Publications by authors named "Yichuan Wang"

51 Publications

Pharmaceutical Electrospinning and 3D printing scaffold design for bone regeneration.

Adv Drug Deliv Rev 2021 May 12. Epub 2021 May 12.

Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, P. R. China; Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, 20520 Finland. Electronic address:

Bone regenerative engineering provides a great platform for bone tissue regeneration covering cells, growth factors and other dynamic forces for fabricating scaffolds. Diversified biomaterials and their fabrication methods have emerged for fabricating patient specific bioactive scaffolds with controlled microstructures for bridging complex bone defects. The goal of this review is to summarize the points of scaffold design as well as applications for bone regeneration based on both electrospinning and 3D bioprinting. It first briefly introduces biological characteristics of bone regeneration and summarizes the applications of different types of material and the considerations for bone regeneration including polymers, ceramics, metals and composites. We then discuss electrospinning nanofibrous scaffold applied for the bone regenerative engineering with various properties, components and structures. Meanwhile, diverse design in the 3D bioprinting scaffolds for osteogenesis especially in the role of drug and bioactive factors delivery are assembled. Finally, we discuss challenges and future prospects in the development of electrospinning and 3D bioprinting for osteogenesis and prominent strategies and directions in future.
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http://dx.doi.org/10.1016/j.addr.2021.05.007DOI Listing
May 2021

Prognostic Value of Computed Tomography and/or F-Fluorodeoxyglucose Positron Emission Tomography Radiomics Features in Locally Advanced Non-small Cell Lung Cancer.

Clin Lung Cancer 2021 Mar 27. Epub 2021 Mar 27.

Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA. Electronic address:

Introduction: We investigated whether adding computed tomography (CT) and/or F-fluorodeoxyglucose (F-FDG) PET radiomics features to conventional prognostic factors (CPFs) improves prognostic value in locally advanced non-small cell lung cancer (NSCLC).

Materials And Methods: We retrospectively identified 39 cases with stage III NSCLC who received chemoradiotherapy and underwent planning CT and staging F-FDG PET scans. Seven CPFs were recorded. Feature selection was performed on 48 CT and 49 PET extracted radiomics features. A penalized multivariate Cox proportional hazards model was used to generate models for overall survival based on CPFs alone, CPFs with CT features, CPFs with PET features, and CPFs with CT and PET features. Linear predictors generated and categorized into 2 risk groups for which Kaplan-Meier survival curves were calculated. A log-rank test was performed to quantify the discrimination between the groups and calculated the Harrell's C-index to quantify the discriminatory power. A likelihood ratio test was performed to determine whether adding CT and/or PET features to CPFs improved model performance.

Results: All 4 models significantly discriminated between the 2 risk groups. The discriminatory power was significantly increased when CPFs were combined with PET features (C-index 0.82; likelihood ratio test P < .01) or with both CT and PET features (0.83; P < .01) compared with CPFs alone (0.68). There was no significant improvement when CPFs were combined with CT features (0.68).

Conclusion: Adding PET radiomics features to CPFs yielded a significant improvement in the prognostic value in locally advanced NSCLC; adding CT features did not.
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http://dx.doi.org/10.1016/j.cllc.2021.03.015DOI Listing
March 2021

Cyclodextrin capped gold nanoparticles (AuNP@CDs): from synthesis to applications.

J Mater Chem B 2021 03 5;9(11):2584-2593. Epub 2021 Mar 5.

Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China.

As a multifunctional platform, cyclodextrin capped gold nanoparticles (AuNP@CDs) have attracted extensive attention due to their advantages of high specific surface area and high loading capacity. AuNP@CDs have a core-shell structure, retaining the advantages of the two materials. AuNPs act as the support for the monolayer assembly of CDs. Some functional molecules can enter the hydrophobic cavity of CD through the host-guest interaction. In this brief review, we discuss the strategies for the synthesis of AuNP@CDs depending on the type and order of bonding. Their applications in drug delivery, catalysis, detection and bioimaging are highlighted. We hope to further stimulate AuNP@CD related research.
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http://dx.doi.org/10.1039/d0tb02857fDOI Listing
March 2021

Close Temporal Relationship between Oscillating Cytosolic K and Growth in Root Hairs of .

Int J Mol Sci 2020 Aug 27;21(17). Epub 2020 Aug 27.

Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China.

