Publications by authors named "Caiqin Zhang"

29 Publications

  • Page 1 of 1

Intestinal microbiota: A potential target for enhancing the antitumor efficacy and reducing the toxicity of immune checkpoint inhibitors.

Cancer Lett 2021 Jul 14;509:53-62. Epub 2021 Apr 14.

Division of Cancer Biology, Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address:

Accumulating evidence suggests that the intestinal microbiota is associated with the antitumor efficacy of immune checkpoint inhibitors (ICIs) and the occurrence of immune-related adverse events (irAEs) following ICI treatment. However, the mechanisms underlying these interactions remain unclear. Recent technological advances have allowed more extensive investigation into the interplay between the intestinal microbiota and the tumor immune microenvironment. Breakthroughs by two research groups revealed that Bifidobacterium enhanced the efficacy of ICIs via the stimulator of interferon genes (STING) and adenosine 2A receptor (AR) signaling pathways, highlighting the molecular mechanisms through which the intestinal microbiota modulates immunotherapy. In this review, we summarize recent findings related to the potential role and mechanisms of the gut microbiota in ICI therapy, available microbiota-targeting strategies, and ongoing clinical trials. Further we discuss the associated challenges that remain in this field of research. The current review aims to evaluate the potential of the intestinal microbiota in maximizing the antitumor efficacy of ICIs while minimizing their toxic effects and guiding the development of more specific treatment regimens.
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http://dx.doi.org/10.1016/j.canlet.2021.04.001DOI Listing
July 2021

Bisphenol S increases the obesogenic effects of a high-glucose diet through regulating lipid metabolism in Caenorhabditis elegans.

Food Chem 2021 Mar 9;339:127813. Epub 2020 Aug 9.

School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, PR China. Electronic address:

Bisphenol S (BPS), a structural analog of Bisphenol A (BPA), has been widely used as a substitute for epoxy resin, food packaging materials, and other products due to the limited application of BPA. Studies in vivo and in vitro have indicated that BPA could induce fat accumulation like an obesogen. The main goal of this study was to investigate the role and mechanism of BPS in lipid metabolism using Caenorhabditis elegans (C. elegans) as a model. Results showed that both the overall fat deposition and the triglyceride level were significantly increased in a non-monotonically increasing trend, and the low dose of BPS (0.01 μM) exhibited a stronger influence. Additionally, BPS enhanced fat synthesis depending on daf-16, fat-5, fat-6 and fat-7, and inhibited fatty acid oxidation via nhr-49 and acs-2. This study further indicate that fat accumulation induced by BPS requires nhr-49, which also mediated the nuclear hormone signaling pathway.
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http://dx.doi.org/10.1016/j.foodchem.2020.127813DOI Listing
March 2021

Establishment and characterization of patient-derived xenografts for hormone-naïve and castrate-resistant prostate cancers to improve treatment modality evaluation.

Aging (Albany NY) 2020 02 24;12(4):3848-3861. Epub 2020 Feb 24.

Division of Cancer Biology, Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Prostate cancer (PC) is a heterogeneous disease characterized by variable morphological patterns. Thus, establishing a patient-derived xenograft (PDX) model that retains the key features of the primary tumor for each type of PC is important for appropriate evaluation. In this study, we established PDX models of hormone-naïve (D17225) and castration-resistant (B45354) PC by implanting fresh tumor samples, obtained from patients with advanced PC under the renal capsule of immune-compromised mice. Supplementation with exogenous androgens shortened the latent period of tumorigenesis and increased the tumor formation rate. The PDX models exhibited the same major genomic and phenotypic features of the disease in humans and maintained the main pathological features of the primary tumors. Moreover, both PDX models showed different outcomes after castration or docetaxel treatment. The hormone-naïve D17225 PDX model displayed a range of responses from complete tumor regression to overt tumor progression, and the development of castrate-resistant PC was induced after castration. The responses of the two PDX models to androgen deprivation and docetaxel were similar to those observed in patients with advanced PC. These new preclinical PC models will facilitate research on the mechanisms underlying treatment response and resistance.
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http://dx.doi.org/10.18632/aging.102854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066917PMC
February 2020

Toxicity and multigenerational effects of bisphenol S exposure to on developmental, biochemical, reproductive and oxidative stress.

Toxicol Res (Camb) 2019 Sep 3;8(5):630-640. Epub 2019 Jun 3.

School of Food and Biological Engineering , Jiangsu University , Zhenjiang 212013 , PR China . Email: ; ; Tel: +86-511-88797202.

Bisphenol A (BPA) is a typical endocrine disruptor. Bisphenol S (BPS) has been widely used as a substitute for various plastic materials due to the limited application of BPA. However, it does not mean that BPS is a safe substitute due to the lack of effective evaluation of BPS. In this study, the clinical model of () was used to study the effects of BPS on the locomotion behavior, growth, reproduction, lifespan and antioxidant system. Our study found that exposed to 0.01 μM BPS could have significantly inhibited locomotion behavior and growth, as well as damaged reproductive and antioxidant systems and lifespan. It is interesting to note that in multi-generational exposure studies, we found that BPS exhibits complex genotoxicity. With the transmission to the offspring, BPS showed more significant inhibition of the head thrashes of the nematode, while the effect on the body bends and body length was gradually weakened. The effect of BPS on the brood size shows different rules according to different concentrations and offsprings. Therefore, the safety of BPS still needs further evaluation, especially the multi-generational genotoxicity.
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http://dx.doi.org/10.1039/c9tx00055kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737401PMC
September 2019

NIRF Optical/PET Dual-Modal Imaging of Hepatocellular Carcinoma Using Heptamethine Carbocyanine Dye.

Contrast Media Mol Imaging 2018 8;2018:4979746. Epub 2018 Mar 8.

