Publications by authors named "Ziyi Li"

164 Publications

Insights Gained from Single-Cell Analysis of Immune Cells in the Tumor Microenvironment.

Annu Rev Immunol 2021 Feb 26. Epub 2021 Feb 26.

Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Sciences, Peking University, Beijing 100871, China; email:

Understanding tumor immune microenvironments is critical for identifying immune modifiers of cancer progression and developing cancer immunotherapies. Recent applications of single-cell RNA sequencing (scRNA-seq) in dissecting tumor microenvironments have brought important insights into the biology of tumor-infiltrating immune cells, including their heterogeneity, dynamics, and potential roles in both disease progression and response to immune checkpoint inhibitors and other immunotherapies. This review focuses on the advances in knowledge of tumor immune microenvironments acquired from scRNA-seq studies across multiple types of human tumors, with a particular emphasis on the study of phenotypic plasticity and lineage dynamics of immune cells in the tumor environment. We also discuss several imminent questions emerging from scRNA-seq observations and their potential solutions on the horizon. Expected final online publication date for the , Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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http://dx.doi.org/10.1146/annurev-immunol-110519-071134DOI Listing
February 2021

Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade.

Cancer Discov 2021 Feb 15. Epub 2021 Feb 15.

Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health

Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NF-kB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0812DOI Listing
February 2021

Corrigendum: Roles of N6-Methyladenosine (mA) in Stem Cell Fate Decisions and Early Embryonic Development in Mammals.

Front Cell Dev Biol 2021 21;9:640806. Epub 2021 Jan 21.

Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China.

[This corrects the article DOI: 10.3389/fcell.2020.00782.].
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http://dx.doi.org/10.3389/fcell.2021.640806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861199PMC
January 2021

A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells.

Cell 2021 Feb;184(3):792-809.e23

BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing 100871, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China; Peking University International Cancer Institute, Beijing 100191, China. Electronic address:

Tumor-infiltrating myeloid cells (TIMs) are key regulators in tumor progression, but the similarity and distinction of their fundamental properties across different tumors remain elusive. Here, by performing a pan-cancer analysis of single myeloid cells from 210 patients across 15 human cancer types, we identified distinct features of TIMs across cancer types. Mast cells in nasopharyngeal cancer were found to be associated with better prognosis and exhibited an anti-tumor phenotype with a high ratio of TNF/VEGFA cells. Systematic comparison between cDC1- and cDC2-derived LAMP3 cDCs revealed their differences in transcription factors and external stimulus. Additionally, pro-angiogenic tumor-associated macrophages (TAMs) were characterized with diverse markers across different cancer types, and the composition of TIMs appeared to be associated with certain features of somatic mutations and gene expressions. Our results provide a systematic view of the highly heterogeneous TIMs and suggest future avenues for rational, targeted immunotherapies.
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http://dx.doi.org/10.1016/j.cell.2021.01.010DOI Listing
February 2021

TRIM28 maintains genome imprints and regulates development of porcine SCNT embryos.

Reproduction 2021 Feb 1. Epub 2021 Feb 1.

Z Li, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China.

Pre-implantation embryos undergo genome-wide DNA demethylation, however certain regions, like imprinted loci remain methylated. However, the mechanisms ensuring demethylation resistance by TRIM28 in epigenetic reprogramming remain poorly understood. Here, TRIM28 was knocked down in oocytes, and its effects on porcine somatic cell nuclear transfer (SCNT) embryo development was examined. Our results showed that SCNT embryos constructed from Trim28 knockdown oocytes had significantly lower cleavage (53.9±3.4% vs 64.8±2.7%) and blastocyst rates (12.1±4.3% vs 19.8±1.9%) than control-SCNT embryos. The DNA methylation levels at the promoter regions of the imprinting gene IGF2 and H19 were significantly decreased in the 4-cell stage, and the transcript abundance of other imprinting gene was substantially increased. We also identified an aberrant 2-fold decrease in the expression of CXXC1and H3K4me3 methyltransferase (ASH2L and MLL2), and the signal intensity of H3K4me3 had a transient drop in SCNT 2-cell embryos. Our results indicated that maternal TRIM28 knockdown disrupted the genome imprints and caused epigenetic variability in H3K4me3 levels, which blocked the transcription activity of zygote genes and affected the normal developmental progression of porcine SCNT embryos.
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http://dx.doi.org/10.1530/REP-20-0602DOI Listing
February 2021

The regulatory effect of 6-TG on lncRNA-miRNA-mRNA ceRNA network in triple-negative breast cancer cell line.

Biosci Rep 2021 Feb;41(2)

Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun 130021, China.