Root hair elongation relies on polarized cell expansion at the growing tip. As a major osmotically active ion, potassium is expected to be continuously assimilated to maintain cell turgor during hair tip growth. However, due to the lack of practicable detection methods, the dynamics and physiological role of K in hair growth are still unclear. In this report, we apply the small-molecule fluorescent K sensor NK3 in root hairs for the first time. By employing NK3, oscillating cytoplasmic K dynamics can be resolved at the tip of growing root hairs, similar to the growth oscillation pattern. Cross-correlation analysis indicates that K oscillation leads the growth oscillations by approximately 1.5 s. Artificially increasing cytoplasmic K level showed no significant influence on hair growth rate, but led to the formation of swelling structures at the tip, an increase of cytosolic Ca level and microfilament depolymerization, implying the involvement of antagonistic regulatory factors (e.g., Ca signaling) in the causality between cytoplasmic K and hair growth. These results suggest that, in each round of oscillating root hair elongation, the oscillatory cell expansion accelerates on the heels of cytosolic K increment, and decelerates with the activation of antagonistic regulators, thus forming a negative feedback loop which ensures the normal growth of root hairs.
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http://dx.doi.org/10.3390/ijms21176184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504304PMC
August 2020

Caution against corticosteroid-based COVID-19 treatment.

Lancet 2020 06 25;395(10239):1759-1760. Epub 2020 May 25.

Gastrointestinal Cancer Center, Peking University Cancer Hospital, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China; Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Shijingshan District, Beijing, China.

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http://dx.doi.org/10.1016/S0140-6736(20)30749-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247780PMC
June 2020

The RALF1-FERONIA Complex Phosphorylates eIF4E1 to Promote Protein Synthesis and Polar Root Hair Growth.

Mol Plant 2020 05 3;13(5):698-716. Epub 2020 Jan 3.

State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, and Hunan Key Laboratory of Plant Functional Genomics and Developmental Regulation, Hunan University, Changsha 410082, P.R. China; State Key Laboratory of Hybrid Rice, Hunan Hybrid Rice Research Center, Changsha 410125, P.R. China. Electronic address:

The molecular links between extracellular signals and the regulation of localized protein synthesis in plant cells are poorly understood. Here, we show that in Arabidopsis thaliana, the extracellular peptide RALF1 and its receptor, the FERONIA receptor kinase, promote root hair (RH) tip growth by modulating protein synthesis. We found that RALF1 promotes FERONIA-mediated phosphorylation of eIF4E1, a eukaryotic translation initiation factor that plays a crucial role in the control of mRNA translation rate. Phosphorylated eIF4E1 increases mRNA affinity and modulates mRNA translation and, thus, protein synthesis. The mRNAs targeted by the RALF1-FERONIA-eIF4E1 module include ROP2 and RSL4, which are important regulators of RH cell polarity and growth. RALF1 and FERONIA are expressed in a polar manner in RHs, which facilitate eIF4E1 polar localization and thus may control local ROP2 translation. Moreover, we demonstrated that high-level accumulation of RSL4 exerts negative-feedback regulation of RALF1 expression by directly binding the RALF1 gene promoter, determining the final RH size. Our study reveals that the link between RALF1-FERONIA signaling and protein synthesis constitutes a novel component regulating cell expansion in these polar growing cells.
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http://dx.doi.org/10.1016/j.molp.2019.12.014DOI Listing
May 2020

Salicylic Acid Suppresses Apical Hook Formation via NPR1-Mediated Repression of EIN3 and EIL1 in Arabidopsis.

Plant Cell 2020 03 30;32(3):612-629. Epub 2019 Dec 30.

Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen, Guangdong 518055, China

Salicylic acid (SA) and ethylene (ET) are important phytohormones that regulate numerous plant growth, development, and stress response processes. Previous studies have suggested functional interplay of SA and ET in defense responses, but precisely how these two hormones coregulate plant growth and development processes remains unclear. Our present work reveals antagonism between SA and ET in apical hook formation, which ensures successful soil emergence of etiolated dicotyledonous seedlings. Exogenous SA inhibited ET-induced expression of () in Arabidopsis () in a manner dependent on ETHYLENE INSENSITIVE3 (EIN3) and EIN3-LIKE1 (EIL1), the core transcription factors in the ET signaling pathway. SA-activated NONEXPRESSER OF PR GENES1 (NPR1) physically interacted with EIN3 and interfered with the binding of EIN3 to target gene promoters, including the promoter. Transcriptomic analysis revealed that NPR1 and EIN3/EIL1 coordinately regulated subsets of genes that mediate plant growth and stress responses, suggesting that the interaction between NPR1 and EIN3/EIL1 is an important mechanism for integrating the SA and ET signaling pathways in multiple physiological processes. Taken together, our findings illuminate the molecular mechanism underlying SA regulation of apical hook formation as well as the antagonism between SA and ET in early seedling establishment and possibly other physiological processes.
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http://dx.doi.org/10.1105/tpc.19.00658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054027PMC
March 2020

