Publications by authors named "Weijun Shi"

18 Publications

  • Page 1 of 1

NLRP3 promotes immune escape by regulating immune checkpoints: A pan-cancer analysis.

Int Immunopharmacol 2022 Jan 10;104:108512. Epub 2022 Jan 10.

Department of Hepatobiliary Pancreatic Surgery, the First Hospital of Ningbo City, Ningbo 315010, China. Electronic address:

NLRP3 plays a pathogenic role in tumorigenesis by regulating innate and acquired immunity, apoptosis, differentiation, and intestinal microbes in tumors. Our research aimed to investigate the role of NLRP3 in pan-cancers based on multi-omics data in the TCGA database. Most types of tumors showed increased expression of NLRP3. Among them, the overexpressed NLRP3 in liver hepatocellular carcinoma (LIHC) and ovarian cancer (OV) indicated worse overall survival (OS). Further analysis also confirmed overexpressed NLRP3 in colon cancer (COAD) indicated a high probability of microsatellite instability (MSI) and low tumor mutational burden (TMB), which indicated a better response to immune checkpoint inhibitors (ICIs). Interestingly, overexpression of NLRP3 was closely related to high infiltration of immune cells (T cells, B cells, etc.) and overexpressed immune checkpoints (PD-1, PD-L1, LAG3, etc.). These results demonstrated NLRP3 promoted immune escape in cancers. Finally, we investigated the expression of various immune checkpoints by treating NLRP3 inhibitor MCC950 during the co-culture of peripheral blood mononuclear cells (PBMC) and LIHC cell line Hep3B. MCC950 significantly repressed the expression of PD-L1 and LAG3, and promoted the apoptosis rate of Hep3B. In conclusion, our research demonstrated the role of NLRP3 in pan-cancer, especially in LIHC. Inhibition of NLRP3 promoted the killing effect of T cells to cancer cells by repressing the expression of immune checkpoints.
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http://dx.doi.org/10.1016/j.intimp.2021.108512DOI Listing
January 2022

Integrated analysis of long non-coding RNA-microRNA-mRNA competing endogenous RNAregulatory networks in thromboangiitis obliterans.

Bioengineered 2021 12;12(2):12023-12037

Department of Vascular Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.

Thromboangiitis obliterans (TAO) is a non-atherosclerotic, segmental, chronic vascular inflammatory disease. Our aim was to explore the underlying mechanisms of long non-coding RNA (lncRNA)-related competing endogenous RNAs (ceRNAs) in TAO. Six blood samples were collected from patients with TAO and healthy individuals (three for each category). Total RNA was extracted from the blood of each participant and sequenced. Differentially expressed lncRNAs (DE-lncRNAs) and miRNAs (DE-miRNAs) were screened, and ceRNA networks associated with TAO were constructed. Thereafter, the genes in the ceRNA network were subjected to functional analyses. Finally, a ceRNA relationship (lncRNA NEAT1-hsa-miR-1-3p-mRNA GNA12) was selected for further validation. Analysis revealed that 347 DE-lncRNAs (150 downregulated and 197 upregulated) and 16 DE-miRNAs (3 downregulated and 13 upregulated) were identified in TAO. Further, TAO-associated ceRNA networks, which included 219 lncRNAs, 6 miRNAs, and 53 mRNAs, were proposed and subjected to gene annotation and pathway analysis. Additionally, NEAT1 and GNA12 levels were significantly upregulated, while miR-1-3p levels were evidently downregulated in TAO patients, as compared with those in healthy controls. Dual luciferase reporter assays showed that NEAT1, miR-1-3p, and GNA12 interacted with each other. We report potential TAO-associated ceRNA regulatory networks and suggest activation of NEAT1/miR-1-3p/GNA12 signaling as a novel mechanism for TAO progression.
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http://dx.doi.org/10.1080/21655979.2021.2002497DOI Listing
December 2021

The role of multiple metabolic genes in predicting the overall survival of colorectal cancer: A study based on TCGA and GEO databases.

PLoS One 2021 16;16(8):e0251323. Epub 2021 Aug 16.

Department of Gastroenterology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China.

