Publications by authors named "Xia Han"

225 Publications

Metagenomic Next-Generation Sequencing in the Diagnosis of HHV-1 Reactivation in a Critically Ill COVID-19 Patient: A Case Report.

Front Med (Lausanne) 2021 4;8:715519. Epub 2021 Oct 4.

The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China.

Secondary infections pose tremendous challenges in Coronavirus disease 2019 (COVID-19) treatment and are associated with higher mortality rates. Clinicians face of the challenge of diagnosing viral infections because of low sensitivity of available laboratory tests. A 66-year-old woman initially manifested fever and shortness of breath. She was diagnosed as critically ill with COVID-19 using quantitative reverse transcription PCR (RT-qPCR) and treated with antiviral therapy, ventilator and extracorporeal membrane oxygenation (ECMO). However, after the condition was relatively stabled for a few days, the patient deteriorated with fever, frequent cough, increased airway secretions, and increased exudative lesions in the lower right lung on chest X-rays, showing the possibility of a newly acquired infection, though sputum bacterial and fungal cultures and smears showed negative results. Using metagenomic next-generation sequencing (mNGS), we identified a reactivation of latent human herpes virus type 1 (HHV-1) in the respiratory tract, blood and gastrointestinal tract, resulting in a worsened clinical course in a critically ill COVID-19 patient on ECMO. Anti-HHV-1 therapy guided by these sequencing results effectively decreased HHV-1 levels, and improved the patient's clinical condition. After 49 days on ECMO and 67 days on the ventilator, the 66-year-old patient recovered and was discharged. This case report demonstrates the potential value of mNGS for evidence-based treatment, and suggests that potential reactivation of latent viruses should be considered in critically ill COVID-19 patients.
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http://dx.doi.org/10.3389/fmed.2021.715519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520926PMC
October 2021

Novel Hemizygous Mutations of Cause Meiotic Arrest and Non-obstructive Azoospermia in Chinese Han Population.

Front Genet 2021 21;12:741355. Epub 2021 Sep 21.

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

Testis-expressed gene 11 () mutation has been associated with non-obstructive azoospermia (NOA) and meiotic arrest. An analogous mutation of in the mouse impairs meiosis and can be rescued by expansion of SSCs and gene therapy. However, a lack of genetic screening of a large cohort of Asian patients (including pedigree analysis) and proper functional evaluation limit the clinical application of mutation screening. Thus, we performed whole-exome sequencing (WES) in 479 patients with NOA and identified three novel mutations (two splicing mutations and one missense mutation) in in three pairs of siblings from three families and four novel pathogenic mutations (three frameshift mutations and a non-sense mutation) of in four sporadic NOA-affected cases. Novel variants among family members were segregated by disease phenotype, and all the seven mutations were predicted to be pathogenic. Histological analysis showed that three patients with mutations underwent meiotic arrest. The four mutations that resulted in protein truncations and defective meiosis-specific sporulation domain SPO22 were validated by Western blot. In total, we find seven of 479 patients of NOA (1.5%) carrying mutations. Our study expands the knowledge of mutations of gene in Asian patients with NOA. The high prevalence and X-linked inherited mode indicated that might be included in genetic screening panels for the clinical evaluation of patients with NOA.
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http://dx.doi.org/10.3389/fgene.2021.741355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491544PMC
September 2021

The Endoplasmic Reticulum Stress Response Mediates Shikonin-Induced Apoptosis of 5-Fluorouracil-Resistant Colorectal Cancer Cells.

Biomol Ther (Seoul) 2021 Oct 5. Epub 2021 Oct 5.

Department of Biochemistry, Jeju National University College of Medicine, Jeju 63243, Republic of Korea.

Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonininduced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.
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http://dx.doi.org/10.4062/biomolther.2021.118DOI Listing
October 2021

Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study.

Lancet Oncol 2021 10 10;22(10):1403-1415. Epub 2021 Sep 10.

Center for Hematologic Malignancies, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA.

Background: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort.

Methods: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 10 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing.

Findings: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported.

Interpretation: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy).

Funding: Novartis Pharmaceuticals.
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http://dx.doi.org/10.1016/S1470-2045(21)00375-2DOI Listing
October 2021

Characterization of a novel reassortment Tibet orbivirus isolated from spp. in Yunnan, PR China.

J Gen Virol 2021 Sep;102(9)

Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, PR China.

