Publications by authors named "Na-Na Zhang"

57 Publications

Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer.

Eur J Med Chem 2021 Dec 20;229:114055. Epub 2021 Dec 20.

State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550025, PR China. Electronic address:

The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 μM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.
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http://dx.doi.org/10.1016/j.ejmech.2021.114055DOI Listing
December 2021

Long-term stability and protection efficacy of the RBD-targeting COVID-19 mRNA vaccine in nonhuman primates.

Signal Transduct Target Ther 2021 12 24;6(1):438. Epub 2021 Dec 24.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, 100071, Beijing, China.

Messenger RNA (mRNA) vaccine technology has shown its power in preventing the ongoing COVID-19 pandemic. Two mRNA vaccines targeting the full-length S protein of SARS-CoV-2 have been authorized for emergency use. Recently, we have developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor-binding domain (RBD) of SARS-CoV-2 (termed ARCoV), which confers complete protection in mouse model. Herein, we further characterized the protection efficacy of ARCoV in nonhuman primates and the long-term stability under normal refrigerator temperature. Intramuscular immunization of two doses of ARCoV elicited robust neutralizing antibodies as well as cellular response against SARS-CoV-2 in cynomolgus macaques. More importantly, ARCoV vaccination in macaques significantly protected animals from acute lung lesions caused by SARS-CoV-2, and viral replication in lungs and secretion in nasal swabs were completely cleared in all animals immunized with low or high doses of ARCoV. No evidence of antibody-dependent enhancement of infection was observed throughout the study. Finally, extensive stability assays showed that ARCoV can be stored at 2-8 °C for at least 6 months without decrease of immunogenicity. All these promising results strongly support the ongoing clinical trial.
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http://dx.doi.org/10.1038/s41392-021-00861-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703211PMC
December 2021

Transient acquisition of cross-species infectivity during the evolution of SARS-CoV-2.

Natl Sci Rev 2021 Nov 4;8(11):nwab167. Epub 2021 Sep 4.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, China.

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http://dx.doi.org/10.1093/nsr/nwab167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499877PMC
November 2021

Liver involvement in patients with erythropoietic protoporphyria: retrospective analysis of clinicopathological features of 5 cases.

Ann Diagn Pathol 2022 Feb 17;56:151859. Epub 2021 Nov 17.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China. Electronic address:

Erythropoietic protoporphyria (EPP) is a rare inherited disease whose morbidity is about 1:75,000 to 1:200,000. It is caused by the deficiency of porphyrin ferrochelatase (FECH). Liver involvement in EPP is even rarer. The diagnosis of EPP with liver involvement mainly relies on clinical manifestations, laboratory examinations, histopathological examinations and genetic testing, which is still a huge challenge for both clinicians and pathologists. Here, 5 cases of EPP with liver injury were collected, and the clinicopathological features of these patients were analyzed. The clinical manifestations and laboratory examinations varied from person to person, whereas the liver biopsies showed that there were dark brown deposits within the hepatocytes, Kupffer cells, bile canaliculi and the lumen of bile ducts, which was a constant finding by histopathological examination. Gene tests were conducted in two of the five cases, and the results confirmed the diagnosis. Fully understanding of the diseases can help us reduce the rate of missed diagnosis and provide proper treatment as early as possible.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151859DOI Listing
February 2022

Double lock of a potent human therapeutic monoclonal antibody against SARS-CoV-2.

Natl Sci Rev 2021 Mar 18;8(3):nwaa297. Epub 2020 Dec 18.

Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, NIFDC, Beijing 102629, China.

Receptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by SARS-CoV-2. Halting these steps can cure COVID-19. Here we have identified and characterized a potent human monoclonal antibody, HB27, that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations. Remarkably, HB27 can also prevent SARS-CoV-2 membrane fusion. Consequently, a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models. Rhesus macaques showed no obvious adverse events when administrated with 10 times the effective dose of HB27. Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to the ACE2 receptor. Binding of the antibody also restrains any further conformational changes of the receptor binding domain, possibly interfering with progression from the prefusion to the postfusion stage. These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19.
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http://dx.doi.org/10.1093/nsr/nwaa297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798916PMC
March 2021

Prognostic impact of tertiary lymphoid structures in breast cancer prognosis: a systematic review and meta-analysis.

Cancer Cell Int 2021 Oct 15;21(1):536. Epub 2021 Oct 15.

Center for Regenerative and Reconstructive Medicine, Med-X Institute of Western China Science and Technology Innovation Harbour, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China.