The recent advances in gene chip technology have led to the identification of multiple metabolism-related genes that are closely associated with colorectal cancer (CRC). Nevertheless, none of these genes could accurately diagnose or predict CRC. The prognosis of CRC has been made by previous prognostic models constructed by using multiple genes, however, the predictive function of multi-gene prognostic models using metabolic genes for the CRC prognosis remains unexplored. In this study, we used the TCGA-CRC cohort as the test dataset and the GSE39582 cohort as the experimental dataset. Firstly, we constructed a prognostic model using metabolic genes from the TCGA-CRC cohort, which were also associated with CRC prognosis. We analyzed the advantages of the prognostic model in the prognosis of CRC and its regulatory mechanism of the genes associated with the model. Secondly, the outcome of the TCGA-CRC cohort analysis was validated using the GSE39582 cohort. We found that the prognostic model can be employed as an independent prognostic risk factor for estimating the CRC survival rate. Besides, compared with traditional clinical pathology, it can precisely predict CRC prognosis as well. The high-risk group of the prognostic model showed a substantially lower survival rate as compared to the low-risk group. In addition, gene enrichment analysis of metabolic genes showed that genes in the prognostic model are enriched in metabolism and cancer-related pathways, which may explain its underlying mechanism. Our study identified a novel metabolic profile containing 11 genes for prognostic prediction of CRC. The prognostic model may unravel the imbalanced metabolic microenvironment, and it might promote the development of biomarkers for predicting treatment response and streamlining metabolic therapy in CRC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251323PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367004PMC
November 2021

Thromboangiitis obliterans plasma-derived exosomal miR-223-5p inhibits cell viability and promotes cell apoptosis of human vascular smooth muscle cells by targeting VCAM1.

Ann Med 2021 12;53(1):1129-1141

Department of Vascular Surgery, Shanghai Pudong Hospital Affiliated to Fudan University, Shanghai, China.

Exosomes-encapsulated microRNAs (miRNAs) have been established to be implicated in the pathogenesis of different diseases. Nevertheless, circulating exosomal miRNAs of thromboangiitis obliterans (TAO) remains poorly understood. This study aimed to explore the effects of exosomal miRNAs associated with TAO on human vascular smooth muscle cells (HVSMCs). The exosomes were isolated from the plasma of TAO patients and normal controls and then were sent for small RNA sequencing. Differentially expressed miRNAs (DE-miRNAs) were identified by bioinformatics analysis and were confirmed by RT-qPCR. After that, PKH67 staining was used to label exosomes and co-cultured with HVSMCs. Cell viability and apoptosis were, respectively, tested by CCK-8 assay and flow cytometry. Finally, dual-luciferase reporter assay was used to confirm the downstream targets of miR-223-5p. A total of 39 DE-miRNAs were identified between TAO patients and normal controls, of which, miR-223-5p was one of the most significantly up-regulated miRNAs. TAO plasma-derived exosomes or miR-223-5p mimics inhibited cell viability of HVSMCs and promoted cell apoptosis. The pro-apoptotic effect of TAO plasma-derived exosomes was alleviated by miR-223-5p inhibitor. Additionally, the expressions of VCAM1 and IGF1R were down-regulated by exosomes and miR-223-5p mimics, and were abrogated by miR-223-5p inhibitor. Dual-luciferase report showed that VCAM1 was the target of miR-223-5p. Our findings imply that circulating exosomal miR-223-5p may play an essential role in the pathogenesis of TAO, and provide a basis for miR-6515-5p/VCAM1 as novel therapeutic targets and pathways for TAO treatment.
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http://dx.doi.org/10.1080/07853890.2021.1949487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281010PMC
December 2021

The genomic basis of geographic differentiation and fiber improvement in cultivated cotton.

Nat Genet 2021 06 15;53(6):916-924. Epub 2021 Apr 15.

State Key Laboratory of Cotton Biology, Institute of Cotton Research of the Chinese Academy of Agricultural Sciences, Anyang, China.