Breast cancer is one of the most prevalent and recurring cancer types that leads to deaths in women. Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of therapeutic targets. Many studies have focused on identifying drugs for use as alternative treatments for breast cancer. Thioguanine (6-TG) exerts antitumor effects in cancer. Increasing evidence has demonstrated that competitive endogenous ribonucleic acids (ceRNAs) are involved in cancer processes. However, the mechanism by which 6-TG regulates lncRNA-miRNA-mRNAs has not been elucidated. We evaluated the antitumor effect of 6-TG in MDA-MB-231 cells and comprehensively analyzed the RNA-Seq data of MDA-MB-231 cells treated with 6-TG. Our results showed that most tumor pathways were blocked by 6-TG. The hub genes were FN1, FLNA, FLNB, VCL, GSN, MYH10, ACTN4, KDR and EREG, and they were all down-regulated after 6-TG treatment. The coexpression network consisted of 18 microRNAs (miRNAs), 9 long noncoding RNAs (lncRNAs) and 20 mRNAs. Hsa-mir-16-5p and Hsa-mir-335-5p targeted the greatest number of mRNAs in the network. These molecules could bind to PAX8-AS1 and eliminate the inhibition of target mRNA expression. We showed that PAX8-AS1 is the main lncRNA affected by 6-TG and that PAX8-AS1 regulates the hub genes in tumor pathways by competitively binding with miR-16-5p and miR-335-5p.
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http://dx.doi.org/10.1042/BSR20203890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859320PMC
February 2021

Construction and analysis of competing endogenous RNA network of MCF-7 breast cancer cells based on the inhibitory effect of 6-thioguanine on cell proliferation.

Oncol Lett 2021 Feb 10;21(2):104. Epub 2020 Dec 10.

Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China.

Previous research has proven that 6-thioguanine (6-TG) inhibits the growth of MCF-7 breast cancer cells. Accumulating evidence indicates that long non-coding (lnc)RNAs are involved in the development of various cancer types as competitive endogenous (ce)RNA molecules. The present study was conducted to investigate the regulatory mechanism underlying the function of lncRNAs as ceRNA molecules in MCF-7 cells and to identify more effective prognostic biomarkers for breast cancer treatment. The expression profiles of lncRNAs in untreated MCF-7 cells and 6-TG-treated MCF-7 cells were compared by RNA-seq. The regulatory associations among lncRNAs, micro (mi)RNAs and mRNAs were analyzed and verified by the TargetScan, miRDB and miRTarBas databases. The ceRNA networks were constructed by Cytoscape. The expression levels of two lncRNAs and two miRNAs in the ceRNA network were measured by reverse transcription-quantitative PCR. The OncoLnc and Kaplan-Meier plotter network databases were utilized to determine the effects of lncRNA and miRNA expression on the survival of patients with breast cancer. A ceRNA network was constructed for MCF-7 breast cancer cells treated with 6-TG, and this network may provide valuable information for further research elucidating the molecular mechanism underlying the effects of 6-TG on breast cancer. Moreover, LINC00324, MIR22HG, miR-370-3p and miR-424-5p were identified as potential prognostic and therapeutic biomarkers for breast cancer.
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http://dx.doi.org/10.3892/ol.2020.12365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751352PMC
February 2021

Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells.

Cell Stem Cell 2020 Dec 15. Epub 2020 Dec 15.

Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266071, China. Electronic address:

Telomeres play vital roles in ensuring chromosome stability and are thus closely linked with the onset of aging and human disease. Telomeres undergo extensive lengthening during early embryogenesis. However, the detailed molecular mechanism of telomere resetting in early embryos remains unknown. Here, we show that Dcaf11 (Ddb1- and Cul4-associated factor 11) participates in telomere elongation in early embryos and 2-cell-like embryonic stem cells (ESCs). The deletion of Dcaf11 in embryos and ESCs leads to reduced telomere sister-chromatid exchange (T-SCE) and impairs telomere lengthening. Importantly, Dcaf11-deficient mice exhibit gradual telomere erosion with successive generations, and hematopoietic stem cell (HSC) activity is also greatly compromised. Mechanistically, Dcaf11 targets Kap1 (KRAB-associated protein 1) for ubiquitination-mediated degradation, leading to the activation of Zscan4 downstream enhancer and the removal of heterochromatic H3K9me3 at telomere/subtelomere regions. Our study therefore demonstrates that Dcaf11 plays important roles in telomere elongation in early embryos and ESCs through activating Zscan4.
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http://dx.doi.org/10.1016/j.stem.2020.11.018DOI Listing
December 2020

The Potential Migrated Mechanism of Water-Soluble Components in Pellets Prepared by Wet Extrusion/Spheronization: Effect of Drying Rate.

Curr Drug Deliv 2020 Nov 23. Epub 2020 Nov 23.

Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009. China.

Background: At present, there were numerous researches on the migration of components in tablets and granules, the investigation in the pharmaceutical literatrue concerning the effect of drying rate on the migration of water-soluble components of pellets was limited. Temperature and relative humidity (RH) were crucial parameters during the drying process which was an essential step in the preparation of pellets via wet extrusion/spheronization. To quantify these variables, the water loss percentage of pellets per minute was defined as drying rate.