Orbiviruses are arboviruses with 10 double-stranded linear RNA segments, and some have been identified as pathogens of dramatic epizootics in both wild and domestic ruminants. Tibet orbivirus (TIBOV) is a new orbivirus isolated from hematophagous insects in recent decades, and, currently, most of the strains have been isolated from insects in PR China, except for two from Japan. In this study, we isolated a novel reassortment TIBOV strain, YN15-283-01, from spp. To identify and understand more characteristics of YN15-283-01, electrophoresis profiles of the viral genome, electron microscopic observations, plaque assays, growth curves in various cell lines, and bioinformatic analysis were conducted. The results indicated that YN15-283-01 replicated efficiently in mosquito cells, rodent cells and several primate cells. Furthermore, the maximum likelihood phylogenetic trees and simplot analysis of the 10 segments indicated that YN15-283-01 is a natural reassortment isolate that had emerged mainly from XZ0906 and SX-2017a.
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http://dx.doi.org/10.1099/jgv.0.001645DOI Listing
September 2021

Association of Genetic Variants in miR-217 Gene with Risk of Coronary Artery Disease: A Case-Control Study.

Pharmgenomics Pers Med 2021 28;14:1081-1086. Epub 2021 Aug 28.

Shandong Second Provincial General Hospital, Jinan, Shandong Province, 250000, People's Republic of China.

Objective: To evaluate the associations of genetic variants of the miR-217 gene with coronary artery disease (CAD) risk, as well as plasma level of vascular endothelial growth factor (VEGF).

Methods: A case-control study with 498 CAD patients and 499 frequency-matched healthy controls was conducted to evaluate the associations of four tagSNPs of the miR-217 gene, including rs6724872, rs4999828, rs10206823, and rs41291177, with CAD risk and plasma level of VEGF.

Results: SNP rs6724872 and rs4999828 were significantly associated with increased risk of CAD (P value was smaller than 0.05 even after Bonferroni multiple adjustment). Compared with the G allele, C allele of rs6724872 was significantly associated with 1.73-fold increased risk of CAD (95% CI: 1.25-2.39; P = 0.001). While C allele of rs4999828 was significantly associated with 1.75-fold increased risk of CAD, compared with T allele (95% CI: 1.34-2.29; P = 4 × 10). Meanwhile, rs6724872 and rs4999828 were also significantly associated with higher level of VEGF (P < 0.001).

Conclusion: These findings highlighted the important role of genetic variants of the miR-217 gene in the pathogenesis of CAD and potential targets for intervention.
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http://dx.doi.org/10.2147/PGPM.S324767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409599PMC
August 2021

RNA-binding protein ELAVL2 plays post-transcriptional roles in the regulation of spermatogonia proliferation and apoptosis.

Cell Prolif 2021 Sep 23;54(9):e13098. Epub 2021 Jul 23.

Department of Andrology, The Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objectives: RNA-binding proteins (RBPs) play essential post-transcriptional roles in regulating spermatogonial stem cells (SSCs) maintenance and differentiation. We identified a conserved and SSCs-enriched RBP ELAVL2 from our single-cell sequencing data, but its function and mechanism in SSCs were unclear.

Materials And Methods: Expressions of ELAVL2 during human and mouse testis development were validated. Stable C18-4 and TCam-2 cell lines with overexpression and knockdown of ELAVL2 were established, which were applied to proliferation and apoptosis analysis. RNA immunoprecipitation and sequencing were used to identify ELAVL2 targets, and regulatory functions of ELAVL2 on target mRNAs were studied. Proteins interacting with ELAVL2 in human and mouse testes were identified using immunoprecipitation and mass spectrometric, which were validated by in vivo and in vitro experiments.

Results: ELAVL2 was testis-enriched and preferentially expressed in human and mouse SSCs. ELAVL2 was down-regulated in NOA patients. ELAVL2 promoted proliferation and inhibited apoptosis of C18-4 and TCam-2 cell lines via activating ERK and AKT pathways. ELAVL2 associated with mRNAs encoding essential regulators of SSCs proliferation and survival, and promoted their protein expression at post-transcriptional level. ELAVL2 interacted with DAZL in vivo and in vitro in both human and mouse testes.

Conclusions: Taken together, these results indicate that ELAVL2 is a conserved SSCs-enriched RBP that down-regulated in NOA, which regulates spermatogonia proliferation and apoptosis by promoting protein expression of targets.
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http://dx.doi.org/10.1111/cpr.13098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450129PMC
September 2021

The complete chloroplast genome and phylogenetic analysis of subsp. (Rupr.) P.S.Green & M.C.Chang from Qinghai Province, China.

Mitochondrial DNA B Resour 2021 Jun 3;6(7):1829-1831. Epub 2021 Jun 3.