Large-scale genomic surveys of crop germplasm are important for understanding the genetic architecture of favorable traits. The genomic basis of geographic differentiation and fiber improvement in cultivated cotton is poorly understood. Here, we analyzed 3,248 tetraploid cotton genomes and confirmed that the extensive chromosome inversions on chromosomes A06 and A08 underlies the geographic differentiation in cultivated Gossypium hirsutum. We further revealed that the haplotypic diversity originated from landraces, which might be essential for understanding adaptative evolution in cultivated cotton. Introgression and association analyses identified new fiber quality-related loci and demonstrated that the introgressed alleles from two diploid cottons had a large effect on fiber quality improvement. These loci provided the potential power to overcome the bottleneck in fiber quality improvement. Our study uncovered several critical genomic signatures generated by historical breeding effects in cotton and a wealth of data that enrich genomic resources for the research community.
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http://dx.doi.org/10.1038/s41588-021-00844-9DOI Listing
June 2021

A Single-Nucleotide Mutation in a GLUTAMATE RECEPTOR-LIKE Gene Confers Resistance to Fusarium Wilt in .

Adv Sci (Weinh) 2021 04 19;8(7):2002723. Epub 2021 Feb 19.

National Key Laboratory of Crop Genetic Improvement Huazhong Agricultural University Wuhan Hubei 430070 China.

Fusarium wilt (FW) disease of cotton, caused by the fungus f. sp. (), causes severe losses in cotton production worldwide. Though significant advancements have been made in development of FW-resistant Upland cotton () in resistance screening programs, the precise resistance genes and the corresponding molecular mechanisms for resistance to remain unclear. Herein it is reported that , a gene unlike canonical plant disease-resistance () genes, putatively encoding a GLUTAMATE RECEPTOR-LIKE (GLR) protein, confers resistance to race 7 in Upland cotton. A single nucleotide polymorphism (SNP) (C/A) in , resulting in an amino acid change (L/I), is associated with resistance. A PCR-based DNA marker ( ) is developed and shown to cosegregate with the resistance. CRISPR/Cas9-mediated knockout of results in cotton lines extremely susceptible to race 7 with a loss of the ability to induce calcium influx in response to total secreted proteins (SEPs) of . Furthermore, coinfiltration of SEPs with results in a hypersensitive response. This first report of a GLR-encoding gene that functions as an gene provides a new insight into plant-pathogen interactions and a new handle to develop cotton cultivars with resistance to race 7.
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http://dx.doi.org/10.1002/advs.202002723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025038PMC
April 2021

miRNAs regulating the expressions of NTF3, GNG2 and ITGA7 are involved in the pathogenesis of abdominal aortic aneurysm in mice.

Gen Physiol Biophys 2021 Jan;40(1):1-16

Department of Vascular Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, but effective treatment strategies remain lacking. The objective of this study was to screen underlying therapeutic targets by investigating the molecular mechanisms of AAA using mouse models. The mRNA (GSE109639) and miRNA (GSE51229 and GSE54943) expression profiles of mouse AAA models were downloaded from Gene Expression Omnibus database. A total of 1367 differentially expressed genes (DEGs) were identified between AAA and sham group, 490 of which were used for constructing the Protein-Protein Interaction (PPI) network. NTF3, GNG2 and ITGA7 in the PPI network were suggested to be hub genes according to their ranking of topological features. Furthermore, hub gene GNG2 was enriched in module 1, while ITGA7 was enriched in module 3. Eighteen differentially expressed miRNAs (DEMs) were shared in two datasets, 6 of which were predicted to regulate 130 DEGs (i.e. mmu-miR-677-ITGA7, mmu-miR-350-NTF3 and mmu-miR-292-3p-GNG2) to establish the miRNA-mRNA regulatory network. Function enrichment analysis showed NTF3 was involved in cell motion and MAPK signaling pathway; ITGA7 affected extracellular matrix (ECM)-receptor interaction; GNG2 participated in cell proliferation and chemokine signaling pathway. In conclusion, miRNAs regulating the expressions of NTF3, GNG2 and ITGA7 may represent underlying targets for treatment of AAA.
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http://dx.doi.org/10.4149/gpb_2020033DOI Listing
January 2021

The Construction and Analysis of ceRNA Network and Patterns of Immune Infiltration in Colon Adenocarcinoma Metastasis.

Front Cell Dev Biol 2020 4;8:688. Epub 2020 Aug 4.

Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Colon adenocarcinoma (COAD) is a malignant and lethal tumor in digestive system and distance metastasis lead to poor prognosis. The metastasis-specific ceRNAs (competitive endogenous RNAs) and tumor-infiltrating immune cells might associate with tumor prognosis and distance metastasis. Nonetheless, few studies have concentrated on ceRNAs and Immune cells in COAD.

Methods: The gene expression profile and clinical information of COAD were downloaded from TCGA and divided into two groups: primary tumors with or without distance metastasis. We applied comprehensive bioinformatics methods to analyze differential expression genes (DEGs) related to metastasis and establish the ceRNA networks. The Cox analysis and Lasso regression were utilized to screen the pivotal genes and prevent overfitting. Based on them, the prognosis prediction nomograms were established. The cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm was then applied to screen significant tumor immune-infiltrating cells associated with COAD metastasis and established another prognosis prediction model. Ultimately, co-expression analysis was applied to explore the relationship between key genes in ceRNA networks and significant immune cells. Multiple databases and preliminary clinical specimen validation were used to test the expressions of key biomarkers at the cellular and tissue levels.

Results: We explored 1 significantly differentially expressed lncRNA, 1 significantly differentially expressed miRNA, 8 survival-related immune-infiltrating cells, 5 immune cells associated with distance metastasis. Besides, 3 pairs of important biomarkers associated with COAD metastasis were also identified: T cells follicular helper and hsa-miR-125b-5p ( = -0.200, < 0.001), Macrophages M0 and hsa-miR-125b-5p ( = 0.170, < 0.001) and Macrophages M0 and FAS ( = -0.370, < 0.001). Multidimensional validation and preliminary clinical specimen validation also supported the results.

Conclusion: In this research, we found some significant ceRNAs (FAS and hsa-miR-125b-5p) and tumor-infiltrating immune cells (T cells follicular helper and Macrophages M0) might related to distance metastasis and prognosis of COAD. The nomograms could assist scientific and medical researchers in clinical management.
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http://dx.doi.org/10.3389/fcell.2020.00688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417319PMC
August 2020

Comprehensive analysis of competitive endogenous RNAs network reveals potential prognostic lncRNAs in gastric cancer.

Heliyon 2020 May 17;6(5):e03978. Epub 2020 May 17.

Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China.

Long non-coding RNAs (lncRNAs) are key regulators of a range of human diseases, including various cancers, with multiple previous studies having explored lncRNA dysregulation in the context of gastric cancer (GC). The present study sought to expand upon these previous results by downloading lncRNA, mRNA, and microRNA (miRNA) expression profiles derived from 180 GC tissues and 24 normal control tissues within the Cancer Genome Atlas (TCGA) database. These datasets were then interrogated to identify GC-related differentially expressed (DE) RNAs (|fold change| ≥ 2, FDR< 0.01), leading to the identification of 1946 DE lncRNAs, 123 DE miRNAs, and 3159 DE mRNAs. These results were then used to generate a putative GC-related competitive endogenous RNA (ceRNA) network composed of 131 lncRNAs, 9 miRNAs, and 78 mRNAs. Subsequent survival analyses based upon this network revealed 17 of these lncRNAs to be significantly associated with GC patient survival ( < 0.05). Further multivariable Cox regression and lasso analyses allowed for the construction of an 8-lncRNA risk score that was able to effectively predict GC patient survival with good discriminative ability. The Kaplan-Meier Plotter database further confirmed that network hub genes that were related to these 8 lncRNAs were associated with GC patient prognosis ( < 0.05). As the ceRNA network in the present study was constructed with a focus on both disease stage and differential gene expression, it represents a key resource that will offer valuable insights into the mechanistic roles of ceRNA pathways in GC development and progression.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235626PMC
May 2020

Development of a triplex real-time PCR assay for detection and differentiation of gene-deleted and wild-type African swine fever virus.

J Virol Methods 2020 06 23;280:113875. Epub 2020 Apr 23.