Objective: The study aimed to investigate the influence of drying rate on the migration of water-soluble components in wet pellets and the potential migrated mechanism.

Methods: The pellets containing tartrazine as a water-soluble model drug and microcrystalline cellulose as a matrix former were prepared by extrusion/spheronization and dried at four different drying temperature and relative humidity. Afterward, the extent of migrated tartrazine was assessed regarding appearance, in-vitro dissolution test, Differential Scanning Calorimetry, X-Ray Powder Diffraction, Attenuated total reflectance Fourier transform infrared spectroscopy and Confocal Raman Mapping.

Results: Results demonstrated that red spots of tartrazine appeared on the surface of pellets and more than 40% tartrazine were burst released within 5 minutes when pellets dried at 60℃/RH 10%. While pellets dried at 40℃/RH 80%, none of these aforementioned phenomena was observed.

Conclusion: In conclusion, the faster drying rate was, the more tartrazine migrated to the exterior of pellets. Adjusting drying temperature and relative humidity appropriately could inhibit the migration of water-soluble components within wet extrusion/spheronization pellets.
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http://dx.doi.org/10.2174/1567201817666201124113741DOI Listing
November 2020

More Caution Needed for Patients Recovered From COVID-19.

Front Public Health 2020 2;8:562418. Epub 2020 Nov 2.

Center for Clinical Epidemiology and Methodology (CCEM), Guangdong Second Provincial General Hospital, Guangzhou, China.

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http://dx.doi.org/10.3389/fpubh.2020.562418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667189PMC
November 2020

NO removal with efficient recycling of NO from iron-ore sintering flue gas: A novel cyclic adsorption process.

J Hazard Mater 2021 Apr 27;407:124380. Epub 2020 Oct 27.

Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109-2136, United States.

Conventional flue gas nitrogen oxides (NO) abatement technologies commonly convert NO into harmless compounds, while less effort has been made to recycle NO as a profitable chemical in many industries. Towards this end, adsorption is a promising technology for which an advanced technique for NO desorption and efficient sorbent regeneration provides the key step for success in practical applications. This work reports a novel cyclic adsorption process for NO removal with recycling of NO from iron-ore sintering flue gas of a steel plant. This process using self-prepared and validated pelletized Na-ZSM-5 zeolites as low-cost sorbents involves NO catalytic adsorption and reversible desorption using multiple hot gas circulations (GC) within the enclosed fixed bed followed by scavenging and purge at mild conditions. In comparison to conventional cyclic processes, greater amount of recyclable NO was obtained, rendering the NO recovery of >92% and the mean NO concentration of >2% significantly enriched from original 20 ppm in feed gas. A robust adsorption-desorption performance with appreciable NO working capacity was achieved for up to 16 cycles. The key role of the segmentation of GC in boosting NO regenerability was addressed, providing an economical three-tower strategy for continuous NO production for practical use.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124380DOI Listing
April 2021

Thioguanine Induces Apoptosis in Triple-Negative Breast Cancer by Regulating PI3K-AKT Pathway.

Front Oncol 2020 30;10:524922. Epub 2020 Oct 30.

Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China.

Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of biological targets and poor sensitivity to conventional therapies. Chemotherapy is the main clinical therapy, but the effective screening strategy for chemotherapy drugs is poorly investigated. Drug repositioning has been the center of attention in recent years attracting numerous studies. Here, we firstly found multiple common features between leukemia and TNBC by analyzing the global transcriptome profiles based on the transformed comparison data from NCI60. Therefore, we investigated the role of the classic leukemia drug thioguanine (6-TG) in TNBC cancer cells. Our results indicated that 6-TG inhibited cell proliferation and tumor cell progression by suppressing PI3K-AKT pathway downregulating the DNA methylation level of . Moreover, apoptosis was induced the activation of PI3K-AKT downstream and the downregulation of methylation levels of , , and These findings indicated 6TG exerts its anti-tumor effects and through regulating the DNA methylation levels of genes involved in PI3K-AKT and apoptosis pathway. Meanwhile, our study suggested that transcriptome-based drug screening has potential implications for breast cancer therapy and drug selection.
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http://dx.doi.org/10.3389/fonc.2020.524922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662440PMC
October 2020

TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment.

Nucleic Acids Res 2021 01;49(D1):D1420-D1430

Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200060, China.

Cancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors but posed computational challenges on integrating and utilizing the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH, http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly 2 million cells from 76 high-quality tumor datasets across 27 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, clustering, cell-type annotation, malignant cell classification, differential expression analysis and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME.
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http://dx.doi.org/10.1093/nar/gkaa1020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778907PMC
January 2021

Asymmetric Mannich reactions of ()---butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles.

Beilstein J Org Chem 2020 29;16:2671-2678. Epub 2020 Oct 29.

Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, Jiangsu, China.