PEGylated Tantalum Nanoparticles: A Metallic Photoacoustic Contrast Agent for Multiwavelength Imaging of Tumors.

Small 2019 10 22;15(41):e1903596. Epub 2019 Aug 22.

State Key Laboratory of Advanced Welding and Joining, Harbin Institute of Technology, Harbin, 150001, China.

Elemental tantalum is a well-known biomedical metal in clinics due to its extremely high biocompatibility, which is superior to that of other biomedical metallic materials. Hence, it is of significance to expand the scope of biomedical applications of tantalum. Herein, it is reported that tantalum nanoparticles (Ta NPs), upon surface modification with polyethylene glycol (PEG) molecules via a silane-coupling approach, are employed as a metallic photoacoustic (PA) contrast agent for multiwavelength imaging of tumors. By virtue of the broad optical absorbance from the visible to near-infrared region and high photothermal conversion efficiency (27.9%), PEGylated Ta NPs depict high multiwavelength contrast capability for enhancing PA imaging to satisfy the various demands (penetration depth, background noise, etc.) of clinical diagnosis as needed. Particularly, the PA intensity of the tumor region postinjection is greatly increased by 4.87, 7.47, and 6.87-fold than that of preinjection under 680, 808, and 970 nm laser irradiation, respectively. In addition, Ta NPs with negligible cytotoxicity are capable of eliminating undesirable reactive oxygen species, ensuring the safety for biomedical applications. This work introduces a silane-coupling strategy for the surface engineering of Ta NPs, and highlights the potential of Ta NPs as a biocompatible metallic contrast agent for multiwavelength photoacoustic image.
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http://dx.doi.org/10.1002/smll.201903596DOI Listing
October 2019

Circ_0136474 and MMP-13 suppressed cell proliferation by competitive binding to miR-127-5p in osteoarthritis.

J Cell Mol Med 2019 10 11;23(10):6554-6564. Epub 2019 Aug 11.

Department of Orthopedics, Peking University First Hospital, Beijing, China.

Osteoarthritis (OA) is a prevalent degenerative joint disease whose pathogenesis remains unclear. The research aims to investigate the roles of Circ_0136474/miR-127-5p/MMP-13 axis in OA. Differentially expressed circRNAs and miRNAs in OA cartilage tissue were screened out and visualized by R project based on RNA-seq data and microarray data respectively. qRT-PCR was carried out for detection of relative expression levels of Circ_0136474, miR-127-5p, MMP-13 and other inflammatory factors and Western blot analysis was conducted to detect the protein expression level of MMP-13. CCK-8 assay and flow cytometry were conducted to determine cell proliferation and cell apoptotic ability respectively. RNA-fluorescence in situ hybridization (RNA-FISH) experiments were conducted to confirm the immune-localization of the Circ_0136474 and MMP-13 in human tissues. Targeted relationships were predicted by bioinformatic analysis and verified by dual-luciferase reporter assay. Our findings revealed that the expression levels of both Circ_0136474 and MMP-13 in OA cartilage tissue were significantly higher than that in normal cartilage tissue. Circ_0136474 could suppress cell proliferation by facilitating MMP-13 expression and suppressing miR-127-5p expression in OA. Overexpression of miR-127-5p negatively regulated MMP-13 expression to enhance cell proliferation. Our study demonstrated that Circ_0136474 and MMP-13 suppressed cell proliferation, while enhanced cell apoptosis by competitive binding to miR-127-5p in OA, which may well provide us with a new therapeutic strategy for osteoarthritis.
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http://dx.doi.org/10.1111/jcmm.14400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787461PMC
October 2019

Improved Method for Measuring the Permeability of Nanoporous Material and its Application to Shale Matrix with Ultra-Low Permeability.