Inspection and Quarantine Center for Animals and Plants, Shenzhen Customs, Shenzhen, 518045, PR China. Electronic address:

African swine fever (ASF) is an infectious disease of domestic and wild pigs, caused by ASF virus (ASFV). In this study, a triplex real-time PCR assay was developed to detect and differentiate the gene-deleted and wild-type ASFV strains. Three pairs of primers and probes were designed to target the conserved region of B646L gene (p72), MGF_360-14L gene (located in the middle of MGF360-505R gene) and CD2v gene, respectively. Gene-deleted (with MGF360-505R and / or CD2v genes deletion) and wild-type ASFV strains were detected specifically and simultaneously by the assay developed without cross-reactions with other nucleic acids of PCV-2, CSFV, PRRSV, FMDV or SVA. The detection limits of the triplex rPCR were 7.9 copies, 9.7 copies, and 9.6 copies of standard plasmid DNA containing B646L gene, MGF_360-14L gene and CD2v gene, respectively. A total of 1215 field samples were tested in parallel by the triplex rPCR and real-time PCR recommended by OIE, and the B646L gene detection results were completely consistent between these two assays. The triplex rPCR assay was successfully developed to identify pigs infected with wild-type ASFV strains or immunized with the ASFV gene-deleted vaccine.
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http://dx.doi.org/10.1016/j.jviromet.2020.113875DOI Listing
June 2020

Discovery of a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors.

Eur J Med Chem 2020 May 16;193:112239. Epub 2020 Mar 16.

Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China. Electronic address:

CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.
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http://dx.doi.org/10.1016/j.ejmech.2020.112239DOI Listing
May 2020

SPH3643: A novel cyclin-dependent kinase 4/6 inhibitor with good anticancer efficacy and strong blood-brain barrier permeability.

Cancer Sci 2020 May 24;111(5):1761-1773. Epub 2020 Mar 24.

Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, China.

The cyclin-dependent kinase (CDK)4/6-cyclin D1-Rb-p16/ink4a pathway is responsible for regulating cell progression past the G restriction point during the cell cycle. The development of a majority of human tumors is associated with dysregulation of this pathway, resulting in increased cancer cell proliferation. Both CDK4 and CDK6, well-validated cancer drug targets, function primarily as catalytic enzymes that mediate the phosphorylation of retinoblastoma protein (Rb). Here, we determined that SPH3643 is a novel potent antiproliferative agent that inhibits CDK4/6 kinase activity. In biochemical assays, SPH3643 showed more potent inhibition of both CDK4 and CDK6 than did 2 published CDK4/6 inhibitors, LY2835219 and palbociclib, and had better selectivity than LY2835219. Further in vitro study revealed that SPH3643 blocked Cdk/Rb signaling by inhibiting the phosphorylation of Rb and arrested the MCF-7 cancer cells at G /G phase, resulting in marked inhibition of the proliferation of Rb-positive cancer cell lines. In vivo SPH3643 treatment in mice bearing xenograft tumor models of breast cancer, colon cancer, acute myelocytic leukemia, and glioblastoma resulted in significant decreases in tumor growth. SPH3643 was able to particularly strongly inhibit glioblastoma (U87-MG) cell growth in the brains of orthotopic carcinoma xenograft mice due to its high degree of intracerebral penetration and significant persistence in this setting. Together these results revealed that SPH3643 is a potent, orally active small-molecule inhibitor of CDK4/6 with robust anticancer efficacy and a high degree of blood-brain barrier permeability.
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http://dx.doi.org/10.1111/cas.14367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226180PMC
May 2020

Discovery of 6-(2-(dimethylamino)ethyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine as a highly potent cyclin-dependent kinase 4/6 inhibitor for treatment of cancer.

Eur J Med Chem 2019 Sep 4;178:352-364. Epub 2019 Jun 4.

Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China. Electronic address:

Targeting CDK4/6 has been identified as an effective therapeutics for treatment of cancer. We herein reported the discovery of a series of 6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine derivatives as CDK4/6 inhibitors against cancer. Compound 3c, which displayed high potency and selectivity on CDK4/6 (IC = 0.710/1.10 nM) over a variety of other kinases, possessed desirable antiproliferative activities, excellent metabolic properties, and favorable pharmacokinetic characters. In MCF-7, Colo-205, and A549 xenograft models, compound 3c exhibited significant tumor growth inhibitions with low toxicities, which could be a promising drug candidate for further development.
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http://dx.doi.org/10.1016/j.ejmech.2019.06.005DOI Listing
September 2019

Dissection of complicate genetic architecture and breeding perspective of cottonseed traits by genome-wide association study.