In the present work, arylethynes were studied as new C-nucleophiles in the asymmetric Mannich addition reactions with ()---butylsulfinyl-3,3,3-trifluoroacetaldimine. The reactions were conducted under operationally convenient conditions affording the corresponding Mannich adducts with up to 87% yield and 70:30 diastereoselectivity. The isomeric products can be separated using regular column chromatography to afford diastereomerically pure compounds. The purified Mannich addition products were deprotected to give the target enantiomerically pure trifluoromethylpropargylamines. A mechanistic rationale for the observed stereochemical outcome is discussed.
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http://dx.doi.org/10.3762/bjoc.16.217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607431PMC
October 2020

The emerging prospects of circular RNA in tumor immunity.

Ann Transl Med 2020 Sep;8(17):1091

Research Center and Tumor Research Institute, the Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China.

Circular RNA (circRNA), as a cluster of endogenous non-coding RNA (ncRNA) with tissue-specific expression in various eukaryotic species, may be involved in a variety of human physiological and pathological processes. With the continuous development of high-throughput sequencing in recent years, circRNA has been increasingly widely studied and become a hot spot in the field of tumor research. The immune system plays a crucial and complex role in tumor development. It is not only capable of inhibiting tumor progression, but it can also create conditions suitable for tumor development, thereby promoting tumor progression. Moreover, through ncRNA, tumor immunotherapy, as an essential means of tumor therapy, may regulate tumor immunity to achieve the purpose of treatment. This article reviews the role of circRNA in tumor immunity to supply a sufficient theoretical basis for tumor immunotherapy.
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http://dx.doi.org/10.21037/atm-19-4751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575963PMC
September 2020

Complete deconvolution of DNA methylation signals from complex tissues: a geometric approach.

Bioinformatics 2020 Nov 2. Epub 2020 Nov 2.

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Motivation: It is a common practice in epigenetics research to profile DNA methylation on tissue samples, which is usually a mixture of different cell types. To properly account for the mixture, estimating cell compositions has been recognized as an important first step. Many methods were developed for quantifying cell compositions from DNA methylation data, but they mostly have limited applications due to lack of reference or prior information.

Results: We develop Tsisal, a novel complete deconvolution method which accurately estimate cell compositions from DNA methylation data without any prior knowledge of cell types or their proportions. Tsisal is a full pipeline to estimate number of cell types, cell compositions, and identify cell-type-specific CpG sites. It can also assign cell type labels when (full or part of) reference panel is available. Extensive simulation studies and analyses of seven real data sets demonstrate the favorable performance of our proposed method compared with existing deconvolution methods serving similar purpose.

Availability: The proposed method Tsisal is implemented as part of the R/Bioconductor package TOAST at https://bioconductor.org/packages/TOAST.

Contact: ziyi.li@emory.edu and hao.wu@emory.edu.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa930DOI Listing
November 2020

Spatial distribution and sources of winter black carbon and brown carbon in six Chinese megacities.

Sci Total Environ 2021 Mar 17;762:143075. Epub 2020 Oct 17.

Key Lab of Aerosol Chemistry & Physics, SKLLQG, Institute of Earth Environment, Chinese Academy of Sciences, Xi'an, China.

The light-absorbing carbonaceous aerosols, including black carbon (BC) and brown carbon (BrC), influenced heavily on aerosol environmental quality and the Earth's radiation. Here, a winter campaign to characterize BC and BrC in PM was conducted simultaneously in six Chinese megacities (i.e., Harbin, Beijing, Xi'an, Shanghai, Wuhan, and Guangzhou) using continual aethalometers. The combinations of advanced aethalometer and generalized additive model (GAM) were used to precisely quantify the BC and BrC sources in these megacities. The averaged light-absorbing coefficients of BC (b-BC) and BrC (b-BrC) were 28.6 and 21.8 Mm in northern cities, they were 1.4 and 2.7 times higher than those in southern cities. The BrC dominated the total b (>40%) in northern cities but low to 20% in southern cities. On the other hand, the BC fractions were high in the southern cities, with the contributions of 62.4-79.7%, whereas much lower values of 53.7-59.4% in the northern cities. Source apportionment showed that the combustion of liquid fuels (e.g., gasoline or diesel) was highly dominant to b-BC (>80%) in Guangzhou and Wuhan. This was further supported by the high NO loadings in the GAM model. Solid fuels (i.e., biomass or coal) contributed a substantial portion to total b-BC in the other four cities where the high abundances of primary b-BrC were observed. The diurnal trend showed the peaks of secondary-BrC (b-BrC) and b-BrC/ΔCO in the northern cities occurred at high relative humidity in nighttime, implying the secondary BrC formation was possibly related to aqueous reactions in winter. In contrast, in the southern cities of Shanghai and Guangzhou, the accumulation of vehicle emissions during the morning traffic rush hours lead the formation of secondary BrC through photochemical reactions. The results of this work can be applied for the development of more effective practices to control BC and BrC on regional scale.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143075DOI Listing
March 2021

Association between frailty and risk of fall among diabetic patients.