State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Combining near-infrared fluorescence (NIRF) and nuclear imaging techniques provides a novel approach for hepatocellular carcinoma (HCC) diagnosis. Here, we report the synthesis and characteristics of a dual-modality NIRF optical/positron emission tomography (PET) imaging probe using heptamethine carbocyanine dye and verify its feasibility in both nude mice and rabbits with orthotopic xenograft liver cancer. This dye, MHI-148, is an effective cancer-specific NIRF imaging agent and shows preferential uptake and retention in liver cancer. The corresponding NIRF imaging intensity reaches 10/cm tumor area at 24 h after injection in mice with HCC subcutaneous tumors. The dye can be further conjugated with radionuclide Ga (Ga-MHI-148) for PET tracing. We applied the dual-modality methodology toward the detection of HCC in both patient-derived orthotopic xenograft (PDX) models and rabbit orthotopic transplantation models. NIRF/PET images showed clear tumor delineation after probe injection (MHI-148 and Ga-MHI-148). The tumor-to-muscle (T/M) standardized uptake value (SUV) ratios were obtained from PET at 1 h after injection of Ga-MHI-148, which was helpful for effectively capturing small tumors in mice (0.5 cm × 0.3 cm) and rabbits (1.2 cm × 1.8 cm). This cancer-targeting NIRF/PET dual-modality imaging probe provides a proof of principle for noninvasive detection of deep-tissue tumors in mouse and rabbit and is a promising technique for more accurate and early detection of HCC.
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http://dx.doi.org/10.1155/2018/4979746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863326PMC
July 2019

Insights into Macrophage Autophagy in Latent Tuberculosis Infection: Role of Heat Shock Protein 16.3.

DNA Cell Biol 2018 May 20;37(5):442-448. Epub 2018 Feb 20.

Division of Infection and Immunology, Laboratory Animals Center, Fourth Military Medical University , Xi'an, China .

Tuberculosis (TB) is a major bacterial infectious disease worldwide that is predominantly caused by Mycobacterium tuberculosis (Mtb). The comorbidity of multiple drug-resistant TB strains with HIV and diabetes is widespread. In the presence of these diseases, host immunity is weakened, allowing the recovery of dormant bacilli and leading to recurrent TB infection. As an important component of the host innate and adaptive immune responses, macrophage autophagy plays a significant role in protecting the host against TB. However, dormant bacilli can escape from autophagosomes and/or suppress autophagy, thus surviving within the host for an extended period of time, although the underlying mechanism remains elusive. Heat shock protein 16.3 (Hsp16.3, HspX, Rv2031c, and Acr) is one of the immunodominant proteins expressed during latent TB infection (LTBI). It may help maintain the protein stability and long-term viability of Mtb by inhibiting macrophage autophagy, resulting in LBTI. In this review, we discuss how dormant bacilli escape from autophagosomes, and we focus on the role of Hsp16.3 in regulating macrophage autophagy in LTBI so as to provide a firm basis for further studies. Hsp16.3 may represent a potential biomarker of LTBI and novel pharmacological target for anti-tubercular drugs.
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http://dx.doi.org/10.1089/dna.2017.4066DOI Listing
May 2018

Effects of Mycobacterium tuberculosis Mutant Strain Hsp16.3 Gene on Murine RAW 264.7 Macrophage Autophagy.

DNA Cell Biol 2018 Jan 25;37(1):7-14. Epub 2017 Oct 25.

Division of Infection and Immunology, Laboratory Animals Center, Fourth Military Medical University , Xi'an, China .

Heat shock protein Hsp16.3 is closely related to latent Mycobacterium tuberculosis (MTB) infection and plays an important role in sustained survival when MTB is dormant. In this study, the Hsp16.3 gene mutant MTB H37Rv strain (Hsp16.3ΔMTB) was obtained through gene recombination and infected into murine RAW 264.7 macrophages. Western blotting and immunofluorescence showed increased expression of the autophagy-related protein LC3, and transmission electron microscopy showed significantly increased macrophage autophagosomes, suggesting that Hsp16.3ΔMTB facilitates murine macrophage autophagy. These findings have implications for preventing and controlling tuberculosis.
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http://dx.doi.org/10.1089/dna.2016.3599DOI Listing
January 2018

Heptamethine carbocyanine DZ-1 dye for near-infrared fluorescence imaging of hepatocellular carcinoma.

Oncotarget 2017 Aug 24;8(34):56880-56892. Epub 2017 May 24.

Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Near-infrared fluorescence (NIRF) dyes have recently emerged as promising tools for non-invasive imaging of different types of cancers. Here, we explored the potential utility of a NIRF DZ-1 dye, with dual imaging and tumour targeting functions, in hepatocellular carcinoma (HCC). We showed the preferential uptake of DZ-1 by HCC cells and in derived subcutaneous/orthotopic tumour xenografts, accompanied by a minimal effect on normal cells. DZ-1 simplified tumour growth profiling as well, since we were able to correlate NIRF signals with tumour volume and/or tumour-emitting luminescence in mice. Using both orthotopic tumour transplantation and cirrhosis models in parallel, we demonstrated the ability of DZ-1 to differentiate liver tumour from cirrhosis. DZ-1 showed superiority in HCC imaging over indocyanine green by demonstrating significantly enhanced tumour-targeting specificity. At the cellular level, DZ-1 was mainly retained in mitochondria and lysosomes. Additionally, DZ-1 fluorescence spectroscopy has been used for the intraoperative navigation of rabbit liver cancer, to determine surgical margins. We showed that tumor hypoxia and select organic anion-transporting polypeptide genes mediate NIRF dye uptake in HCC, which was supported by clinical evidence. All these findings represent the first evidence that DZ-1 is an effective molecular probe for tumour-specific imaging in HCC, and provide insights into the development of a new generation of imaging agents for intraoperative guidance of cancer surgery.
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http://dx.doi.org/10.18632/oncotarget.18131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593610PMC
August 2017

The Application of Heptamethine Cyanine Dye DZ-1 and Indocyanine Green for Imaging and Targeting in Xenograft Models of Hepatocellular Carcinoma.