BMC Genomics 2018 Jun 13;19(1):451. Epub 2018 Jun 13.

Institute of crop science and Institute of Bioinformatics, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310058, People's Republic of China.

Background: Cottonseed is one of the most important raw materials for plant protein, oil and alternative biofuel for diesel engines. Understanding the complex genetic basis of cottonseed traits is requisite for achieving efficient genetic improvement of the traits. However, it is not yet clear about their genetic architecture in genomic level. GWAS has been an effective way to explore genetic basis of quantitative traits in human and many crops. This study aims to dissect genetic mechanism seven cottonseed traits by a GWAS for genetic improvement.

Results: A genome-wide association study (GWAS) based on a full gene model with gene effects as fixed and gene-environment interaction as random, was conducted for protein, oil and 5 fatty acids using 316 accessions and ~ 390 K SNPs. Totally, 124 significant quantitative trait SNPs (QTSs), consisting of 16, 21, 87 for protein, oil and fatty acids (palmitic, linoleic, oleic, myristic, stearic), respectively, were identified and the broad-sense heritability was estimated from 71.62 to 93.43%; no QTS-environment interaction was detected for the protein, the palmitic and the oleic contents; the protein content was predominantly controlled by epistatic effects accounting for 65.18% of the total variation, but the oil content and the fatty acids except the palmitic were mainly determined by gene main effects and no epistasis was detected for the myristic and the stearic. Prediction of superior pure line and hybrid revealed the potential of the QTSs in the improvement of cottonseed traits, and the hybrid could achieve higher or lower genetic values compared with pure lines.

Conclusions: This study revealed complex genetic architecture of seven cottonseed traits at whole genome-wide by mixed linear model approach; the identified genetic variants and estimated genetic component effects of gene, gene-gene and gene-environment interaction provide cotton geneticist or breeders new knowledge on the genetic mechanism of the traits and the potential molecular breeding design strategy.
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http://dx.doi.org/10.1186/s12864-018-4837-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998501PMC
June 2018

Efficient production of human goose-type lysozyme 2 in the methylotrophic yeast Pichia pastoris.

J Biotechnol 2018 Jun 13;275:44-52. Epub 2018 Apr 13.

School of Basic Medicine, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Rd, Shanghai 201318, China. Electronic address:

Infectious diseases caused by antibiotic multidrug-resistant microorganisms are major causes of morbidity and mortality in humans. Hence, there is an urgent need to search for new antimicrobial agents. Initially known as a defensive effector in the innate immunity of certain organs of the human body, human goose-type lysozyme 2 (hLysG2) has been shown to possess therapeutically useful potential against multidrug-resistant microorganisms. Developing a novel strategy for large-scale production that provides high yields of this protein with high purity, quality, and potency is critical for pharmaceutical applications. To overcome the issues related to prokaryotic expression, here we report the production of recombinant hLysG2 (rhLysG2) using the methylotrophic yeast Pichia pastoris as expression host. The strong inducible alcoholoxidase 1 (AOX1) promoter was used to drive expression of the optimized hLysG2 gene. Under the optimal expression conditions, the lytic activity of rhLysG2 reached 113 U/mL of culture supernatant in shake flask cultivation and this was increased to 2084 U/mL in fed-batch fermentation. Using chitin affinity chromatography and size-exclusion chromatography, rhLysG2 was produced with a yield of 137 mg/L, purity of > 99%, molecular weight of 21,504.6 Da, and specific activity of 13,500 U/mg. In vitro assays indicated that rhLysG2 possessed muramidase activity, isopeptidase activity, and free radical scavenging activity. This report describes an efficient strategy for the production of biologically active rhLysG2 in P. pastoris on a large scale with a high yield, which provides a solid foundation for possible future pharmaceutical applications.
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http://dx.doi.org/10.1016/j.jbiotec.2018.04.010DOI Listing
June 2018

Genomic analyses in cotton identify signatures of selection and loci associated with fiber quality and yield traits.

Nat Genet 2017 Jul 5;49(7):1089-1098. Epub 2017 Jun 5.