Endocr Connect 2020 Oct;9(10):1057-1064

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.

Background: Several epidemiological studies have demonstrated the risk factors for fall, while few studies investigated the association between frailty and risk of fall in diabetic patients aged ≥45 years.

Methods: In this multicity observational study, participants with type 2 diabetes aged ≥45 years were enrolled. Frailty status was measured by a frailty index (FI) of deficit accumulation. We used multivariable regression models to examine the relationship between frailty and fall in diabetic patients, and further investigated the associations between frailty and fall in varied subgroups.

Results: A total of 2049 participants with type 2 diabetes were identified in our study. Our results showed a per-s.d. and a per-0.01 increment of FI were associated with an increased risk of fall, with a fully adjusted OR of 1.89 (95% CI: 1.50, 2.38), 1.06 (95% CI: 1.04, 1.09), respectively. The effects were magnified when frailty was considered as dichotomous, with an OR of 3.08 (95% CI: 2.18, 4.34). In further subgroup analyses, we found that the females, the older, rural residents, individuals with no sitting toilet, people with poor balance performance and those in poor health status were susceptible to fall. Especially, for the risk of fall in the older, a per-s.d. increase of FI corresponded to an OR of 2.46 (95% CI: 1.68, 3.62). When frailty was regarded as a binary variable, the effect increased to 4.62 (95% CI: 2.54, 8.38) in the older subgroup.

Conclusion: Frailty was associated with a higher risk of fall in people with type 2 diabetes, and the effects were higher in vulnerable groups. This evidence suggested that more attention should be paid to vulnerable groups for fall prevention.
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http://dx.doi.org/10.1530/EC-20-0405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707831PMC
October 2020

Clonal tracing reveals diverse patterns of response to immune checkpoint blockade.

Genome Biol 2020 10 15;21(1):263. Epub 2020 Oct 15.

Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Background: Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but only a minority of cancer patients respond. Multiple studies have sought to identify general biomarkers of ICB response, but elucidating the molecular and cellular drivers of resistance for individual tumors remains challenging. We sought to determine whether a tumor with defined genetic background exhibits a stereotypic or heterogeneous response to ICB treatment.

Results: We establish a unique mouse system that utilizes clonal tracing and mathematical modeling to monitor the growth of each cancer clone, as well as the bulk tumor, in response to ICB. We find that tumors derived from the same clonal populations showed heterogeneous ICB response and diverse response patterns. Primary response is associated with higher immune infiltration and leads to enrichment of pre-existing ICB-resistant cancer clones. We further identify several cancer cell-intrinsic gene expression signatures associated with ICB resistance, including increased interferon response genes and glucocorticoid response genes. These findings are supported by clinical data from ICB treatment cohorts.

Conclusions: Our study demonstrates diverse response patterns from the same ancestor cancer cells in response to ICB. This suggests the value of monitoring clonal constitution and tumor microenvironment over time to optimize ICB response and to design new combination therapies. Furthermore, as ICB response may enrich for cancer cell-intrinsic resistance signatures, this can affect interpretations of tumor RNA-seq data for response-signature association studies.
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http://dx.doi.org/10.1186/s13059-020-02166-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559192PMC
October 2020

Cloning, expression and biochemical characterization of a novel amidase from Thauera sinica K11.

Protein Expr Purif 2021 Jan 14;177:105751. Epub 2020 Sep 14.

Centre for Bioengineering and Biotechnology, College of Chemical Engineering, China University of Petroleum (East China), Qingdao, 266580, China. Electronic address:

A novel amidase (TAM) was identified and cloned from the genome of Thauera sinica K11. The recombinant protein was purified to homogeneity by one-step affinity chromatography for up to 26.4-fold with a yield of 38.1%. Gel filtration chromatography and SDS-PAGE revealed that the enzyme was a tetramer with a subunit of approximately 37.5 kDa. The amidase exhibited the maximum acyl transfer activity at 45 °C and pH 7.0, and it was highly stable over a wide pH range of 6.0-11.0. Inhibition of enzyme activity was observed in the presence of metal ions, thiol reagents and organic solvents. TAM showed a broad substrate spectrum toward aliphatic, aromatic and heterocyclic amides. For linear aliphatic monoamides, the acyl transfer activity of TAM was decreased with the extension of the carbon chain length, and thus the highest activity of 228.2 U/mg was obtained when formamide was used as substrate. This distinct selectivity of amidase to linear aliphatic monoamides expanded the findings of signature amidases to substrate specificity.
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http://dx.doi.org/10.1016/j.pep.2020.105751DOI Listing
January 2021

ZEB1-Mediated Transcriptional Upregulation of circWWC3 Promotes Breast Cancer Progression through Activating Ras Signaling Pathway.

Mol Ther Nucleic Acids 2020 Aug 19;22:124-137. Epub 2020 Aug 19.

Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China; Key Laboratory for Tumor Diagnosis, Prevention and Therapy in Hebei Province, Shijiazhuang, Hebei 050017, P.R. China. Electronic address:

Zinc finger E-box binding homeobox 1 (ZEB1) has been widely recognized as an important driver of tumor growth and metastasis. However, nothing is known about ZEB1-regulated circular (circ)RNAs in cancer. In the current study, we evaluated the function of a novel ZEB1-regulated circRNA derived from the WWC3 gene locus, circWWC3 in breast cancer progression. We found that ZEB1 upregulated circWWC3 expression but not the linear WWC3 mRNA expression. circWWC3 is highly expressed in breast cancer tissues and is associated with the poor prognosis of breast cancer patients. Silencing of circWWC3 significantly suppresses the proliferation, migration, and invasion of breast cancer cells. Mechanically, circWWC3 upregulates multiple oncogenes' expression of the Ras signaling pathway through acting as the sponge of microRNA (miR)-26b-3p and miR-660-3p. Moreover, short hairpin (sh)RNA-mediated knockdown of circWWC3 partially antagonized ZEB1-mediated breast cancer growth and metastasis in vivo. Our findings reveal that ZEB1-mediated upregulation of circWWC3 promotes breast cancer progression through activating Ras signaling pathway, which provides a potential therapeutic target and prognostic biomarker for breast cancer.
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http://dx.doi.org/10.1016/j.omtn.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490471PMC
August 2020

Effects of shuxuetong injection for cerebral infarction: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2020 Aug;99(35):e21929

The Second Affiliated Hospital of Nanchang University, Nanchang.

Background: Cerebral infarction (CI) is a common disease with high morbidity and disability. Shuxuetong (SXT) injection is a Chinese Materia Medica standardized product used in the treatment of CI. Currently, there is a lack of high-quality evidence to support the effectiveness and safety of SXT on patients with CI. This systematic review protocol aims at describing a meta-analysis to evaluate the efficacy of SXT for the treatment of CI.

Methods: We will search the databases of PubMed, MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, China national knowledge infrastructure database (CNKI), Wan fang database, Chongqing VIP information, and SinoMed from their inception to Jun 2020. Two reviewers will independently screen Randomized controlled trials of SXT for the treatment of CI. The meta-analysis will be conducted using RevMan V.5.3 software.

Results: The results of this study will be published in a peer-reviewed journal.

Conclusion: The conclusion of our systematic review will provide evidence to judge whether SXT is an effective intervention for patients with CI.

Trial Registration Number: 10.17605/OSF.IO/3F6ZH.
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http://dx.doi.org/10.1097/MD.0000000000021929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458199PMC
August 2020

IL2RG-deficient minipigs generated via CRISPR/Cas9 technology support the growth of human melanoma-derived tumours.

Cell Prolif 2020 Oct 1;53(10):e12863. Epub 2020 Sep 1.

Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, Jilin University, Changchun, China.

Objectives: Immunodeficient mice injected with human cancer cell lines have been used for human oncology studies and anti-cancer drug trials for several decades. However, rodents are not ideal species for modelling human cancer because rodents are physiologically dissimilar to humans. Therefore, anti-tumour drugs tested effective in rodents have a failure rate of 90% or higher in phase III clinical trials. Pigs are similar to humans in size, anatomy, physiology and drug metabolism rate, rendering them a desirable pre-clinical animal model for assessing anti-cancer drugs. However, xenogeneic immune rejection is a major barrier to the use of pigs as hosts for human tumours. Interleukin (IL)-2 receptor γ (IL2RG), a common signalling subunit for multiple immune cytokines including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, is required for proper lymphoid development.

Materials And Methods: IL2RG pigs were generated by CRISPR/Cas9 technology, and examined for immunodeficiency and ability to support human oncogenesis.

Results: Compared to age-matched wild-type pigs, IL2RG pigs exhibited a severely impaired immune system as shown by lymphopenia, lymphoid organ atrophy, poor immunoglobulin function, and T- and NK-cell deficiency. Human melanoma Mel888 cells generated tumours in IL2RG pigs but not in wild-type littermates. The human tumours grew faster in IL2RG pigs than in nude mice.

Conclusions: Our results indicate that these pigs are promising hosts for modelling human cancer in vivo, which may aid in the discovery and development of anti-cancer drugs.
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http://dx.doi.org/10.1111/cpr.12863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574875PMC
October 2020

Roles of N6-Methyladenosine (mA) in Stem Cell Fate Decisions and Early Embryonic Development in Mammals.

Front Cell Dev Biol 2020 11;8:782. Epub 2020 Aug 11.

Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China.