Int J Mol Sci 2017 Jun 21;18(6). Epub 2017 Jun 21.

Laboratory Animal Center, the Fourth Military Medical University, Xi'an 710032, China.

Near infrared fluorescence (NIRF) imaging has strong potential for widespread use in noninvasive tumor imaging. Indocyanine green (ICG) is the only Food and Drug Administration (FDA) -approved NIRF dye for clinical diagnosis; however, it is unstable and poorly targets tumors. DZ-1 is a novel heptamethine cyanine NIRF dye, suitable for imaging and tumor targeting. Here, we compared the fluorescence intensity and metabolism of DZ-1 and ICG. Additionally, we assayed their specificities and abilities to target tumor cells, using cultured hepatocellular carcinoma (HCC) cell lines, a nude mouse subcutaneous xenograft model of liver cancer, and a rabbit orthotopic transplantation model. We found that DZ-1 accumulates in tumor tissue and specifically recognizes HCC in subcutaneous and orthotopic models. The NIRF intensity of DZ-1 was one order of magnitude stronger than that of ICG, and DZ-1 showed excellent intraoperative tumor targeting in the rabbit model. Importantly, ICG accumulated at tumor sites, as well as in the liver and kidney. Furthermore, DZ-1 analog-gemcitabine conjugate (NIRG) exhibited similar tumor-specific targeting and imaging properties, including inhibition of tumor growth, in HCC patient-derived xenograft (PDX) mice. DZ-1 and NIRG demonstrated superior tumor-targeting specificity, compared to ICG. We show that DZ-1 is an effective molecular probe for specific imaging, targeting, and therapy in HCC.
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http://dx.doi.org/10.3390/ijms18061332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486152PMC
June 2017

Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death.

Cancer Lett 2017 01 31;385:128-136. Epub 2016 Oct 31.

Laboratory Animal Center, Fourth Military Medical University, Xi'an, China. Electronic address:

Itraconazole is a common antifungal which may have promise for treating various human cancers. We report that itraconazole was cytotoxic to MCF-7 and SKBR-3 breast cancer cell lines via apoptosis by altering mitochondria membrane potential, reducing BCL-2 expression and elevating caspase-3 activity. Itraconazole also induced autophagic cell death via LC3-II expression upregulation, P62/SQSTM1 degradation, autophagosome formation and increases in autophagic puncta. Itraconazole treatment inhibited hedgehog pathway key molecular expression, such as SHH and Gli1, resulting in promotion of apoptosis and autophagy. The anti-proliferation effect of itraconazole-induced apoptosis and autophagy via hedgehog pathway inhibition was confirmed with Gli1 inhibitor GANT61 and SHH siRNA, GANT61 and SHH siRNA synergistically enhanced cytotoxicity induced by itraconazole. A human xenograft nude mouse model corroborated the anti-breast cancer activity as evidenced by reduced tumor size, and increased tumor tissue apoptosis and autophagy. Thus, itraconazole has a potent anti-breast cancer activity that may be improved when combined with hedgehog pathway inhibitors.
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http://dx.doi.org/10.1016/j.canlet.2016.10.034DOI Listing
January 2017

Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death.

Mol Med Rep 2016 Oct 19;14(4):3013-20. Epub 2016 Aug 19.

Laboratory Animal Center, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

Cabazitaxel has been used to treat castration-resistant prostate cancer since its approval by the US Food and Drug Administration in 2010. However, whether cabazitaxel may inhibit the proliferation of other tissue‑derived cancer cells, and its underlying mechanism, remains unknown. In the present study, the A549 lung adenocarcinoma cancer cell line was exposed to cabazitaxel, in order to investigate its cytotoxic effect and determine the underlying mechanism. The results demonstrated that cabazitaxel was able to induce autophagy in A549 cells, as evidenced by the formation of autophagosomes, upregulated LC3‑II expression and increased LC3 puncta. Cabazitaxel‑induced autophagy had a cytotoxic effect on A549 cells, as evidenced by the induction of cell death and cell cycle arrest at G2/M phase, which was independent of the apoptotic pathway. Furthermore, transfection with Beclin1 small interfering RNA and treatment with the autophagy inhibitor 3‑methyladenine protected cells from cabazitaxel‑induced cell death, thus confirming that cabazitaxel‑induced autophagy contributed to A549 cell death. In addition, cabazitaxel targeted the phosphoinositide 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway to induce autophagy, as indicated by reduced phosphorylation of Akt and mTOR. In conclusion, the present study demonstrated that cabazitaxel exerts a cytotoxic effect on A549 cells by acting on the PI3K/Akt/mTOR pathway to promote autophagic cell death. This result supports the potential use of cabazitaxel as a chemotherapeutic agent for the treatment of lung cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042750PMC
http://dx.doi.org/10.3892/mmr.2016.5648DOI Listing
October 2016

Optical imaging of gastric cancer with near-infrared heptamethine carbocyanine fluorescence dyes.