Key Laboratory of Restoration Ecology in Cold Region of Qinghai Province, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, China.

subsp. (Rupr.) P. S. Green & M. C. Chang (Oleaceae) is a shrub or tree with high medicinal value as well as great ecological significance as an urban garden plant. To better understand the molecular genetics and evolutionary of subsp. , its complete chloroplast genome was sequenced and annotated. The assembled chloroplast genome is a circular 156,141 bp sequence, consisting of 87,108 bp large single copy (LSC) region and 17,239 bp small single copy (SSC) region, which were flanked by a pair of 25,897 bp inverted repeats (IRs). The GC content of the chloroplast genome is 36.14%. Moreover, a total of 132 functional genes were annotated, including 88 protein-coding, 36 tRNA, and eight rRNA genes. Phylogenetic analysis showed that subsp. was most closely related to subsp. and the genus is paraphyletic group. This study provides important information for further phylogenetic studies on subsp. and its allies.
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http://dx.doi.org/10.1080/23802359.2021.1934150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183553PMC
June 2021

Circulating Level of Monocyte Chemoattractant Protein-1 and Risk of Coronary Artery Disease: A Case-Control and Mendelian Randomization Study.

Pharmgenomics Pers Med 2021 11;14:553-559. Epub 2021 May 11.

Department of Cardiology, Jinan People's Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, 271100, People's Republic of China.

Background: Coronary artery disease (CAD) ranks the leading cause of death worldwide, and inflammation has been implicated in all stages of CAD and is considered to contribute to the pathophysiological basis of atherogenesis.

Methods: Here, we implemented a case-control study and a two-sample Mendelian randomization (MR) study to explore the associations between CAD risk and genetic predisposition to circulating level of monocyte chemoattractant protein-1 (MCP1), the most important regulator of monocyte trafficking.

Results: In case-control study, we found circulating level of MCP1 was significantly associated with increased risk of CAD (OR for per quartile increment: 1.33, 95% CI: 1.19-1.49, P<0.001). Further, genetically predicted higher level of MCP1 was significantly associated with higher risk of CAD (OR for 1-SD increase: 1.05, 95% CIs: 1.02-1.08, P value: 0.002) in MR analysis. Sensitivity analyses were also conducted to validate the main findings, and we also did not detect any directional pleiotropy effects using the MR Egger intercept test (P=0.831).

Conclusion: To sum up, our study suggested that increased CAD risk was associated with a predisposition to higher level of MCP1. Additional insight into the contribution of MCP1 to the occurrence of CAD is still needed.
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http://dx.doi.org/10.2147/PGPM.S303362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124014PMC
May 2021

Community structure of environmental microorganisms associated with COVID-19 affected patients.

Aerobiologia (Bologna) 2021 May 4:1-9. Epub 2021 May 4.

College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, 100853 China.

To clarify the characteristics and distribution of hospital environmental microbiome associated with confirmed COVID-19 patients. Environmental samples with varying degrees of contamination which were associated with confirmed COVID-19 patients were collected, including 13 aerosol samples collected near eight patients in different wards, five swabs from one patient's skin and his personal belongings, and two swabs from the surface of positive pressure respiratory protective hood and the face shield from a physician who had close contact with one patient. Metagenomic next-generation sequencing (mNGS) was used to analyze the composition of the microbiome. One of the aerosol samples (near patient 4) was detected positive for COVID-19, and others were all negative. The environmental samples collected in different wards possessed protean compositions and community structures, the dominant genera including , , , , , and . Top 10 of genera accounted for more than 76.72%. Genera abundance and proportion of human microbes and pathogens radiated outward from the patient, while the percentage of environmental microbes increased. The abundance of the pathogenic microorganism of medical supplies is significantly higher than other surface samples. The microbial compositions of the aerosol collected samples nearby the patients were mostly similar to those from the surfaces of the patient's skin and personal belongings, but the abundance varied greatly. The positive rate of COVID-19 RNA detected from aerosol around patients in general wards was quite low. The ward environment was predominantly inhabited by species closely related to admitted patients. The spread of hospital microorganisms via aerosol was influenced by the patients' activity.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10453-021-09708-5.
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http://dx.doi.org/10.1007/s10453-021-09708-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093081PMC
May 2021

Clinical value of atomization therapy in children with bronchopneumonia.

Minerva Pediatr (Torino) 2021 May 5. Epub 2021 May 5.

Medical Clinic, Air Force Health Care Center for Special Services Hangzhou, Hangzhou, China -

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http://dx.doi.org/10.23736/S2724-5276.21.06373-4DOI Listing
May 2021

Arid1a-Plagl1-Hh signaling is indispensable for differentiation-associated cell cycle arrest of tooth root progenitors.