Background: Tertiary lymphoid structures (TLSs), organizationally resemble lymph nodes, are frequently present in breast cancer (BCa). It is usually, but not always, associated with a positive prognosis or immunotherapy response in cancer patients. This meta-analysis was performed to assess the prognostic and clinical impact of TLSs in BCa.

Methods: We conducted a systematic search in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and WanFang Database to obtain eligible research data up to May 30, 2021. This meta-analysis is focusing on the studies evaluated the prognostic value of TLSs and the associated clinicopathologic indicators, related gene expression and survival. STATA software 16.0 software was used to assess the prognostic significance and clinical impact of TLSs.

Results: Nine studies involved with 2281 cases were incorporated in this meta-analysis, in which four of them evaluated the prognostic value of TLSs. There are 6 studies assessed the relationship of TLSs and 4 studies investigated the clinicopathologic parameters as well as the key gene expression, respectively. The results showed the presence of TLSs were predicting a better OS (HR = 0.61, 95% CI: 0.51-0.73, p < 0.001) and DFS (HR = 0.40, 95% CI: 0.17-0.93, p < 0.001) of BCa patients. It also revealed that the presence of TLSs was significantly correlated with tumor differentiation (p < 0.001), pTNM stage (p < 0.001), lymph node metastasis (p < 0.001), and TILs density (p < 0.001) of BCa, and the expression of Her2 (p < 0.001), ER (p < 0.001), PR (p < 0.001) and Ki67 (p = 0.009) of the tumor cell.

Conclusion: Our results indicated that high levels of TLSs could predict a favorable prognosis for BCa. Moreover, the TLSs were significantly correlated with the clinicopathological indicators and the critical gene expression of BCa, indicating its potential clinical impact on BCa patients.
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http://dx.doi.org/10.1186/s12935-021-02242-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520238PMC
October 2021

Gm364 coordinates MIB2/DLL3/Notch2 to regulate female fertility through AKT activation.

Cell Death Differ 2021 Oct 11. Epub 2021 Oct 11.

State Key Lab of Reproductive Medicine, Nanjing Medical University, 101 Longmian Ave., Nanjing, 211166, Jiangsu, China.

Many integral membrane proteins might act as indispensable coordinators in specific functional microdomains to maintain the normal operation of known receptors, such as Notch. Gm364 is a multi-pass transmembrane protein that has been screened as a potential female fertility factor. However, there have been no reports to date about its function in female fertility. Here, we found that global knockout of Gm364 decreased the numbers of primordial follicles and growing follicles, impaired oocyte quality as indicated by increased ROS and γ-H2AX, decreased mitochondrial membrane potential, decreased oocyte maturation, and increased aneuploidy. Mechanistically, Gm364 directly binds and anchors MIB2, a ubiquitin ligase, on the membrane. Subsequently, membrane MIB2 ubiquitinates and activates DLL3. Next, the activated DLL3 binds and activates Notch2, which is subsequently cleaved within the cytoplasm to produce NICD2, the intracellular active domain of Notch2. Finally, NICD2 can directly activate AKT within the cytoplasm to regulate oocyte meiosis and quality.
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http://dx.doi.org/10.1038/s41418-021-00861-5DOI Listing
October 2021

Design, synthesis and evaluation of tetrahydrocarbazole derivatives as potential hypoglycemic agents.

Bioorg Chem 2021 10 17;115:105172. Epub 2021 Jul 17.

State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China. Electronic address:

Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.
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http://dx.doi.org/10.1016/j.bioorg.2021.105172DOI Listing
October 2021

Recapitulating Zika Virus Infection in Vagina of Tree Shrew .

Front Cell Infect Microbiol 2021 25;11:687338. Epub 2021 Jun 25.

Faculty of Life Science and Technology, Yunnan Provincial Center for Molecular Medicine, Kunming University of Science and Technology, Kunming, China.

Sexual transmission of Zika Virus (ZIKV) elevates the risk of its dissemination in the female reproductive tract and causes a serious threat to the fetus. However, the available animal models are not appropriate to investigate sexual transmission, dynamics of ZIKV infection, replication, and shedding. The use of tree shrew as a small animal model of ZIKV vaginal infection was assessed in this study. A total of 23 sexually mature female tree shrews were infected with ZIKV GZ01 the intravaginal route. There was no significant difference in change of body weight, and the temperature between ZIKV infected and control animals. Viral RNA loads were detected in blood, saliva, urine, and vaginal douching. ZIKV RNA was readily detected in vaginal lavage of 22 animals (95.65%, 22/23) at 1 dpi, and viral load ranged from 104.46 to 107.35 copies/ml, and the peak of viral load appeared at 1 dpi. The expression of key inflammatory genes, such as IL6, 8, CCL5, TNF-a, and CXCL9, was increased in the spleen of ZIKV infected animals. In the current study, female tree shrews have been successfully infected with ZIKV through the vaginal route for the first time. Interestingly, at first, ZIKV replicates at the local site of infection and then spreads throughout the host body to develop a robust systemic infection and mounted a protective immune response. This small animal model is not only valuable for exploring ZIKV sexual transmission and may also help to explain the cause of debilitating manifestations of the fetus .
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http://dx.doi.org/10.3389/fcimb.2021.687338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270636PMC
July 2021

