lung pathogenesis between male and female hamsters provided experimental evidence that SARS-CoV-2 infection and the severity of COVID-19 are associated with gender.
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http://dx.doi.org/10.1038/s41392-021-00552-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009924PMC
March 2021

RALYL increases hepatocellular carcinoma stemness by sustaining the mRNA stability of TGF-β2.

Nat Commun 2021 03 9;12(1):1518. Epub 2021 Mar 9.

Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.

Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-β2 mRNA stability by decreasing N6-methyladenosine (mA) modification. TGF-β signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-β2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC.
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http://dx.doi.org/10.1038/s41467-021-21828-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943813PMC
March 2021

Clofazimine broadly inhibits coronaviruses including SARS-CoV-2.

Nature 2021 05 16;593(7859):418-423. Epub 2021 Mar 16.

Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) in 2012. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.
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http://dx.doi.org/10.1038/s41586-021-03431-4DOI Listing
May 2021

Identification and functional characterization of the transcription factor coding gene in large yellow croaker .

Heliyon 2021 Feb 26;7(2):e06299. Epub 2021 Feb 26.

Guangxi Key Laboratory of Beibu Gulf Marine Biodiversity Conservation, Beibu Gulf University, Qinzhou, 536011, China.

The transcription factor Dp1, as a binding partner, often forms a dimerization complex with typical E2F to play a central role in regulating gene expression during G1/S cell cycle progression. In this study, a full-length cDNA () was successfully cloned and characterized from the large yellow croaker . The nucleotidic sequence of is 1,427 bp long with an open reading frame (ORF) of 1,239 bp encoding a putative protein of 412 amino acids, a 5'-untranslated region of 116 bp and a 3'-untranslated region of 70 bp. Prediction of protein domains showed that PcDp1 contains a DNA-binding domain (DBD) with a DEF box, a dimerization domain and an acidic region at with transcription activity. Homology comparisons indicated that PcDp1 shared the highest sequence identity of 98.55% with dp1, followed by 88.72% identity with dp1 and a relatively low identity of 78.91-80.55% with its mammalian and amphibian counterparts. The mRNA of showed ubiquitously expression in all analyzed tissues, with the highest level of expression in the body kidney. Moderate expression levels of was found in several immune-related tissues including the gills, head kidney and liver, indicating that PcDp1 might play an important role in osmotic pressure regulation and immune response of the large yellow croaker. The subcellular localization of PcDp1 revealed that it is mainly distributed in the cytoplasm both in COS-7 and parenchymal cells of the spleen, head kidney and kidney tissues. Furthermore, the recombinant PcDp1 exhibited DNA-binding activity to E2F site . In conclusion, these results indicated that PcDp1 may participate in immune regulation and provide a foundation for further study of the regulatory mechanism of Dp1 in teleosts.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921785PMC
February 2021

Gender convergence or divergence in the relationship between late-life depression and multiple stressors: evidence from a national survey in China.

J Women Aging 2021 Mar 10:1-14. Epub 2021 Mar 10.

Department of Social Work, Fudan University, Shanghai, China.

This study aimed to investigate gender convergence or divergence among older adults in China, a Confucian society with strong persistence of gender role differentiation. We examined how multiple stressors influence depression simultaneously, with gender comparison approach. The data were drawn from the China Longitudinal Aging Social Survey study ( = 8,097). Results indicated that older women reported significantly higher levels of depression than men, yet overall depressive symptoms showed many gender similarities. Surprisingly, our analyses supported the hypothesis of gender convergence in stressors predicting late-life depression. Recommendations for practice and further research priorities based on findings are discussed.
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http://dx.doi.org/10.1080/08952841.2021.1894081DOI Listing
March 2021

Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle.

J Virol 2021 04 12;95(9). Epub 2021 Apr 12.

Department of Microbiology, The University of Hong Kong, Hong Kong, China

Influenza A viruses (IAVs) continue to pose an imminent threat to humans due to annual influenza epidemic outbreaks and episodic pandemics with high mortality rates. In this context, the suboptimal vaccine coverage and efficacy, coupled with recurrent events of viral resistance against a very limited antiviral portfolio, emphasize an urgent need for new additional prophylactic and therapeutic options, including new antiviral targets and drugs with new mechanisms of action to prevent and treat influenza virus infection. Here, we characterized a novel influenza A virus nucleoprotein (NP) inhibitor, FA-6005, that inhibited a broad spectrum of human pandemic and seasonal influenza A and B viruses and protects mice against lethal influenza A virus challenge. The small molecule FA-6005 targeted a conserved NP I41 domain and acted as a potentially broad, multimechanistic anti-influenza virus therapeutic since FA-6005 suppressed influenza virus replication and perturbed intracellular trafficking of viral ribonucleoproteins (vRNPs) from early to late stages. Cocrystal structures of the NP/FA-6005 complex reconciled well with concurrent mutational studies. This study provides the first line of direct evidence suggesting that the newly identified NP I41 pocket is an attractive target for drug development that inhibits multiple functions of NP. Our results also highlight FA-6005 as a promising candidate for further development as an antiviral drug for the treatment of IAV infection and provide chemical-level details for inhibitor optimization. Current influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Therefore, there is an urgent need for broad-spectrum inhibitors to address the considerable challenges posed by the rapid evolution of influenza viruses that limit the effectiveness of vaccines and lead to the emergence of antiviral drug resistance. Here, we identified a novel influenza A virus NP antagonist, FA-6005, with broad-spectrum efficacy against influenza viruses, and our study presents a comprehensive study of the mode of action of FA-6005 with the crystal structure of the compound in complex with NP. The influenza virus inhibitor holds promise as an urgently sought-after therapeutic option offering a mechanism of action complementary to existing antiviral drugs for the treatment of influenza virus infection and should further aid in the development of universal therapeutics.
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http://dx.doi.org/10.1128/JVI.01432-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104107PMC
April 2021
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