Oncotarget 2016 Aug;7(35):57277-57289

Laboratory Animal Center, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the tumor-specific targeting ability of NIRF heptamethine carbocyanine MHI-148 dye in cultured gastric cancer cells, gastric cancer cell-derived and patient-derived tumor xenograft (PDX) models. We show that the NIRF dye specifically accumulated in tumor regions of both xenograft models, suggesting the potential utility of the dye for tumor-specific imaging and targeting in gastric cancer. We also demonstrated significant correlations between NIRF signal intensity and tumor volume in PDX models. Mechanistically, the higher cellular uptake of MHI-148 in gastric cancer cells than in normal cells was stimulated by hypoxia and activation of a group of organic anion-transporting polypeptide (OATP) genes. Importantly, this NIRF dye was not retained in inflammatory stomach tissues induced by gastric ulcer in mice. In addition, fresh clinical gastric tumor specimens, when perfused with NIR dye, exhibited increased uptake of NIR dye in situ. Together, these results show the possibility of using NIRF dyes as novel candidate agents for clinical imaging and detection of gastric cancer.
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http://dx.doi.org/10.18632/oncotarget.10031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302988PMC
August 2016

Defect-Controlled Preparation of UiO-66 Metal-Organic Framework Thin Films with Molecular Sieving Capability.

Chem Asian J 2016 Jan 16;11(2):207-10. Epub 2015 Nov 16.

Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano and Soft Materials (FUNSOM) and, Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, 199 Ren'ai Road, Suzhou Industrial Park, Suzhou, 215123, China.

Metal-organic framework (MOF) UiO-66 thin films are solvothermally grown on conducting substrates. The as-synthesized MOF thin films are subsequently dried by a supercritical process or treated with polydimethylsiloxane (PDMS). The obtained UiO-66 thin films show excellent molecular sieving capability as confirmed by the electrochemical studies for redox-active species with different sizes.
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http://dx.doi.org/10.1002/asia.201501079DOI Listing
January 2016

Protective and therapeutic effects of the resuscitation-promoting factor domain and its mutants against Mycobacterium tuberculosis in mice.

Pathog Dis 2015 Apr 5;73(3). Epub 2015 Jan 5.

Division of Infection and Immunology, Laboratory Animal Center, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China

The resuscitation-promoting factor (Rpf), a secretory protein first reported in Micrococcus luteus, plays a critical role in mycobacterial survival and infection. There are five functionally redundant Rpf-like proteins identified in M. tuberculosis (Mtb). All these Rpfs share a conserved Rpf domain (Rpfd) composed of approximately 70 amino acids, which possesses the same biological functions as the full-length Rpf protein. Glutamic acid at position 54 in Rpfd (E54) has been implicated in mediating multiple physiological processes, and a single amino acid substitution at residue E54 can affect the protein biological activity. In order to determine the effects of different amino acid substitutions of E54 in Rpfd on its immunogenic activity, we generated three recombinant Rpfd mutants, Rpfd1 (E54K), Rpfd2 (E54A) and Rpfd3 (E54K and D48A), based on T-cell epitope prediction and tested their potential protective/therapeutic effects against Mtb in mice. Our results demonstrated that replacement of E54 by different amino acids in Rpfd distinctively influenced its resuscitation-promoting activities and Th1-type immune responses induced in mice. Administration of Rpfd2 mutant enhanced Th1-type cellular responses (IFN-γ and IL-2) in mice (P < 0.05, Rpfd2 versus control) and provided effective protection against Mtb in mice by significantly inhibiting the growth of Mtb during the initial stage of infection. Four weeks after the challenge, the slightest pathological injury in lung was observed in the Rpfd2-immunized group among all three Rfpd mutant-immunized groups. Furthermore, Rpfd2 therapy significantly decreased the bacterial load in lung and alleviated histopathological damage in Mtb-infected mice. Together, our results suggest Rpfd2 as a novel effective vaccine candidate against Mtb.
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http://dx.doi.org/10.1093/femspd/ftu025DOI Listing
April 2015

Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1α/OATPs signaling axis.

Oncotarget 2014 Oct;5(20):10114-26

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Near-infrared (NIR) fluorescence imaging agents are promising tools for noninvasive cancer imaging. This study explored the specific uptake and retention of a NIR heptamethine carbocyanine MHI-148 dye by canine cancer cells and tissues and human prostate cancer (PCa) specimens and also the dye uptake mechanisms. The accumulation of MHI-148 was detected specifically in canine cancer cells and tissues and freshly harvested human PCa tissues xenografted in mice by NIR fluorescence microscopy and whole-body NIR optical imaging. Specific dye uptake in canine spontaneous tumors was further confirmed by PET imaging. Higher hypoxia-inducible factor-1α (HIF-1α) and organic anion-transporting polypeptide (OATP) protein and mRNA expression was demonstrated by multiplex quantum dots labeling and qPCR in tumors over that of normal tissues. Treating cancer cells with HIF-1α stabilizers activated HIF-1α downstream target genes, induced OATP superfamily gene expression and enhanced cellular uptake and retention of NIR dyes. Moreover, silencing HIF-1α by siRNA significantly decreased OATP mRNA expression and blocked NIR dye uptake in cancer cells. Together, these results demonstrated the preferential uptake of NIR dyes by canine and human cancer cells and tissues via the HIF-1α/OATPs signaling axis, which provides insights into future application of these dyes for cancer detection and treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259409PMC
http://dx.doi.org/10.18632/oncotarget.2464DOI Listing
October 2014

Mycobacterium tuberculosis Secreted Proteins As Potential Biomarkers for the Diagnosis of Active Tuberculosis and Latent Tuberculosis Infection.

J Clin Lab Anal 2015 Sep 17;29(5):375-82. Epub 2014 Aug 17.

Division of Infection and Immunology, Laboratory Animal Center, Fourth Military Medical University, Xi'an, P.R. China.