Fecal Fusobacterium nucleatum harbored virulence gene fadA are associated with ulcerative colitis and clinical outcomes.

Microb Pathog 2021 Aug 20;157:104964. Epub 2021 May 20.

Department of Gastroenterology and Hepatology, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China. Electronic address:

Object: Fusobacterium nucleatum (F.nucleatum), a gram-negative, obligately anaerobe of oral commensal,has been regarded as culprit of periodontal diseases previously and is being unveiled as possible pathogen of gastrointestinal disorders. The key virulence factor of F.nucleatum is FadA adhesin for binding and invading of the host's epithelial cells. Here, we detected fecal F.nucleatum and virulence gene fadA in patients with ulcerative colitis(UC) and evaluated the clinical relevance with UC.

Methods And Subjects: A total of 310 subjects were enrolled including 100 patients with UC, 70 healthy controls (HC), 70 patients with irritable bowel syndrome subtype diarrhea(IBS-D), and 70 colorectal cancer patients(CRC). Stool samples of UC patients compared with healthy controls as well as IBS-D and CRC patients were collected for Polymerase Chain Reaction(PCR) detection of F.nucleatum (based on 16s rRNA) and virulence gene fadA.

Results: The detection rate of 16s rRNA based PCR for F.nucleatum of UC patients(39/100, 39.00%) and CRC(26/70, 37.14%) patients are significantly higher than HC (12/70, 17.14%, P < 0.01) and IBS-D patients (14/70, 20.00%, P < 0.01). Moreover, 19 samples were detected fadA positive from 39 F.nucleatum positive samples of UC patients (19/39, 48.72%), which is significantly higher than HC(2/12, 16.66%, P < 0.05). There were 3 samples detected fadA positive from 14 F.nucleatum positive samples of IBS-D patients(3/14, 21.43%) and 13 out of 26(50.00%) of CRC patients, which were both no significant differences compared with UC patients(21.4% vs 48.72%, P > 0.05; 50.00% vs 48.72%, P > 0.05). For both F.nucleatum and fadA gene positive patients, there were no statistical significances between erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cells(WBC), and hemoglobin compared with negative patients(defined by either F.nucleatum or fadA negative, or both negative). However, it is worth noting that detection rate of F.nucleatum with virulence gene fadA in patients of severe ulcerative colitis was significantly higher than patients with mild and moderate colitis(28.89% vs 10.91%, P < 0.05). In addition, the fecal F.nucleatum and fadA gene positive patients were more likely to have pancolitis other than left-sided colitis(pancolitis/left-sided colitis: 26.92% vs 10.42%, P < 0.05).

Conclusions: The presence of F.nucleatum and fadA gene increased in UC patients, especially in patients with severe colitis and pancolitis. Strains of F.nucleatum harbored virulence gene fadA are suggested to play a role in the pathogenesis of UC.
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http://dx.doi.org/10.1016/j.micpath.2021.104964DOI Listing
August 2021

H NMR-based chemometric metabolomics characterization of soymilk fermented by Bacillus subtilis BSNK-5.

Food Res Int 2020 12 11;138(Pt A):109686. Epub 2020 Oct 11.

Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China. Electronic address:

Microbial fermentation can endow food with unique flavors, increase its nutritional value and enhance functional characteristics. Our previous research has shown that liquid fermentation of soymilk by Bacillus subtilis BSNK-5 imparted new functional properties of to the fermented product via production of nattokinase. In this study, in order to further investigate the changes in the flavor, nutritional quality and functional characteristics of soymilk during fermentation using proton nuclear magnetic resonance (H NMR) metabolomics to monitor the metabolite profile of BSNK-5-fermented soymilk. A total of 44 differential metabolites were identified between BSNK-5-fermented soymilk and uninoculated/unfermented soymilk, among which the levels of flavor-related substances (acetate, isovalerate and 2-methylbutyrate), nutrient-related substances (12 free amino acids), and functional substances (taurine, GABA and genistein) significantly increased after fermentation. These metabolites were closely associated with eight potential metabolic pathways. This work highlighted the significance of BSNK-5 strain in improving the nutritional quality and functional characteristics of fermented soymilk; however, the use of the strain also caused flavor deterioration. This study lays a theoretical foundation for the improvement and development of fermented soy products via liquid fermentation with B. subtilis.
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http://dx.doi.org/10.1016/j.foodres.2020.109686DOI Listing
December 2020

Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection.