Cell Rep 2021 04;35(1):108964

Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA. Electronic address:

Chromatin remodelers often show broad expression patterns in multiple cell types yet can elicit cell-specific effects in development and diseases. Arid1a binds DNA and regulates gene expression during tissue development and homeostasis. However, it is unclear how Arid1a achieves its functional specificity in regulating progenitor cells. Using the tooth root as a model, we show that loss of Arid1a impairs the differentiation-associated cell cycle arrest of tooth root progenitors through Hedgehog (Hh) signaling regulation, leading to shortened roots. Our data suggest that Plagl1, as a co-factor, endows Arid1a with its cell-type/spatial functional specificity. Furthermore, we show that loss of Arid1a leads to increased expression of Arid1b, which is also indispensable for odontoblast differentiation but is not involved in regulation of Hh signaling. This study expands our knowledge of the intricate interactions among chromatin remodelers, transcription factors, and signaling molecules during progenitor cell fate determination and lineage commitment.
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http://dx.doi.org/10.1016/j.celrep.2021.108964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132592PMC
April 2021

De novo full length transcriptome analysis of Arachis glabrata provides insights into gene expression dynamics in response to biotic and abiotic stresses.

Genomics 2021 May 2;113(3):1579-1588. Epub 2021 Apr 2.

Biotechnology Research Center, Shandong Academy of Agricultural Sciences, Shandong Provincial Key Laboratory of Crop Genetic Improvement, Ecology and Physiology, Jinan 250100, People's Republic of China; College of Life Sciences, Shandong Normal University, Jinan 250014, People's Republic of China. Electronic address:

The perennial ornamental peanut Arachis glabrata represents one of the most adaptable wild Arachis species. This study used PacBio combined with BGISEQ-500 RNA-seq technology to study the transcriptome and gene expression dynamics of A. glabrata. Of the total 109,747 unique transcripts obtained, >90,566 transcripts showed significant homology to known proteins and contained the complete coding sequence (CDS). RNA-seq revealed that 1229, 1039, 1671, 3923, 1521 and 1799 transcripts expressed specifically in the root, stem, leaf, flower, peg and pod, respectively. We also identified thousands of differentially expressed transcripts in response to drought, salt, cold and leaf spot disease. Furthermore, we identified 30 polyphenol oxidase encoding genes associated with the quality of forage, making A. glabrata suitable as a forage crop. Our findings presented the first transcriptome study of A. glabrata which will facilitate genetic and genomics studies and lays the groundwork for a deeper understanding of the A. glabrata genome.
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http://dx.doi.org/10.1016/j.ygeno.2021.03.030DOI Listing
May 2021

Application of Metagenomic Next-Generation Sequencing in the Diagnosis of Pulmonary Infectious Pathogens From Bronchoalveolar Lavage Samples.

Front Cell Infect Microbiol 2021 11;11:541092. Epub 2021 Mar 11.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Metagenomic next-generation sequencing (mNGS) is a powerful method for pathogen detection. In this study, we assessed the value of mNGS for bronchoalveolar lavage (BAL) samples in the diagnosis of pulmonary infections.

Methods: From February 2018 to April 2019, BAL samples were collected from 235 patients with suspected pulmonary infections. mNGS and microbial culture were performed to evaluate the effectiveness of mNGS in pulmonary infection diagnosis.

Results: We employed mNGS to evaluate the alpha diversity, results suggesting that patients with confirmed pathogens had a lower microbial diversity index compared to that of patients with uncertain pathogens. For the patients admitted to the respiratory intensive care unit (RICU) or on a ventilator, they experienced a lower diversity index than that of the patients in the general ward or not on a ventilator. In addition, mNGS of BAL had a diagnostic sensitivity of 88.89% and a specificity of 14.86% in pulmonary infection, with 21.16% positive predictive value (PPV) and 83.87% negative predictive value (NPV). When rare pathogens were excluded, the sensitivity of mNGS decreased to 73.33%, and the specificity increased to 41.71%. For patients in the simple pulmonary infection group and the immunocompromised group, the main infection types were bacterial infection (58.33%) and mixed-infection (43.18%). Furthermore, mNGS had an advantage over culture in describing polymicrobial ecosystem, demonstrating the microbial distribution and the dominant strains of the respiratory tract in patients with different underlying diseases.

Conclusions: The study indicated that mNGS of BAL samples could provide more accurate diagnostic information in pulmonary infections and demonstrate the changes of respiratory microbiome in different underlying diseases. This method might play an important role in the clinical use of antimicrobial agents in the future.
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http://dx.doi.org/10.3389/fcimb.2021.541092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991794PMC
June 2021

Surface modification by poly(ethylene glycol) with different end-grafted groups: Experimental and theoretical study.

Biointerphases 2021 03 16;16(2):021002. Epub 2021 Mar 16.

Key Laboratory for Advanced Materials and School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, People's Republic of China.