N6-methyladenosine (mA) is one of the most abundant internal mRNA modifications, and it affects multiple biological processes related to eukaryotic mRNA. The majority of mA sites are located in stop codons and 3'UTR regions of mRNAs. mA regulates RNA metabolism, including alternative splicing (AS), alternative polyadenylation (APA), mRNA export, decay, stabilization, and translation. The mA metabolic pathway is regulated by a series of mA writers, erasers and readers. Recent studies indicate that mA is essential for the regulation of gene expression, tumor formation, stem cell fate, gametogenesis, and animal development. In this systematic review, we summarized the recent advances in newly identified mA effectors and the effects of mA on RNA metabolism. Subsequently, we reviewed the functional roles of RNA mA modification in diverse cellular bioprocesses, such as stem cell fate decisions, cell reprogramming and early embryonic development, and we discussed the potential of mA modification to be applied to regenerative medicine, disease treatment, organ transplantation, and animal reproduction.
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http://dx.doi.org/10.3389/fcell.2020.00782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431753PMC
August 2020

Integrative analysis of circRNAs, miRNAs, and mRNAs profiles to reveal ceRNAs networks in chicken intramuscular and abdominal adipogenesis.

BMC Genomics 2020 Aug 26;21(1):594. Epub 2020 Aug 26.

Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, 130021, Jilin, China.

Background: Tissue-specific fat deposition is regulated by a series of complex regulatory mechanisms. Reports indicate that epigenetic regulators, such as circular RNAs (circRNAs), are crucial in diseases progression, animal development, metabolism, and adipogenesis. In this study, to assess the functional roles of circRNAs in adipogenesis and tissue-specific fat deposition, we comprehensively analyzed the Ribo-Zero RNA-Seq and miRNAs data during chicken intramuscular and abdominal adipogenic differentiation.

Results: circRNAs and miRNAs profiles during chicken adipogenic differentiation were found in adipocytes derived from various adipose tissues. It was also discovered that high levels of downregulated miRNAs potentially promote adipogenesis by activating their target genes which are associated with fatty acid metabolism and adipogenic differentiation. Through analysis of the correlation between the expression levels of circRNAs and adipogenic genes, as well as the dynamic expression patterns of circRNAs during adipogenic differentiation, several candidate circRNAs were identified. Moreover, competing endogenous RNA (ceRNAs) networks were constructed during chicken intramuscular and abdominal adipogenesis by combining miRNAs with mRNAs data. Several candidate circRNAs potentially influence adipogenesis by regulating miRNAs via PPAR and fatty acid metabolism-related pathways were identified, such as circLCLAT1, circFNDC3AL, circCLEC19A and circARMH1.

Conclusion: In conclusion, our findings reveal that circRNAs and the circRNA-miRNAs-mRNAs-ceRNAs network may play important roles in chicken adipocytes differentiation and tissue-specific fat deposition.
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http://dx.doi.org/10.1186/s12864-020-07000-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450580PMC
August 2020

LncRNA TTN-AS1 promotes the progression of cholangiocarcinoma via the miR-320a/neuropilin-1 axis.

Cell Death Dis 2020 08 15;11(8):637. Epub 2020 Aug 15.

The Hepatosplenic Surgery Center, the First Affiliated Hospital of Harbin Medical University, 150001, Harbin, China.

Neuropilin-1 regulated by miR-320a participates in the progression of cholangiocarcinoma by serving as a co-receptor that activates multiple signaling pathways. The present study sought to investigate upstream lncRNAs that control the expression of miR-320a/neuropilin-1 axis and dissect some of the underlying mechanisms. Here we report lncRNA TTN-AS1 (titin-antisense RNA1) acts as a sponging ceRNA to downregulate miR-320a and is highly expressed in human cholangiocarcinoma tissues and cells. The expression of the above three molecules is correlated with the clinicopathologic parameters of cholangiocarcinoma patients. In this study, multiple bioinformatics tools and databases were employed to seek potential lncRNAs that have binding sites with miR-320a and TTN-AS1 was identified because it exhibited the largest folds of alteration between cholangiocarcinoma and normal bile duct epithelial cells. The regulatory role of TTN-AS1 on miR-320a was further evaluated by luciferase reporter and RNA pulldown assays, coupled with in situ hybridization and RNA immunoprecipitation analyses, which showed that TTN-AS1 bound to miR-320a through an argonaute2-dependent RNA interference pathway in the cytoplasm of cholangiocarcinoma cells. Knockdown and overexpression assays showed that the regulatory effect between TTN-AS1 and miR-320 was in a one-way manner. TTN-AS1 promoted the proliferation and migration of cholangiocarcinoma cells via the miR-320a/ neuropilin-1 axis. The function of TTN-AS1 on tumor growth and its interaction with miR-320a were confirmed in animal models. Further mechanistic studies revealed that TTA-AS1, through downregulating miR-320a, promoted cell cycle progression, epithelial-mesenchymal transition, and tumor angiogenesis by upregulating neuropilin-1, which co-interacted with the hepatocyte growth factor/c-Met and transforming growth factor (TGF)-β/TGF-β receptor I pathways. In conclusion, the present results demonstrate that lncRNA TTA-AS1 is a sponging ceRNA for miR-320a, which in turn downregulates neuropilin-1 in cholangiocarcinoma cells, indicating these three molecules represent potential biomarkers and therapeutic targets in the management of cholangiocarcinoma.
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http://dx.doi.org/10.1038/s41419-020-02896-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429853PMC
August 2020

Precursor Engineering of Vapor-Exchange Processes for 20%-Efficient 1 cm Inverted-Structure Perovskite Solar Cells.