Cell Res 2021 01 1;31(1):25-36. Epub 2020 Dec 1.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases/National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.

Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.
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http://dx.doi.org/10.1038/s41422-020-00444-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705443PMC
January 2021

Type-IInterferon-Inducible SERTAD3 Inhibits Influenza A Virus Replication by Blocking the Assembly of Viral RNA Polymerase Complex.

Cell Rep 2020 11;33(5):108342

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Influenza A virus (IAV) infection stimulates a type I interferon (IFN-I) response in host cells that exerts antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). However, most ISGs are poorly studied for their roles in the infection of IAV. Herein, we demonstrate that SERTA domain containing 3 (SERTAD3) has a significant inhibitory effect on IAV replication in vitro. More importantly, Sertad3 mice develop more severe symptoms upon IAV infection. Mechanistically, we find SERTAD3 reduces IAV replication through interacting with viral polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acidic protein (PA) to disrupt the formation of the RNA-dependent RNA polymerase (RdRp) complex. We further identify an 8-amino-acid peptide of SERTAD3 as a minimum interacting motif that can disrupt RdRp complex formation and inhibit IAV replication. Thus, our studies not only identify SERTAD3 as an antiviral ISG, but also provide the mechanism of potential application of SERTAD3-derived peptide in suppressing influenza replication.
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http://dx.doi.org/10.1016/j.celrep.2020.108342DOI Listing
November 2020

GTPases Arf5 and Arl2 function partially distinctly during oocyte meiosis.

J Cell Biochem 2021 02 27;122(2):198-208. Epub 2020 Sep 27.

Nanjing Medical University, Nanjing, Jiangsu, China.

Mammalian female meiosis must be tightly regulated to produce high-quality mature oocytes for subsequent regular fertilization and healthy live birth of the next generation. GTPases control many important signal pathways involved in diverse cellular activities. ADP-ribosylation factor family members (Arfs) in mice possess GTPase activities, and some members have been found to function in meiosis. However, whether other Arfs play a role in meiosis is unknown. In this study, we found that Arl2 and Arf5 are the richest among Arfs in mouse oocytes, and they are more abundant in oocytes than in granular cells. Furthermore, Arl2 and Arf5 depletion both impeded meiotic progression, but by affecting spindles and microfilaments, respectively. Moreover, Arl2 and Arf5 depletion both significantly increased regular reactive oxygen species levels and decreased mitochondrial membrane potential and autophagy, indicating that oocyte quality was damaged by Arl2 and Arf5 depletion. These results suggest that Arl2 and Arf5 are two novel essential GTPases required for oocyte meiosis and quality control.
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http://dx.doi.org/10.1002/jcb.29839DOI Listing
February 2021

A Thermostable mRNA Vaccine against COVID-19.

Cell 2020 09 23;182(5):1271-1283.e16. Epub 2020 Jul 23.

Suzhou Abogen Biosciences Co., Ltd., Suzhou 215123, China. Electronic address:

There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.
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http://dx.doi.org/10.1016/j.cell.2020.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377714PMC
September 2020

Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy.

Science 2020 09 30;369(6511):1603-1607. Epub 2020 Jul 30.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.
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http://dx.doi.org/10.1126/science.abc4730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574913PMC
September 2020

A Mouse Model of SARS-CoV-2 Infection and Pathogenesis.

Cell Host Microbe 2020 07 27;28(1):124-133.e4. Epub 2020 May 27.

Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China. Electronic address:

Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.
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http://dx.doi.org/10.1016/j.chom.2020.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250783PMC
July 2020

Fam70A binds Wnt5a to regulate meiosis and quality of mouse oocytes.

Cell Prolif 2020 Jun 11;53(6):e12825. Epub 2020 May 11.

State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.

Objectives: Little is known about the roles of integral membrane proteins beyond channels, carriers or receptors in meiotic oocytes. The transmembrane protein Fam70A was previously identified as a likely "female fertility factor" in Fox3a-knockout mouse ovaries where almost all follicles underwent synchronous activation and the mice became infertile very early. However, whether Fam70A functions in oocyte meiosis remains unknown. Therefore, the present study aimed to address this question.