Dihydroxyphenylalanine (DOPA) is extensively reported to be a surface-independent anchor molecule in bioadhesive surface modification and antifouling biomaterial fabrication. However, the mechanisms of DOPA adsorption on versatile substrates and the comparison between experimental results and theoretical results are less addressed. We report the adsorption of DOPA anchored monomethoxy poly(ethylene glycol) (DOPA-mPEG) on substrates and surface wettability as well as antifouling property in comparison with thiol and hydroxyl anchored mPEG (mPEG-SH and mPEG-OH). Gold and hydroxylated silicon were used as model substrates to study the adsorptions of mPEGs. The experimental results showed that the DOPA-mPEG showed higher affinity to both gold and silicon wafers, and the DOPA-mPEG modified surfaces had higher resistance to protein adsorption than those of mPEG-SH and mPEG-OH. It is revealed that the surface wettability is primary for surface fouling, while polymer flexibility is the secondary parameter. We present ab initio calculations of the adsorption of mEGs with different end-functionalities on Au and hydroxylated silicon wafer (Si-OH), where the binding energies are obtained. It is established that monomethoxy ethylene glycol (mEG) with DOPA terminal DOPA-mEG is clearly favored for the adsorption with both gold and Si-OH surfaces due to the bidentate Au-O interactions and the bidentate O-H bond interactions, in agreement with experimental evidence.
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http://dx.doi.org/10.1116/6.0000647DOI Listing
March 2021

Pathogenesis and Immune Response of Ebinur Lake Virus: A Newly Identified That Exhibited Strong Virulence in Mice.

Front Microbiol 2020 1;11:625661. Epub 2021 Feb 1.

Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.

are a group of viruses with significant public and veterinary health importance. These viruses are mainly transmitted through mosquito-, midge-, and tick-vectors, and are endemic to various regions of the world. Ebinur Lake virus (EBIV), a newly identified member of , was isolated from mosquitoes in Northwest China. In the present study, we aimed to characterize the pathogenesis and host immune responses of EBIV in BALB/c mice, as an animal model. Herein, we determined that BALB/c mice are highly susceptible to EBIV infection. The infected mice exhibited evident clinical signs including weight loss, mild encephalitis, and death. High mortality of mice was observed even with inoculation of one plaque-forming unit (PFU) of EBIV, and the infected mice succumbed to death within 5-9 days. After EBIV challenge, rapid viremic dissemination was detected in the peripheral tissues and the central nervous system, with prominent histopathologic changes observed in liver, spleen, thymus, and brain. Blood constituents' analysis of EBIV infected mice exhibited leukopenia, thrombocytopenia, and significantly elevated ALT, LDH-L, and CK. Further, EBIV infection induced obvious cytokines changes in serum, spleen, and brain in mice. Collectively, our data describe the first study that systematically examines the pathogenesis of EBIV and induced immune response in an immunocompetent standard mouse model, expanding our knowledge of this virus, which may pose a threat to One Health.
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http://dx.doi.org/10.3389/fmicb.2020.625661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882632PMC
February 2021

Lhx6 regulates canonical Wnt signaling to control the fate of mesenchymal progenitor cells during mouse molar root patterning.

PLoS Genet 2021 02 17;17(2):e1009320. Epub 2021 Feb 17.

Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, United States of America.

Mammalian tooth crown formation has long served as a model for investigating how patterning and morphogenesis are orchestrated during development. However, the mechanism underlying root patterning and morphogenesis remains poorly understood. In this study, we find that Lhx6 labels a subpopulation of root progenitor cells in the apical dental mesenchyme, which is closely associated with furcation development. Loss of Lhx6 leads to furcation and root number defects, indicating that Lhx6 is a key root patterning regulator. Among the multiple cellular events regulated by Lhx6 is the odontoblast fate commitment of progenitor cells, which it controls in a cell-autonomous manner. Specifically, Lhx6 loss leads to elevated expression of the Wnt antagonist Sfrp2 and down-regulation of Wnt signaling in the furcation region, while overactivation of Wnt signaling in Lhx6+ progenitor cells partially restore the furcation defects in Lhx6-/- mice. Collectively, our findings have important implications for understanding organ morphogenesis and future strategies for tooth root regeneration.
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http://dx.doi.org/10.1371/journal.pgen.1009320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920342PMC
February 2021

Impact on physical and mental health among medical personnel in Wuhan during COVID-19 outbreak: a cluster analysis.

Int J Med Sci 2021 11;18(5):1185-1188. Epub 2021 Jan 11.

Department of Intensive Care, Gansu Province Hospital, Lanzhou, China.