ACS Appl Mater Interfaces 2020 Sep 31;12(37):41303-41311. Epub 2020 Aug 31.

Key Laboratory of Display Materials and Photoelectric Devices (Ministry of Education), Tianjin Key Laboratory for Photoelectric Materials and Devices, School of Materials Science and Engineering, Tianjin University of Technology, Tianjin 300384, P. R. China.

Due to mass diffusion issues, it is challenging to prepare black-phase thick formamidinium-based perovskite (FAPbI) films via vapor approaches. Precursor engineering is employed here to overcome the dilemma of thorough reaction and black-phase stabilization of FAPbI in a sequential vapor approach. For the first time, FAPbBr was used as an additive in the precursor to promote the formation of FAPbI perovskite. To balance off the increased crystallization degree of precursor films due to the addition of FAPbBr, CsI dissolved in dimethyl sulfoxide (DMSO) was further added. It is indicated that the simultaneous incorporation of FAPbBr and CsI-DMSO successfully accelerated the formation rate of perovskite and inhibited the formation of FAPbI yellow phase. The power conversion efficiency of the as-prepared devices of different areas (0.1125 or 1 cm) reached 20%, the first report of large-area 20%-efficiency PSCs based on a vapor approach, highlighting its applicability to large-area manufacture in the future. Furthermore, when blade coating is used in preparing the precursor film, the efficiency reached 19%. When the precursor film was prepared by dip coating, we could prepare conformal FAPbI coatings on carbon fibers, suggesting possible future applications in fabricating wearable PSCs.
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http://dx.doi.org/10.1021/acsami.0c10379DOI Listing
September 2020

Single-Cell Sequencing of Peripheral Mononuclear Cells Reveals Distinct Immune Response Landscapes of COVID-19 and Influenza Patients.

Immunity 2020 09 19;53(3):685-696.e3. Epub 2020 Jul 19.

NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 102206 Beijing, China. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.
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http://dx.doi.org/10.1016/j.immuni.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368915PMC
September 2020

Integrative analyses of single-cell transcriptome and regulome using MAESTRO.

Genome Biol 2020 08 7;21(1):198. Epub 2020 Aug 7.

Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, 02215, USA.

We present Model-based AnalysEs of Transcriptome and RegulOme (MAESTRO), a comprehensive open-source computational workflow ( http://github.com/liulab-dfci/MAESTRO ) for the integrative analyses of single-cell RNA-seq (scRNA-seq) and ATAC-seq (scATAC-seq) data from multiple platforms. MAESTRO provides functions for pre-processing, alignment, quality control, expression and chromatin accessibility quantification, clustering, differential analysis, and annotation. By modeling gene regulatory potential from chromatin accessibilities at the single-cell level, MAESTRO outperforms the existing methods for integrating the cell clusters between scRNA-seq and scATAC-seq. Furthermore, MAESTRO supports automatic cell-type annotation using predefined cell type marker genes and identifies driver regulators from differential scRNA-seq genes and scATAC-seq peaks.
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http://dx.doi.org/10.1186/s13059-020-02116-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412809PMC
August 2020

Conversion of Fibroblast into Functional Leydig-like Cell Using Defined Small Molecules.

Stem Cell Reports 2020 08 30;15(2):408-423. Epub 2020 Jul 30.

Department of Cell Biology, Jinan University, Guangzhou 510632, China; Department of Pharmacology, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Bioengineering Medicine of, Guangzhou 510632, China. Electronic address:

Recent studies have demonstrated that fibroblasts can be directly converted into functional Leydig cells by transcription factors. However, the transgenic approach used in these studies raises safety concerns for its future application. Here, we report that fibroblasts can be directly reprogrammed into Leydig-like cells by exposure to a combination of forskolin, 20α-hydroxycholesterol, luteinizing hormone, and SB431542. These chemical compound-induced Leydig-like cells (CiLCs) express steroidogenic genes and have a global gene expression profile similar to that of progenitor Leydig cells, although not identical. In addition, these cells can survive in testis and produce testosterone in a circadian rhythm. This induction strategy is applicable to reprogramming human periodontal ligament fibroblasts toward Leydig-like cells. These findings demonstrated fibroblasts can be directly converted into Leydig-like cells by pure chemical compounds. This strategy overcomes the limitations of conventional transgenic-based reprogramming and provides a simple, effective approach for Leydig cell-based therapy while simultaneously preserving the hypothalamic-pituitary-gonadal axis.
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http://dx.doi.org/10.1016/j.stemcr.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419716PMC
August 2020