Background: The detection of Mycobacterium tuberculosis (Mtb) specific human antibodies has been an important diagnostic aid in the diagnosis of tuberculosis (TB) cases with smear-negative sputum samples, especially for the screening of high-risk population. This study focused on the analysis and comparison of the four potential Mtb-secreted proteins (ESAT6, CFP10, Ag85B, Hsp16.3) and the fusion protein Ag85B-Hsp16.3 as new markers in the serodiagnosis between active TB and latent TB infection (LTBI).

Methods: These five recombinant proteins were produced and used in optimized ELISA to detect IgG serum antibodies against the four secreted proteins. The capacity of identifying infection was evaluated either in active TB patients or LTBI individuals, which was compared with the control groups consisting of hospitalized non-TB individuals.

Results: The results showed that Ag85B-Hsp16.3/ESAT6 and Hsp16.3/ESAT6 were the best-associated antigens for serology diagnosis of the active TB and LTBI individuals because of their specificity, sensitivity, YI values, and positive rates, respectively. ELISA test demonstrated that 41.67% (25/60) of blood donors respond to Ag85B-Hsp16.3/ESAT6. The consistency of this positive respond with clinical diagnosis almost reached 84% (21/25).

Conclusion: Thus, a combined test of multiple Mtb-secreted proteins Ag85B, Hsp16.3, and ESAT6 may be the ascendant preliminary screening antigens for active TB or LTBI patients.
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http://dx.doi.org/10.1002/jcla.21782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807157PMC
September 2015

Classification and expression diversification of wheat dehydrin genes.

Plant Sci 2014 Jan 16;214:113-20. Epub 2013 Oct 16.

The Applied Plant Genomics Lab, Crop Genomics and Bioinformatics Center & National Key Lab of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Jiangsu 210095, China; Institute of Horticulture, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang Province 310021 China.

Dehydrins (DHNs) are late embryonic abundant proteins characterized by the dehydrin domains that are involved in plant abiotic stress tolerance. In this study, fifty-four wheat DHN unigenes were identified in the expressed sequence tags database. These genes encode seven types of dehydrins (KS, SK3, YSK2, Y2SK2, Kn, Y2SK3, and YSK3) and separate in 32 homologous clusters. The gene amplification differed among the dehydrin types, and members of the YSK2- and Kn-type DHNs are more numerous in wheat than in other cereals. The relative expression of all of these DHN clusters was analyzed using an in silico method in seven tissue types (i.e. normal growing shoots, roots, and reproductive tissues; developing and germinating seeds; drought- and cold-stressed shoots) as well as semi-quantitative reverse transcription polymerase chain reaction in seedling leaves and roots treated by dehydration, cold, and salt, respectively. The role of the ABA pathway in wheat DHN expression regulation was analyzed. Transcripts of certain types of DHNs accumulated specifically according to tissue type and treatment, which suggests their differentiated roles in wheat abiotic stress tolerance.
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http://dx.doi.org/10.1016/j.plantsci.2013.10.005DOI Listing
January 2014

Protective and therapeutic efficacy of Mycobacterium smegmatis expressing HBHA-hIL12 fusion protein against Mycobacterium tuberculosis in mice.

PLoS One 2012 21;7(2):e31908. Epub 2012 Feb 21.

Division of Infection and Immunology, Laboratory Animals Center, Fourth Military Medical University, Xi'an, Shaanxi Province, China.

Tuberculosis (TB) remains a major worldwide health problem. The only vaccine against TB, Mycobacterium bovis Bacille Calmette-Guerin (BCG), has demonstrated relatively low efficacy and does not provide satisfactory protection against the disease. More efficient vaccines and improved therapies are urgently needed to decrease the worldwide spread and burden of TB, and use of a viable, metabolizing mycobacteria vaccine may be a promising strategy against the disease. Here, we constructed a recombinant Mycobacterium smegmatis (rMS) strain expressing a fusion protein of heparin-binding hemagglutinin (HBHA) and human interleukin 12 (hIL-12). Immune responses induced by the rMS in mice and protection against Mycobacterium tuberculosis (MTB) were investigated. Administration of this novel rMS enhanced Th1-type cellular responses (IFN-γ and IL-2) in mice and reduced bacterial burden in lungs as well as that achieved by BCG vaccination. Meanwhile, the bacteria load in M. tuberculosis infected mice treated with the rMS vaccine also was significantly reduced. In conclusion, the rMS strain expressing the HBHA and human IL-12 fusion protein enhanced immunogencity by improving the Th1-type response against TB, and the protective effect was equivalent to that of the conventional BCG vaccine in mice. Furthermore, it could decrease bacterial load and alleviate histopathological damage in lungs of M. tuberculosis infected mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283714PMC
June 2012

Monoclonal antibodies against a Mycobacterium tuberculosis Ag85B-Hsp16.3 fusion protein.

Hybridoma (Larchmt) 2011 Oct;30(5):427-32

Division of Infection and Immunology, Laboratory Animals Center, Fourth Military Medical University, Xi'an, Shaanxi Province, China.

The secreted Mycobacterium tuberculosis (MTB) proteins, Ag85B and Hsp16.3, have been the focus of intensive research in recent years. These proteins have high sensitivity in bacterium-negative tuberculosis (TB) patients, and are valuable for the rapid diagnosis of bacterium-negative TB. Fusion proteins including multiple antigens such as Ag85B and Hsp16.3 provide improved sensitivity and specificity for serological diagnosis of active TB compared with a single antigen. Many studies have shown that the production of MAbs recognizing a specific repertoire of M. tuberculosis antigens and the tests based on monoclonal antibodies have been found to be valuable in positive detection of TB, particularly for smear-positive pulmonary TB. A number of MAbs are currently used for serodiagnosis of TB. Therefore, an Ag85B-Hsp16.3 fusion protein was expressed and purified using an E. coli system in this study. Three Ag85B-Hsp16.3 fusion protein-specific MAbs were generated by routine murine hybridoma techniques. The titer, specificity, and relative affinity of all three MAbs were determined by ELISA and the serological responses were analyzed. The levels of antigens in a proportion of TB patients were shown to be significantly higher than those in healthy controls. The sensitivity and specificity of the currently available detection systems is likely to be improved by the employment of a combination of these MAbs with others that are already in use.
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http://dx.doi.org/10.1089/hyb.2011.0047DOI Listing
October 2011

Proliferation-attenuating and apoptosis-inducing effects of tryptanthrin on human chronic myeloid leukemia K562 cell line in vitro.