Increased stress among medical personnel had been reported in previous virus outbreaks. The novel coronavirus disease (COVID-19) emerged in December 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). No qualitative assessment has yet described the physical and mental health conditions of frontline medical personnel in the COVID-19 outbreaks. Here, 251 frontline medical personnel involved in COVID-19 missions completed electronic questionnaires, consisting of 31 categorical variables related to their physical and mental health status, medical history and environmental conditions. We constructed a correlation amongst these variables through pairwise Kendall rank correlation coefficient test. Then, clusters of highly correlated variables were identified using the leading eigenvector. Finally, we used the network and clusters to clarify the correlations amongst variables. This qualitative study identified the six clusters. Cluster 1 was characterized by skin allergy. Cluster 2 was predominantly associated with anxiety. Cluster 3 consisted mostly of respiratory symptoms. The participants in cluster 4 had medical history. Cluster 5 and cluster 6 were characterized by disinfection and demography, respectively. Finally, we revealed three major findings. First, more than 80% of medical personnel worry about COVID-19-related infection and experience newly appearing anxiety (56.2%), airway or heart symptoms (34.3%) and skin allergies (20.3%). Second, COVID-19-related worry significantly associates with all variables in the anxiety and respiratory symptom clusters. Third, new-onset skin allergies did not associate with either disinfection or anxiety, but did associate with a previous history of allergies. COVID-19-related worry leads to physical and mental health problems amongst medical personnel. Effective responses and interventions could relieve a series of new-onset physical and mental health problems.
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http://dx.doi.org/10.7150/ijms.51315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847622PMC
February 2021

Runx2-Twist1 interaction coordinates cranial neural crest guidance of soft palate myogenesis.

Elife 2021 Jan 22;10. Epub 2021 Jan 22.

Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, Los Angeles, United States.

Cranial neural crest (CNC) cells give rise to bone, cartilage, tendons, and ligaments of the vertebrate craniofacial musculoskeletal complex, as well as regulate mesoderm-derived craniofacial muscle development through cell-cell interactions. Using the mouse soft palate as a model, we performed an unbiased single-cell RNA-seq analysis to investigate the heterogeneity and lineage commitment of CNC derivatives during craniofacial muscle development. We show that Runx2, a known osteogenic regulator, is expressed in the CNC-derived perimysial and progenitor populations. Loss of in CNC-derivatives results in reduced expression of perimysial markers ( and ) as well as soft palate muscle defects in mice. We further reveal that Runx2 maintains perimysial marker expression through suppressing and that myogenesis is restored in mice. Collectively, our findings highlight the roles of Runx2, Twist1, and their interaction in regulating the fate of CNC-derived cells as they guide craniofacial muscle development through cell-cell interactions.
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http://dx.doi.org/10.7554/eLife.62387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826157PMC
January 2021

Different characteristics of critical COVID-19 and thinking of treatment strategies in non-elderly and elderly severe adult patients.

Int Immunopharmacol 2021 Mar 4;92:107343. Epub 2021 Jan 4.

Department of Endocrinology, Tongji Hospital, affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: The differences in the characteristics and main causes of critical COVID-19 infection in non-elderly and elderly severe patients remain unknown.

Methods: We included 273 adult patients with confirmed severe COVID-19 from Tongji Hospital, Wuhan, China from February 10 to March 8, 2020. Clinical characteristics and risk factors for outcomes were compared between the young and middle-aged and the elderly severe patients.

Results: Hemoglobin, neutrophil percentage, inflammatory markers, hepatic, renal, and cardiovascularparameters differed between the non-elderly and elderly severe patients. In young and middle-aged patients, critical patients showed higher high-sensitivity C-reactive protein (hsCRP) during hospitalization than severe patients. However, in the elderly patients, critical patients showed decreased hsCRP during hospitalization and higher proBNP values. The hsCRP fluctuation and proBNP were independent risk factors for intensive care unit (ICU) admission in young and middle-aged severe patients (OR=1.068) and elderly severe patients (OR=1.026), respectively.

Conclusion: The study revealed different potential causes of disease and predictive factors for non-elderly and elderly critical patients and treatment recommendations. Deterioration of inflammatory state was the main cause of ICU admission in young and middle-aged severe COVID-19 patients, while a decline in hsCRP was not associated with better outcomes in elderly severe patients, indicating the need for different treatments for non-elderly and elderly severe patients. Anti-inflammatory therapy with corticosteroids should be considered in the early disease stage among non-elderly severe patients, but cardiovascular protection plays a more important role in elderly severe patients.
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http://dx.doi.org/10.1016/j.intimp.2020.107343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833421PMC
March 2021

Proteasome activator PA200 maintains stability of histone marks during transcription and aging.

Theranostics 2021 1;11(3):1458-1472. Epub 2021 Jan 1.

State Key Laboratory of Cognitive Neuroscience & Learning and Ministry of Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China.