Materials And Methods: Co-immunoprecipitation, immunogold labelling-electron microscopy, co-localization and yeast two-hybrid assays were used to verify the interaction. Antibody or small interfering RNA transfection was used to deplete the proteins. Immunofluorescence, immunohistochemistry and live tracker staining were used to examine the localization or characterize phenotypes. Western blot was used to examine the protein level.

Results: Fam70A was enriched in oocyte membranes important for normal meiosis. Fam70A depletion remarkably disrupted spindle assembly, chromosome congression and first polar body extrusion, which subsequently increased aneuploidy and abnormal fertilization. Moreover, Fam70A directly bound Wnt5a, the most abundant Wnt member within oocytes. Depletion of either Fam70A or Wnt5a remarkably increased adenomatous polyposis coli (APC), which stabilizes active β-catenin and microtubules. Consequently, depletion of either Fam70A or Wnt5a remarkably increased p-β-catenin (inactive form) and acetylated tubulin, while APC knockdown remarkably decreased these two. Furthermore, Fam70A depletion remarkably reduced Akt phosphorylation.

Conclusions: Fam70A regulates meiosis and quality of mouse oocytes through both canonical and non-canonical Wnt5a signalling pathways.
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http://dx.doi.org/10.1111/cpr.12825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309945PMC
June 2020

[Advances in synthesis of artemisinin based on plant genetic engineering].

Zhongguo Zhong Yao Za Zhi 2019 Oct;44(19):4285-4292

School of Medicine,Hangzhou Normal University Hangzhou 310036,China Key Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Province Hangzhou 310036,China Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province Hangzhou 310036,China.

Artemisinin is a kind of sesquiterpene lactone containing endoperoxide bridge,which is the most effective anti-malarial drug at present. However,low content of artemisinin in Artemisia annua,ranging from 0. 1%-1. 0% of dry weight,as well as the complicated extraction process have resulted in low yield and high cost of artemisinin,making it difficult to meet market demand.Based on the development of high-throughput sequencing and molecular biology,the related enzyme genes and transcription factors involved in the artemisinin metabolic pathway were cloned and identified. Metabolic engineering and synthetic biology methods to modify the original metabolic pathway of A. annua and genetic engineering in heterologous host cells have become one of the hotspots in this field. Therefore,the molecular mechanism of artemisin biosynthesis,different strategies of genetic modifications of A. annua,and the research status and application prospect of artemisinin synthesis in heterologous host cells( Nicotiana benthamiana,Physcomitrella patens) were summarized in our review,hoping to provide molecular basis and theoretical basis for breeding new varieties of A. annua with high artemisinin output.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20190416.405DOI Listing
October 2019

Zika NS1-induced ER remodeling is essential for viral replication.

J Cell Biol 2020 02;219(2)

State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.

Zika virus (ZIKV), a recently emerged member of the flavivirus family, forms replication compartments at the ER during its lifecycle. The proteins that are responsible for the biogenesis of replication compartments are not well defined. Here, we show that Zika nonstructural protein 1 (NS1)-induced ER remodeling is essential for viral replication. NS1 expressed in the ER lumen induced ER perinuclear aggregation with an ultrastructure resembling that of the replication compartment. Data from model membrane system indicated that the membrane-binding and membrane-remodeling properties of NS1 depend on its hydrophobic insertion into the membrane. These findings demonstrate that NS1 plays a crucial role in flavivirus replication compartment formation by remodeling the ER structure.
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http://dx.doi.org/10.1083/jcb.201903062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041685PMC
February 2020

Single xenotransplant of rat brown adipose tissue prolonged the ovarian lifespan of aging mice by improving follicle survival.

Aging Cell 2019 12 6;18(6):e13024. Epub 2019 Aug 6.

State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Prolonging the ovarian lifespan is attractive and challenging. An optimal clinical strategy must be safe, long-acting, simple, and economical. Allotransplantation of brown adipose tissue (BAT), which is most abundant and robust in infants, has been utilized to treat various mouse models of human disease. Could we use BAT to prolong the ovarian lifespan of aging mice? Could we try BAT xenotransplantation to alleviate the clinical need for allogeneic BAT due to the lack of voluntary infant donors? In the current study, we found that a single rat-to-mouse (RTM) BAT xenotransplantation did not cause systemic immune rejection but did significantly increase the fertility of mice and was effective for more than 5 months (equivalent to 10 years in humans). Next, we did a series of analysis including follicle counting; AMH level; estrous cycle; mTOR activity; GDF9, BMP15, LHR, Sirt1, and Cyp19a level; ROS and annexin V level; IL6 and adiponectin level; biochemical blood indices; body temperature; transcriptome; and DNA methylation studies. From these, we proposed that rat BAT xenotransplantation rescued multiple indices indicative of follicle and oocyte quality; rat BAT also improved the metabolism and general health of the aging mice; and transcriptional and epigenetic (DNA methylation) improvement in F0 mice could benefit F1 mice; and multiple KEGG pathways and GO classified biological processes the differentially expressed genes (DEGs) or differentially methylated regions (DMRs) involved were identical between F0 and F1. This study could be a helpful reference for clinical BAT xenotransplantation from close human relatives to the woman.
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http://dx.doi.org/10.1111/acel.13024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826128PMC
December 2019