Int J Mol Sci 2011 10;12(6):3831-45. Epub 2011 Jun 10.

Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, #17 West Changle Road, Xi'an 710032, China; E-Mails: (S.M.); (J.S.); (Q.M.).

Tryptanthrin, a kind of indole quinazoline alkaloid, has been shown to exhibit anti-microbial, anti-inflammation and anti-tumor effects both in vivo and in vitro. However, its biological activity on human chronic myeloid leukemia cell line K562 is not fully understood. In the present study, we investigated the proliferation-attenuating and apoptosis-inducing effects of tryptanthrin on leukemia K562 cells in vitro and explored the underlying mechanisms. The results showed that tryptanthrin could significantly inhibit K562 cells proliferation in a time- and dose-dependent manner as evidenced by MTT assay and flow cytometry analysis. We also observed pyknosis, chromatin margination and the formation of apoptotic bodies in the presence of tryptanthrin under the electron microscope. Nuclei fragmentation and condensation by Hoechst 33258 staining were detected as well. The amount of apoptotic cells significantly increased whereas the mitochondrial membrane potential decreased dramatically after tryptanthrin exposure. K562 cells in the tryptanthrin treated group exhibited an increase in cytosol cyt-c, Bax and activated caspase-3 expression while a decrease in Bcl-2, mito cyt-c and pro-caspase-3 contents. However, the changes of pro-caspase-3 and activated caspase-3 could be abolished by a pan-caspase inhibitor ZVAD-FMK. These results suggest that tryptanthrin has proliferation-attenuating and apoptosis-inducing effects on K562 cells. The underlying mechanism is probably attributed to the reduction in mitochondria membrane potential, the release of mito cyt-c and pro-caspase-3 activation.
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http://dx.doi.org/10.3390/ijms12063831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131594PMC
January 2015

Insulin resistance: a potential marker and risk factor for active tuberculosis?

Med Hypotheses 2011 Jul 2;77(1):66-8. Epub 2011 Apr 2.

Laboratory Animal Center, The Fourth Military Medical University, 17 Changlexilu, Xi'an 710032, PR China.

Current tuberculosis control measures are focused on the prompt detection and treatment of active tuberculosis. Despite the measured success of this strategy, tuberculosis continues to be a public health issue of major significance around the world. This unwanted situation suggests the need to expand our control efforts by exploring specific markers for the disease. Insulin resistance is one such marker. Although insulin resistance has been implicated in various diseases, thus far, no attempt has been made to analyze what has proved to be a direct relationship between insulin resistance and Mycobacterium tuberculosis susceptibility. Several studies have shown the role of insulin not only in cellular metabolism but also, more importantly, in phagocytosis of M. tuberculosis. Therefore, we hypothesize that insulin resistance can be considered a potential risk factor for active M. tuberculosis infection.
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http://dx.doi.org/10.1016/j.mehy.2011.03.025DOI Listing
July 2011

Expression and responses to dehydration and salinity stresses of V-PPase gene members in wheat.

J Genet Genomics 2009 Dec;36(12):711-20

Crop Genomics and Bioinformatics Center & National Key Lab of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, China.

Vacuolar H(+)-translocating pyrophosphatase (V-PPase) is a key enzyme related to plant growth as well as abiotic stress tolerance. In this work, wheat V-PPase genes TaVP1, TaVP2 and TaVP3 were identified. TaVP1 and TaVP2 are more similar to each other than to TaVP3. Their deduced polypeptide sequences preserve the topological structure and essential residues of V-PPases. Phylogenetic studies suggested that monocot plants, at least monocot grasses, have three VP paralogs. TaVP3 transcripts were only detected in developing seeds, and no TaVP2 transcripts were found in germinating seeds. TaVP2 was mainly expressed in shoot tissues and down-regulated in leaves under dehydration. Its expression was up-regulated in roots under high salinity. TaVP1 was relatively more ubiquitously and evenly expressed than TaVP2. Its expression level in roots was highest among the tissues examined, and was inducible by salinity stress. These results indicated that the V-PPase gene paralogs in wheat are differentially regulated spatially and in response to dehydration and salinity stresses.
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http://dx.doi.org/10.1016/S1673-8527(08)60164-2DOI Listing
December 2009

Wheat cryptochromes: subcellular localization and involvement in photomorphogenesis and osmotic stress responses.

Plant Physiol 2009 Feb 3;149(2):760-74. Epub 2008 Dec 3.

Applied Plant Genomics Laboratory, Crop Genomics and Bioinformatics Center, Nanjing Agricultural University, Jiangsu 210095, China.