The epigenetic inheritance relies on stability of histone marks, but various diseases, including aging-related disorders, are usually associated with alterations of histone marks. Whether and how the proteasome is responsible for maintaining the histone marks during transcription and aging remain unclear. The core histones can be degraded by the atypical proteasome, which contains the proteasome activator PA200, in an acetylation-dependent manner during somatic DNA damage response and spermiogenesis. By utilizing a substitute of methionine to label proteins metabolically, we analyzed histone degradation genome-wide by sequencing the DNA fragments following pulse-chase assays. The genome-wide RNA-sequencing analysis was performed to analyze transcription and chromatin-immunoprecipitation (ChIP)-sequencing was used for analyses of histone marks. The experimental models included gene-manipulated cells (including both mouse and yeast), mouse liver, and mice. Degradation of H4 or the transcription-coupled histone variant H3.3 could be suppressed by deletion of PA200 or its yeast ortholog Blm10. The histone deacetylase inhibitor accelerated the degradation rates of H3, while the mutations of the putative acetyl-lysine-binding region of PA200 abolished histone degradation in the G1-arrested cells. Deletion of PA200 dramatically altered deposition of the active transcriptional hallmarks (H3K4me3 and H3K56ac) and transcription, especially during cellular aging. Furthermore, deletion of PA200 or Blm10 accelerated cellular aging. Notably, the PA200-deficient mice displayed a range of aging-related deteriorations, including immune malfunction, anxiety-like behavior and shorter lifespan. PA200 promotes the transcription-coupled degradation of the core histones, and plays an important role in maintaining the stability of histone marks during transcription and aging.
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http://dx.doi.org/10.7150/thno.48744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738882PMC
July 2021

Preosteoblast-enriched lnc-Evf2 facilitates osteogenic differentiation by targeting Notch.

Acta Biochim Biophys Sin (Shanghai) 2021 Feb;53(2):179-188

Department of Orthopedic Surgery, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin 300070, China.

Ossification of ligaments (OL) and osteoporosis (OP) are multifactorial disorders without definitive clinical biomarkers. Long non-coding RNAs (lncRNAs) are known to involve in regulating pathogenesis. Here, we have identified a preosteoblast-enriched lnc-Evf2 that was overexpressed in ossified ligamentum flavum (OLF) and down-expressed in OP. lnc-Evf2 is gradually upregulated during osteogenic induction, correlating with the enhanced expression of osteogenic marker genes and matrix mineralization. Moreover, knockdown of lnc-Evf2 significantly inhibits the expression of osteogenic differentiation markers and delays the osteoblastic mineralization process, indicating that this molecule is involved in osteogenesis. Mechanistically, we demonstrated that silencing of lnc-Evf2 decreases the protein level but not the mRNA levels of Notch2, Notch3, and Hes1, all of which correlate with osteogenesis. Taken together, our data demonstrate that lnc-Evf2 promotes osteogenic differentiation and bone formation through the Notch signaling, revealing that lnc-Evf2 may serve as a novel potential clinical target of OL and OP.
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http://dx.doi.org/10.1093/abbs/gmaa156DOI Listing
February 2021

Spatiotemporal cellular movement and fate decisions during first pharyngeal arch morphogenesis.

Sci Adv 2020 Dec 16;6(51). Epub 2020 Dec 16.

Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.

Cranial neural crest (CNC) cells contribute to different cell types during embryonic development. It is unknown whether postmigratory CNC cells undergo dynamic cellular movement and how the process of cell fate decision occurs within the first pharyngeal arch (FPA). Our investigations demonstrate notable heterogeneity within the CNC cells, refine the patterning domains, and identify progenitor cells within the FPA. These progenitor cells undergo fate bifurcation that separates them into common progenitors and mesenchymal cells, which are characterized by and expression, respectively. The common progenitors undergo further bifurcations to restrict them into osteogenic/odontogenic and chondrogenic/fibroblast lineages. Disruption of a patterning domain leads to specific mandible and tooth defects, validating the binary cell fate restriction process. Different from the compartment model of mandibular morphogenesis, our data redefine heterogeneous cellular domains within the FPA, reveal dynamic cellular movement in time, and describe a sequential series of binary cell fate decision-making process.
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http://dx.doi.org/10.1126/sciadv.abb0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744069PMC
December 2020

Ror2-mediated non-canonical Wnt signaling regulates Cdc42 and cell proliferation during tooth root development.

Development 2021 01 21;148(2). Epub 2021 Jan 21.

Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA

The control of size and shape is an important part of regulatory process during organogenesis. Tooth formation is a highly complex process that fine-tunes the size and shape of the tooth, which are crucial for its physiological functions. Each tooth consists of a crown and one or more roots. Despite comprehensive knowledge of the mechanism that regulates early tooth crown development, we have limited understanding of the mechanism regulating root patterning and size during development. Here, we show that Ror2-mediated non-canonical Wnt signaling in the dental mesenchyme plays a crucial role in cell proliferation, and thereby regulates root development size in mouse molars. Furthermore, Cdc42 acts as a potential downstream mediator of Ror2 signaling in root formation. Importantly, activation of Cdc42 can restore cell proliferation and partially rescue the root development size defects in mutant mice. Collectively, our findings provide novel insights into the function of Ror2-mediated non-canonical Wnt signaling in regulating tooth morphogenesis, and suggest potential avenues for dental tissue engineering.
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http://dx.doi.org/10.1242/dev.196360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847279PMC
January 2021

[Research progress on long non-coding RNA (lncRNA) in osteoarthritis].