Materials (Basel) 2019 May 13;12(9). Epub 2019 May 13.

Department of Energy and Power Engineering, Tsinghua University, Beijing 100084, China.

Nanoporous materials have a wide range of applications in clean energy and environmental research. The permeability of nanoporous materials is low, which affects the fluid transport behavior inside the nanopores and thus also affects the performance of technologies based on such materials. For example, during the development of shale gas resources, the permeability of the shale matrix is normally lower than 10 mD and has an important influence on rock parameters. It is challenging to measure small pressure changes accurately under high pressure. Although the pressure decay method provides an effective means for the measurement of low permeability, most apparatuses and experiments have difficulty measuring permeability in high pressure conditions over 1.38 MPa. Here, we propose an improved experimental method for the measurement of low permeability. To overcome the challenge of measuring small changes in pressure at high pressure, a pressure difference sensor is used. By improving the constant temperature accuracy and reducing the helium leakage rate, we measure shale matrix permeabilities ranging from 0.05 to 2 nD at pore pressures of up to 8 MPa, with good repeatability and sample mass irrelevance. The results show that porosity, pore pressure, and moisture conditions influence the matrix permeability. The permeability of moist shale is lower than that of dry shale, since water blocks some of the nanopores.
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http://dx.doi.org/10.3390/ma12091567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539457PMC
May 2019

Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response.

J Clin Invest 2019 03 18;129(3):1314-1328. Epub 2019 Feb 18.

Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA.

It is widely believed that protection against acquisition of HIV or SIV infection requires anti-envelope (anti-Env) antibodies, and that cellular immunity may affect viral loads but not acquisition, except in special cases. Here we provide evidence to the contrary. Mucosal immunization may enhance HIV vaccine efficacy by eliciting protective responses at portals of exposure. Accordingly, we vaccinated macaques mucosally with HIV/SIV peptides, modified vaccinia Ankara-SIV (MVA-SIV), and HIV-gp120-CD4 fusion protein plus adjuvants, which consistently reduced infection risk against heterologous intrarectal SHIVSF162P4 challenge, both high dose and repeated low dose. Surprisingly, vaccinated animals exhibited no anti-gp120 humoral responses above background and Gag- and Env-specific T cells were induced but failed to correlate with viral acquisition. Instead, vaccine-induced gut microbiome alteration and myeloid cell accumulation in colorectal mucosa correlated with protection. Ex vivo stimulation of the myeloid cell-enriched population with SHIV led to enhanced production of trained immunity markers TNF-α and IL-6, as well as viral coreceptor agonist MIP1α, which correlated with reduced viral Gag expression and in vivo viral acquisition. Overall, our results suggest mechanisms involving trained innate mucosal immunity together with antigen-specific T cells, and also indicate that vaccines can have critical effects on the gut microbiome, which in turn can affect resistance to infection. Strategies to elicit similar responses may be considered for vaccine designs to achieve optimal protective efficacy.
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http://dx.doi.org/10.1172/JCI122110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391089PMC
March 2019

Cryo-assisted exfoliation of atomically thin 2D SbSe nanosheets for photo-induced theranostics.

Chem Commun (Camb) 2019 Feb;55(19):2805-2808

School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China.

A liquid-phase exfoliation approach, combined with cryogenic fracturing and bath/probe sonication, is developed to prepare atomically thin 2D anisotropic Sb2Se3 nanosheets for simultaneous photoacoustic imaging and photothermal therapy.
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http://dx.doi.org/10.1039/c9cc00576eDOI Listing
February 2019

On hormonal regulation of the dynamic apical hook development.

New Phytol 2019 05 31;222(3):1230-1234. Epub 2018 Dec 31.

Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.

Contents Summary 1230 I. Introduction 1230 II. Apical hook development is a spatio-temporally dynamic process orchestrated by a complex signaling network 1231 III. Central players of apical hook development: auxin and HOOKLESS1 1232 IV. Towards a cellular-based understanding of hormonal regulation of apical hook development with cutting-edge toolboxes 1232 V. Conclusions 1233 Acknowledgements 1233 References 1233 SUMMARY: To deal with the ever-changing environment, sessile plants adapt diverse and plastic organ structures during postembryonic development. Among these, the apical hook forms shortly after seed germination of most dicots, and protects the delicate shoot meristem from mechanical damage during soil emergence. For decades, this structure has been taken as an excellent model for the investigation of the mechanisms underlying the differential growth of plant tissues. Here, we summarize recent advances in the investigation of the hormonal regulation of apical hook development, focusing on the convergence to auxin and a central regulator HOOKLESS1 (HLS1). We propose the revisitation of hook curvature kinematics at suborgan and single-cell resolution, and further pursuance of the mechanistics of apical hook development through combinatorial approaches of automated imaging and multidimensional modeling.
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http://dx.doi.org/10.1111/nph.15626DOI Listing
May 2019

A prediction model for hypoxemia during routine sedation for gastrointestinal endoscopy.