State Key Laboratory of Crop Genetics and Germplasm Enhancement, Cotton Hybrid R&D Engineering Center (the Ministry of Education), Nanjing Agricultural University, Nanjing, China.

Upland cotton (Gossypium hirsutum) is the most important natural fiber crop in the world. The overall genetic diversity among cultivated species of cotton and the genetic changes that occurred during their improvement are poorly understood. Here we report a comprehensive genomic assessment of modern improved upland cotton based on the genome-wide resequencing of 318 landraces and modern improved cultivars or lines. We detected more associated loci for lint yield than for fiber quality, which suggests that lint yield has stronger selection signatures than other traits. We found that two ethylene-pathway-related genes were associated with increased lint yield in improved cultivars. We evaluated the population frequency of each elite allele in historically released cultivar groups and found that 54.8% of the elite genome-wide association study (GWAS) alleles detected were transferred from three founder landraces: Deltapine 15, Stoneville 2B and Uganda Mian. Our results provide a genomic basis for improving cotton cultivars and for further evolutionary analysis of polyploid crops.
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http://dx.doi.org/10.1038/ng.3887DOI Listing
July 2017

Essential role of proteasomes in maintaining self-renewal in neural progenitor cells.

Sci Rep 2016 Jan 25;6:19752. Epub 2016 Jan 25.

Department of Anatomy, Shanxi Medical University, Taiyuan, 030001, China.

Protein turnover and homeostasis are regulated by the proteasomal system, which is critical for cell function and viability. Pluripotency of stem cells also relies on normal proteasomal activity that mitigates senescent phenotypes induced by intensive cell replications, as previously demonstrated in human bone marrow stromal cells. In this study, we investigated the role of proteasomes in self-renewal of neural progenitor cells (NPCs). Through both in vivo and in vitro analyses, we found that the expression of proteasomes was progressively decreased during aging. Likewise, proliferation and self-renewal of NPCs were also impaired in aged mice, suggesting that the down-regulation of proteasomes might be responsible for this senescent phenotype. Lowering proteasomal activity by loss-of-function manipulations mimicked the senescence of NPCs both in vitro and in vivo; conversely, enhancing proteasomal activity restored and improved self-renewal in aged NPCs. These results collectively indicate that proteasomes work as a key regulator in promoting self-renewal of NPCs. This potentially provides a promising therapeutic target for age-dependent neurodegenerative diseases.
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http://dx.doi.org/10.1038/srep19752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726439PMC
January 2016

Association mapping for epistasis and environmental interaction of yield traits in 323 cotton cultivars under 9 different environments.

PLoS One 2014 8;9(5):e95882. Epub 2014 May 8.

Key Laboratory of Crop Germplasm Resource of Zhejiang Province, Zhejiang University, Hangzhou, China.

Improving yield is a major objective for cotton breeding schemes, and lint yield and its three component traits (boll number, boll weight and lint percentage) are complex traits controlled by multiple genes and various environments. Association mapping was performed to detect markers associated with these four traits using 651 simple sequence repeats (SSRs). A mixed linear model including epistasis and environmental interaction was used to screen the loci associated with these four yield traits by 323 accessions of Gossypium hirsutum L. evaluated in nine different environments. 251 significant loci were detected to be associated with lint yield and its three components, including 69 loci with individual effects and all involved in epistasis interactions. These significant loci explain ∼ 62.05% of the phenotypic variance (ranging from 49.06% ∼ 72.29% for these four traits). It was indicated by high contribution of environmental interaction to the phenotypic variance for lint yield and boll numbers, that genetic effects of SSR loci were susceptible to environment factors. Shared loci were also observed among these four traits, which may be used for simultaneous improvement in cotton breeding for yield traits. Furthermore, consistent and elite loci were screened with -Log10 (P-value) >8.0 based on predicted effects of loci detected in different environments. There was one locus and 6 pairs of epistasis for lint yield, 4 loci and 10 epistasis for boll number, 15 loci and 2 epistasis for boll weight, and 2 loci and 5 epistasis for lint percentage, respectively. These results provided insights into the genetic basis of lint yield and its components and may be useful for marker-assisted breeding to improve cotton production.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095882PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014473PMC
October 2015
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