Cryptochromes (CRYs) are blue light receptors important for plant growth and development. Comprehensive information on monocot CRYs is currently only available for rice (Oryza sativa). We report here the molecular and functional characterization of two CRY genes, TaCRY1a and TaCRY2, from the monocot wheat (Triticum aestivum). The expression of TaCRY1a was most abundant in seedling leaves and barely detected in roots and germinating embryos under normal growth conditions. The expression of TaCRY2 in germinating embryos was equivalent to that in leaves and much higher than the TaCRY1a counterpart. Transition from dark to light slightly affected the expression of TaCRY1a and TaCRY2 in leaves, and red light produced a stronger induction of TaCRY1a. Treatment of seedlings with high salt, polyethylene glycol, and abscisic acid (ABA) up-regulated TaCRY2 in roots and germinating embryos. TaCRY1a displays a light-responsive nucleocytoplasmic shuttling pattern similar to that of Arabidopsis (Arabidopsis thaliana) CRY1, contains nuclear localization domains in both the N and C termini, and includes information for nuclear export in its N-terminal domain. TaCRY2 was localized to the nucleus in the dark. Expression of TaCRY1a-green fluorescent protein or TaCRY2-green fluorescent protein in Arabidopsis conferred a shorter hypocotyl phenotype under blue light. These transgenic Arabidopsis plants showed higher sensitivity to high-salt, osmotic stress, and ABA treatment during germination and postgermination development, and they displayed altered expression of stress/ABA-responsive genes. The primary root growth in transgenic seedlings was less tolerant of ABA. These observations indicate that TaCRY1 and TaCRY2 might be involved in the ABA signaling pathway in addition to their role in primary blue light signal transduction.
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http://dx.doi.org/10.1104/pp.108.132217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633824PMC
February 2009

Identification and mapping of pm2026: a recessive powdery mildew resistance gene in an einkorn (Triticum monococcum L.) accession.

Theor Appl Genet 2008 Aug 27;117(4):471-7. Epub 2008 May 27.

The Applied Plant Genomics Lab, Crop Genomics and Bioinformatics Center and National Key Lab of Crop Genetics and Germplasm Enhancement, College of Agricultural Sciences, Nanjing Agricultural University, Nanjing 210095, Jiangsu, People's Republic of China.

Triticum monococcum accession TA2026 showed resistance to wheat powdery mildew. To identify the resistance gene and transfer it to common wheat, genetic analysis and molecular mapping were conducted using an F2 population and derived F3 families from the cross of TA2026xM389. The results indicated that TA2026 possessed a recessive powdery mildew resistance gene. This gene was mapped to the terminal portion of chromosome 5AmL and flanked by SSR marker loci Xcfd39 and Xgwm126. Eight RFLP markers previously mapped to the terminal chromosome 5AmL were converted into STS markers. Three loci, detected by MAG1491, MAG1493 and MAG1494, the STS markers derived from RFLP probes CDO1312, PSR164 and PSR1201, respectively, were linked to this resistance gene with Xmag1493 only 0.9 cM apart from it. In addition, the STS marker MAG2170 developed from the tentative consensus wheat cDNA encoding the Mlo-like protein identified a locus co-segregating with Xmag1493. This is the first recessive powdery mildew resistance gene identified on chromosome 5Am, and is temporarily designated pm2026. We have successfully transferred it to a tetraploid background, and this resistance stock will now be used as the bridge parent for its transfer to common wheat.
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http://dx.doi.org/10.1007/s00122-008-0791-6DOI Listing
August 2008

A high-density intervarietal map of the wheat genome enriched with markers derived from expressed sequence tags.

Theor Appl Genet 2008 Jul 24;117(2):181-9. Epub 2008 Apr 24.

The Applied Plant Genomics Laboratory, Crop Genomics and Bioinformatics Centre, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, China.

Bread wheat (Triticum aestivum L.) is a hexaploid species with a large and complex genome. A reference genetic marker map, namely the International Triticeae Mapping Initiative (ITMI) map, has been constructed with the recombinant inbred line population derived from a cross involving a synthetic line. But it is not sufficient for a full understanding of the wheat genome under artificial selection without comparing it with intervarietal maps. Using an intervarietal mapping population derived by crossing Nanda2419 and Wangshuibai, we constructed a high-density genetic map of wheat. The total map length was 4,223.1 cM, comprising 887 loci, 345 of which were detected by markers derived from expressed sequence tags (ESTs). Two-thirds of the high marker density blocks were present in interstitial and telomeric regions. The map covered, mostly with the EST-derived markers, approximately 158 cM of telomeric regions absent in the ITMI map. The regions of low marker density were largely conserved among cultivars and between homoeologous subgenomes. The loci showing skewed segregation displayed a clustered distribution along chromosomes and some of the segregation distortion regions (SDR) are conserved in different mapping populations. This map enriched with EST-derived markers is important for structure and function analysis of wheat genome as well as in wheat gene mapping, cloning, and breeding programs.
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http://dx.doi.org/10.1007/s00122-008-0764-9DOI Listing
July 2008

Expression of the nuclear gene TaF(A)d is under mitochondrial retrograde regulation in anthers of male sterile wheat plants with timopheevii cytoplasm.

J Exp Bot 2008 4;59(6):1375-81. Epub 2008 Apr 4.

The Applied Plant Genomics Laboratory, Crop Genomics and Bioinformatics Center & National Key Lab of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Jiangsu 210095, China.

Alterations of mitochondrial-encoded subunits of the F(o)F(1)-ATP synthase are frequently associated with cytoplasmic male sterility (CMS) in plants; however, little is known about the relationship of the nuclear encoded subunits of this enzyme with CMS. In the present study, the full cDNA of the gene TaF(A)d that encodes the putative F(A)d subunit of the F(o)F(1)-ATP synthase was isolated from the wheat (Triticum aestivum) fertility restorer '2114' for timopheevii cytoplasm-based CMS. The deduced 238 amino acid polypeptide is highly similar to its counterparts in dicots and other monocots but has low homology to its mammalian equivalents. TaF(A)d is a single copy gene in wheat and maps to the short arm of the group 6 chromosomes. Transient expression of the TaF(A)d-GFP fusion in onion epidermal cells demonstrated TaF(A)d's mitochondrial location. TaF(A)d was expressed abundantly in stem, leaf, anther, and ovary tissues of 2114. Nevertheless, its expression was repressed in anthers of CMS plants with timopheevii cytoplasm. Genic male sterility did not affect its expression in anthers. The expression of the nuclear gene encoding the 20 kDa subunit of F(o) was down-regulated in a manner similar to TaF(A)d in the T-CMS anthers while that of genes encoding the 6 kDa subunit of F(o) and the gamma subunit of F(1) was unaffected. These observations implied that TaF(A)d is under mitochondrial retrograde regulation in the anthers of CMS plants with timopheevii cytoplasm.
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http://dx.doi.org/10.1093/jxb/ern068DOI Listing
June 2008

Mapping QTLs for tissue culture response of mature wheat embryos.