Zhongguo Gu Shang 2020 Nov;33(11):1085-8

Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing 210029, Jiangsu, China.

Osteoarthritis(OA) is a common clinical disease. The incidence of OA increases significantly with age, and the quality of life of patients is seriously affected. In the pathogenesis of OA, cartilage degeneration is the main cause. There are many long non-coding RNA (lncRNA) specifically expressed in osteoarthritis, which is closely related to the occurrence and development of osteoarthritis. Based on the latest research from 2014 to 2019, this paper summarizes the differential expression of lncRNA in osteoarthritis, the mechanism of lncRNA regulating chondrocyte function, and the mechanism of lncRNA regulating cartilage matrix metabolism. The fact that the expression of lncRNA is altered at different stages of OA development indicates that lncRNA can be developed forlife. The biomarkers and therapeutic targets can provide reference for the prevention, treatment and research of osteoarthritis.
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http://dx.doi.org/10.12200/j.issn.1003-0034.2020.11.020DOI Listing
November 2020

Transmission competence of a new mesonivirus, Yichang virus, in mosquitoes and its interference with representative flaviviruses.

PLoS Negl Trop Dis 2020 11 30;14(11):e0008920. Epub 2020 Nov 30.

Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.

Advances in technology have greatly stimulated the understanding of insect-specific viruses (ISVs). Unfortunately, most of these findings are based on sequencing technology, and laboratory data are scarce on the transmission dynamics of ISVs in nature and the potential effects of these viruses on arboviruses. Mesonivirus is a class of ISVs with a wide geographical distribution. Recently, our laboratory reported the isolation of a novel strain of mesonivirus, Yichang virus (YCV), from Culex mosquitoes, China. In this study, the experimental infection of YCV by the oral route for adult and larvae mosquitoes, and the vertical transmission has been conducted, which suggests that YCV could adopt a mixed-mode transmission. Controlled experiments showed that the infectivity of YCV depends on the mosquito species, virus dose, and infection route. The proliferation curve and tissue distribution of YCV in Cx. quinquefasciatus and Ae. albopictus showed that YCV is more susceptible to Ae. albopictus and is located in the midgut. Furthermore, we also assessed the interference of YCV with flaviviruses both in vitro and in vivo. YCV significantly inhibited the proliferation of DENV-2 and ZIKV, in cell culture, and reduced transmission rate of DENV-2 in Ae. albopictus. Our work provides insights into the transmission of ISVs in different mosquito species during ontogeny and their potential ability to interact with mosquito-borne viruses.
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http://dx.doi.org/10.1371/journal.pntd.0008920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738168PMC
November 2020

Zika virus pathogenesis and current therapeutic advances.

Pathog Glob Health 2021 02 14;115(1):21-39. Epub 2020 Nov 14.

Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences , Wuhan, China.

Zika virus (ZIKV) is an emerging arthropod-borne flavivirus that, upon infection, results in teratogenic effects and neurological disorders. ZIKV infections pose serious global public health concerns, prompting scientists to increase research on antivirals and vaccines against the virus. These efforts are still ongoing as the pathogenesis and immune evasion mechanisms of ZIKV have not yet been fully elaborated. Currently, no specific vaccines or drugs have been approved for ZIKV; however, some are undergoing clinical trials. Notably, several strategies have been used to develop antivirals, including drugs that target viral and host proteins. Additionally, drug repurposing is preferred since it is less costly and takes less time than other strategies because the drugs used have already been approved for human use. Likewise, different platforms have been evaluated for the design of vaccines, including DNA, mRNA, peptide, protein, viral vectors, virus-like particles (VLPSs), inactivated-virus, and live-attenuated virus vaccines. These vaccines have been shown to induce specific humoral and cellular immune responses and reduce viremia and viral RNA both and . Importantly, most of these vaccines have entered clinical trials. Understanding the viral disease mechanism will provide better strategies for developing therapeutic agents against ZIKV. This review provides a comprehensive summary of the viral pathogenesis of ZIKV and current advancements in the development of vaccines and drugs against this virus.
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http://dx.doi.org/10.1080/20477724.2020.1845005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850325PMC
February 2021

Author Correction: A dataset of distribution and diversity of mosquito-associated viruses and their mosquito vectors in China.

Sci Data 2020 Nov 4;7(1):378. Epub 2020 Nov 4.

Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41597-020-00730-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642362PMC
November 2020

Transcriptional and proteomic insights into the host response in fatal COVID-19 cases.

Proc Natl Acad Sci U S A 2020 11 20;117(45):28336-28343. Epub 2020 Oct 20.

Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.
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http://dx.doi.org/10.1073/pnas.2018030117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668053PMC
November 2020
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