The Preparation, Determination of a Flexible Complex Liposome Co-Loaded with Cabazitaxel and β-Elemene, and Animal Pharmacodynamics on Paclitaxel-Resistant Lung Adenocarcinoma.

Molecules 2019 Apr 30;24(9). Epub 2019 Apr 30.

Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, 1378 Wenyi Road, Hangzhou 311121, China.

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and β-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, β-elemene liposome and cabazitaxel-β-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and β-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and β-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and β-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and β-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that β-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.
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http://dx.doi.org/10.3390/molecules24091697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539285PMC
April 2019

Infectivity of Zika virus on primary cells support tree shrew as animal model.

Emerg Microbes Infect 2019 ;8(1):232-241

b Faculty of Life Science and Technology, Yunnan Provincial Center for Molecular Medicine , Kunming University of Science and Technology , Kunming , People's Republic of China.

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused the public health emergency. Recently, we have proved a novel small animal tree shrew was susceptive to ZIKV infection and presented the most common rash symptoms as ZIKV patients. Here we further cultured the primary cells from different tissues of this animal to determine the tissue tropism of ZIKV infection in vitro. The results showed that the primary cells from tree shrew kidney, lung, liver, skin and aorta were permissive to ZIKV infection and could support viral replication by the detection of viral specific RNA intra- and extra-cells. In comparing, the skin fibroblast and vascular endothelial cells were highly permissive to ZIKV infection with high releasing of active virus particles in supernatants proved by its infectivity in established neonatal mouse model. The expressions of ZIKV envelop and nonstructural protein-1, and the effects and strong immune response of primary tree shrew cells were also detected followed by ZIKV infection. These findings provide powerful in vitro cell-level evidence to support tree shrew as animal model of ZIKV infection and may help to explain the rash manifestations in vivo.
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http://dx.doi.org/10.1080/22221751.2018.1559707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455147PMC
July 2019

Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids.

Cell Res 2019 04 27;29(4):265-273. Epub 2019 Feb 27.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, 100071, Beijing, China.

The re-emergence of Zika virus (ZIKV) in the Western Hemisphere has resulted in global public health crisis since 2015. ZIKV preferentially infects and targets human neural progenitor cells (hNPCs) and causes fetal microcephaly upon maternal infection. hNPCs not only play critical roles during fetal brain development, but also persist in adult brain throughout life. Yet the mechanism of innate antiviral immunity in hNPCs remains largely unknown. Here, we show that ZIKV infection triggers the abundant production of virus-derived small interfering RNAs in hNPCs, but not in the more differentiated progenies or somatic cells. Ablation of key RNAi machinery components significantly enhances ZIKV replication in hNPCs. Furthermore, enoxacin, a broad-spectrum antibiotic that is known as an RNAi enhancer, exerts potent anti-ZIKV activity in hNPCs and other RNAi-competent cells. Strikingly, enoxacin treatment completely prevents ZIKV infection and circumvents ZIKV-induced microcephalic phenotypes in brain organoid models that recapitulate human fetal brain development. Our findings highlight the physiological importance of RNAi-mediated antiviral immunity during the early stage of human brain development, uncovering a novel strategy to combat human congenital viral infections through enhancing RNAi.
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http://dx.doi.org/10.1038/s41422-019-0152-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461993PMC
April 2019

The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality.

Aging (Albany NY) 2019 02;11(4):1110-1128

State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, P.R. China.