Mol Cells 2007 Jun;23(3):323-30

The Applied Plant Genomics Lab & National Key Lab of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural Univer-sity, Jiangsu 210095, China.

The mature wheat embryo is arguably one of the best explants for genetic transformation because of its unlimited availability and lack of growth season restriction. However, an efficient regeneration system using mature wheat embryos (Triticum aestivum L.) is still not available. To identify genes related to the tissue culture response (TCR) of wheat, QTLs for callus induction from mature embryos and callus regeneration were mapped using an RIL population derived from the cross of "Wangshuibai" with "Nanda2419" which has a good TCR. By whole genome scanning we identified five, four and four chromosome regions conditioning, respectively, percent embryos forming a callus (PEFC), percent calli regenerating plantlets (PCRP), and number of plantlets per regenerating callus (NPRC). The major QTLs QPefc.nau-2A and QPcrp.nau-2A were mapped to the long arm of chromosome 2A, explaining up to 22.8% and 17.6% of the respective phenotypic variance. Moreover, two major QTLs for NPRC were detected on chromosomes 2D and 5D; these together explained 51.6% of the phenotypic variance. We found that chromosomes 2A, 2D, 5A, 5B and 5D were associated via different intervals with at least two of the three TCR indexes used. Based on this study and other reports, the TCRs of different explant types of wheat may be under the control of shared or tightly linked genes, while different genes or gene combinations may govern the stages from callus induction to plantlet regeneration. The importance of group 2 and 5 chromosomes in controlling the TCRs of Triticeae crops and the likely conservation of the corresponding genes in cereals are discussed.
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June 2007

Genetic mapping of two powdery mildew resistance genes in einkorn (Triticum monococcum L.) accessions.

Theor Appl Genet 2007 Jan 8;114(2):351-8. Epub 2006 Nov 8.

The Applied Plant Genomics Lab and National Key Lab for Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, 210095, Jiangsu, People's Republic of China.

Powdery mildew is a severe foliar disease for wheat and could cause great yield loss in epidemic years. To explore new powdery mildew resistance genes, two einkorn accessions including TA2033 and M80, both resistant to this disease, were studied for the inheritance of resistance. Each accession possessed a single but different dominant resistance gene that was designated as Mlm2033 and Mlm80, respectively. Marker mapping indicated that they are both linked to Xgwm344 on the long arm of chromosome 7A. To establish their genetic relationship with Pm1 on 7AL, five RFLP markers previously reported to co-segregate with Pm1a were converted to STS markers. Three of them detected polymorphism between the mapping parents and were mapped close to Mlm2033 or Mlm80 or both. Xmag2185, the locus determined by the STS marker derived from PSR680, one of the RFLP markers, was placed less than 2 cM away from them. The allelism test indicated that Mlm2033 and Mlm80 are likely allelic to each other. In addition, through comparative and EST mapping, more markers linked to these two genes were identified. The high density mapping of Mlm2033 and Mlm80 will contribute to map-based cloning of the Pm1 locus. The markers for both genes will also facilitate their transfer to wheat.
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http://dx.doi.org/10.1007/s00122-006-0438-4DOI Listing
January 2007

Molecular genetic analysis of five spike-related traits in wheat using RIL and immortalized F2 populations.

Mol Genet Genomics 2007 Jan 11;277(1):31-42. Epub 2006 Oct 11.

The Applied Plant Genomics Lab and National Key Lab of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, China.

Kernel number per spike is one of the most important yield components of wheat. To map QTLs related to kernel number including spike length (SPL), spikelet number per spike (SPN), fertile spikelet number (FSPN), sterile spikelet number (SSPN) and compactness, and to characterize the inheritance modes of the QTLs and two-locus interactions, 136 recombinant inbred lines (RILs) derived from 'Nanda2419' x 'Wangshuibai' and an immortalized F(2 )population (IF(2)) generated by randomly permutated intermating of these RILs were investigated. QTL mapping made use of the previously constructed over 3300 cM linkage map of the RIL population. Three, five, two, two and six chromosome regions were identified, respectively, for their association with SPL, SPN, FSPN, SSPN, and compactness in at least two of the three environments examined. All compactness QTLs but one shared the respective intervals of QSpn.nau-5A and the SPL QTLs. Xcfd46-Xwmc702 interval on chromosome 7D was related to all traits but SSPN and had consistently the largest effects. The fact that not all the compactness QTL intervals were related to both SPL and SPN indicates that compactness is regulated by different mechanisms. Interval coincidence between QTLs of SPL and SPN and between QTLs of FSPN and SSPN was minimal. For all the traits, favorable alleles exist in both parents. Inheritance modes from additiveness to overdominance of the QTLs were revealed and two-locus interactions were detected, implying that the traits studied are under complex genetic control. The results could contribute to wheat yield improvement and better use of Wangshuibai and Nanda2419 the two special germplasms in wheat breeding program.
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http://dx.doi.org/10.1007/s00438-006-0166-0DOI Listing
January 2007