Tight control of energy metabolism is essential for normal cell function and organism survival. PKM (pyruvate kinase, muscle) isoforms 1 and 2 originate from alternative splicing of PKM pre-mRNA. They are key enzymes in oxidative phosphorylation and aerobic glycolysis, respectively, and are essential for ATP generation. The PKM1:PKM2 expression ratio changes with development and differentiation, and may also vary under metabolic stress and other conditions. Until now, there have been no reports about the function and regulation of PKM isozymes in oocytes. Here, we demonstrate that PKM1 or PKM2 depletion significantly disrupts ATP levels and mitochondrial integrity, and exacerbates free-radical generation and apoptosis in mouse oocytes. We also show that KBTBD8, a female fertility factor in the KBTBD ubiquitin ligase family, selectively regulates PKM1 levels through a signaling cascade that includes Erk1/2 and Aurora A kinases as intermediates. Finally, using RNA sequencing and protein network analysis, we identify several regulatory proteins that may be govern generation of mature PKM1 mRNA. These results suggest KBTBD8 affects PKM1 levels in oocytes via a KBTBD8→Erk1/2→Aurora A axis, and may also affect other essential processes involved in maintaining oocyte quality.
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http://dx.doi.org/10.18632/aging.101802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402520PMC
February 2019

Zika Virus Infection in Tupaia belangeri Causes Dermatological Manifestations and Confers Protection against Secondary Infection.

J Virol 2019 04 3;93(8). Epub 2019 Apr 3.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China

Animal models of Zika virus (ZIKV) infection have recently been established in mice, guinea pigs, and nonhuman primates. Tree shrews () are an emerging experimental animal in biomedical applications, but their susceptibility to ZIKV infection has not been explored. In the present study, we show that subcutaneous inoculation of ZIKV led to rapid viremia and viral secretion in saliva, as well as to typical dermatological manifestations characterized by massive diffuse skin rash on the trunk. Global transcriptomic sequencing of peripheral blood mononuclear cells isolated from ZIKV-infected animals revealed systematic gene expression changes related to the inflammatory response and dermatological manifestations. Importantly, ZIKV infection readily triggered the production of high-titer neutralizing antibodies, thus preventing secondary homologous infection in tree shrews. However, neonatal tree shrews succumbed to ZIKV challenge upon intracerebral infection. The tree shrew model described here recapitulates the most common dermatological manifestations observed in ZIKV-infected patients and may greatly facilitate the elucidation of ZIKV pathogenesis and the development of novel vaccines and therapeutics. The reemergence of Zika virus (ZIKV) has caused a global public health crisis since 2016, and there are currently no vaccines or antiviral drugs to prevent or treat ZIKV infection. However, considerable advances have been made in understanding the biology and pathogenesis of ZIKV infection. In particular, various animal models have been successfully established to mimic ZIKV infection and its associated neurological diseases and to evaluate potential countermeasures. However, the clinical symptoms in these mouse and nonhuman primate models are different from the common clinical manifestations seen in human ZIKV patients; in particular, dermatological manifestations are rarely recapitulated in these animal models. Here, we developed a new animal model of ZIKV infection in tree shrews, a rat-sized, primate-related mammal. and characterization of ZIKV infection in tree shrews established a direct link between ZIKV infection and the immune responses and dermatological manifestations. The tree shrew model described here, as well as other available animal models, provides a valuable platform to study ZIKV pathogenesis and to evaluate vaccines and therapeutics.
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http://dx.doi.org/10.1128/JVI.01982-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450121PMC
April 2019

miR-103/miR-195/miR-15b Regulate SALL4 and Inhibit Proliferation and Migration in Glioma.

Molecules 2018 Nov 10;23(11). Epub 2018 Nov 10.

School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.

Glioma is the common highly malignant primary brain tumor. However, the molecular pathways that result in the pathogenesis of glioma remain elusive. In this study, we found that microRNA-103 (miR-103), microRNA-195 (miR-195), or microRNA-15b (miR-15b), which all have the same 5' "seed" miRNA portion and share common binding sites in the SALL4 3'-untranslated region (UTR), were downregulated in glioma tissues and cell lines. These miRNAs suppressed glioma cell proliferation, migration, and invasion, induced cell apoptosis, and decreased the level of the SALL4 protein, but not that of SALL4 mRNA, which was identified as a direct target of all three miRNAs. The caspase-3/7 activity expression in U251 cells overexpressing these miRNAs was rescued during SALL4 upregulation. An obvious inverse correlation was observed between SALL4 and miR-103 or miR-195 expression levels in clinical glioma samples. Moreover, enforced expression of SALL4 stimulated cell proliferation, migration, and invasion. In conclusion, these data suggest that miR-103, miR-195, and miR-15b post-transcriptionally downregulated the expression of SALL4 and suppressed glioma cell growth, migration, and invasion, and increased cell apoptosis. These results provide a potential therapeutic target that may downregulate SALL4 in glioma.
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http://dx.doi.org/10.3390/molecules23112938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278493PMC
November 2018

miR-103/miR-195/miR-15b Regulate SALL4 and Inhibit Proliferation and Migration in Glioma.

Molecules 2018 Nov 10;23(11). Epub 2018 Nov 10.

School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.

Glioma is the common highly malignant primary brain tumor. However, the molecular pathways that result in the pathogenesis of glioma remain elusive. In this study, we found that microRNA-103 (miR-103), microRNA-195 (miR-195), or microRNA-15b (miR-15b), which all have the same 5' "seed" miRNA portion and share common binding sites in the SALL4 3'-untranslated region (UTR), were downregulated in glioma tissues and cell lines. These miRNAs suppressed glioma cell proliferation, migration, and invasion, induced cell apoptosis, and decreased the level of the SALL4 protein, but not that of SALL4 mRNA, which was identified as a direct target of all three miRNAs. The caspase-3/7 activity expression in U251 cells overexpressing these miRNAs was rescued during SALL4 upregulation. An obvious inverse correlation was observed between SALL4 and miR-103 or miR-195 expression levels in clinical glioma samples. Moreover, enforced expression of SALL4 stimulated cell proliferation, migration, and invasion. In conclusion, these data suggest that miR-103, miR-195, and miR-15b post-transcriptionally downregulated the expression of SALL4 and suppressed glioma cell growth, migration, and invasion, and increased cell apoptosis. These results provide a potential therapeutic target that may downregulate SALL4 in glioma.
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http://dx.doi.org/10.3390/molecules23112938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278493PMC
November 2018

Expression of CCL21 by EBV-associated gastric carcinoma cells protects CD8CCR7 T lymphocytes from apoptosis via the mitochondria-mediated pathway.

Pathology 2018 Oct 24;50(6):613-621. Epub 2018 Aug 24.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

About 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV), which are defined as EBV-associated gastric carcinomas (EBVaGCs). EBVaGCs are usually accompanied by massive lymphocytes infiltration, among which CD8 T cells are predominant. To date, the apoptosis of the infiltrating CD8 T cells in EBVaGC has not been investigated. In the present study, we assessed the immunophenotype and apoptosis of tumour infiltrating lymphocytes (TILs) in both EBVaGC and EBV-negative gastric carcinoma (EBVnGC). We found that CD8CCR7 T lymphocytes were increased in EBVaGC compared to EBVnGC [60.53 ± 28.41/high power fields (HPF) vs 19.63 ± 15.97/HPF; p < 0.001]. Moreover, the apoptosis index of TILs was lower in EBVaGC than that in EBVnGC (1.34 ± 0.90 vs 5.94 ± 3.77; p < 0.001). Given that the CCL21-CCR7 axis is reported to be potentially involved in apoptosis, we examined the expression of CCL21 in both EBVaGC and EBVnGC. We found that CCL21 expression was higher in EBVaGC than in EBVnGC (p < 0.001). We also showed that the expression of CCL21 by EBVaGC cells protected CD8CCR7 T lymphocytes from apoptosis. Furthermore, the up-regulation of Bcl-2 contributed to the inhibition of apoptosis in CD8CCR7 T cells. Collectively, these findings suggest that expression of CCL21 by EBVaGC cells protects CD8CCR7 T lymphocytes from apoptosis via the mitochondria-mediated pathway. To our best knowledge, this is the first study to investigate the apoptosis of CD8 T cells in EBVaGC.
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http://dx.doi.org/10.1016/j.pathol.2018.05.004DOI Listing
October 2018

Intranasal infection and contact transmission of Zika virus in guinea pigs.

Nat Commun 2017 11 21;8(1):1648. Epub 2017 Nov 21.

Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.

Zika virus (ZIKV) is primarily transmitted to humans through mosquito bites or sexual contact. The excretion and persistence of contagious ZIKV in various body fluids have been well documented in ZIKV patients; however, the risk of direct contact exposure remains unclear. Here, we show that guinea pigs are susceptible to ZIKV infection via subcutaneous inoculation route; infected guinea pigs exhibit seroconversion and significant viral secretion in sera, saliva, and tears. Notably, ZIKV is efficiently transmitted from infected guinea pigs to naïve co-caged animals. In particular, intranasal inoculation of ZIKV is fully capable of establishing infection in guinea pigs, and viral antigens are detected in multiple tissues including brain and parotid glands. Cynomolgus macaques also efficiently acquire ZIKV infection via intranasal and intragastric inoculation routes. These collective results from animal models highlight the risk of exposure to ZIKV contaminants and raise the possibility of close contact transmission of ZIKV in humans.
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http://dx.doi.org/10.1038/s41467-017-01923-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698318PMC
November 2017
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