Clinics (Sao Paulo) 2018 11 14;73:e513. Epub 2018 Nov 14.

Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.

Objectives: The current study was designed to assess the clinical predictors of hypoxemia and to develop a multivariable, predictive model for hypoxemia during routine gastrointestinal endoscopy.

Methods: In total, 308 patients were enrolled in the analysis. Demographic data, concurrent chronic disease information, anesthetic dose and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores were collected and analyzed statistically.

Results: Multivariate logistic regression indicated that age (OR: 1.04; 95%CI 1.01-1.08), body mass index (BMI) (OR: 1.12; 95%CI: 1.02-1.21) and habitual snoring (OR: 3.71; 95%CI: 1.62-8.48) were independently associated with hypoxemia. A logistic regression function (LR model) was developed to predict hypoxemia considering the parameters of -7.73+0.04 age (years), +0.11 BMI, and +1.31 habitual snoring (yes or no). The area under the receiver operating characteristic (ROC) curve for the LR model was 0.76.

Conclusions: The LR model, consisting of age, BMI and habitual snoring, was a useful predictor of hypoxemia during routine sedation for gastrointestinal endoscopy.
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http://dx.doi.org/10.6061/clinics/2018/e513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218956PMC
November 2018

An Artificial Molecular Shuttle Operates in Lipid Bilayers for Ion Transport.

J Am Chem Soc 2018 12 28;140(51):17992-17998. Epub 2018 Nov 28.

Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering , East China University of Science & Technology , 130 Meilong Road , Shanghai , 200237 , China.

Inspired by natural biomolecular machines, synthetic molecular-level machines have been proven to perform well-defined mechanical tasks and measurable work. To mimic the function of channel proteins, we herein report the development of a synthetic molecular shuttle, [2]rotaxane 3, as a unimolecular vehicle that can be inserted into lipid bilayers to perform passive ion transport through its stochastic shuttling motion. The [2]rotaxane molecular shuttle is composed of an amphiphilic molecular thread with three binding stations, which is interlocked in a macrocycle wheel component that tethers a K carrier. The structural characteristics enable the rotaxane to transport ions across the lipid bilayers, similar to a cable car, transporting K with an EC value of 1.0 μM (3.0 mol % relative to lipid). We expect that this simple molecular machine will provide new opportunities for developing more effective and selective ion transporters.
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http://dx.doi.org/10.1021/jacs.8b09580DOI Listing
December 2018

Integrated Regulation of Apical Hook Development by Transcriptional Coupling of EIN3/EIL1 and PIFs in Arabidopsis.

Plant Cell 2018 09 13;30(9):1971-1988. Epub 2018 Aug 13.

Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen, Guangdong 518055, China

The apical hook protects the meristems of dicot seedlings as they protrude through the soil; multiple factors, including phytohormones and light, mediate apical hook development. () plays an indispensable role, as mutations cause a hookless phenotype. The ETHYLENE INSENSITIVE3 (EIN3) and EIN3-LIKE1 (EIL1) transcription factors integrate multiple signals (ethylene, gibberellins, and jasmonate) and activate expression to enhance hook development. Here, we found that PHYTOCHROME INTERACTING FACTOR (PIF) transcription factors act in parallel with EIN3/EIL1 and promote hook curvature by activating transcription at a distinct binding motif. EIN3/EIL1 and PIFs can promote hook formation in the absence of the other. Jasmonate represses PIF function to inhibit hook development. Like EIN3 and EIL1, MYC2 interacts with PIF4 and hampers its activity. Acting together, EIN3/EIL1 and PIFs alleviate the negative effects of jasmonate/light and facilitate the positive effects of ethylene/gibberellins. Mutating EIN3/EIL1 and PIFs causes a complete hookless phenotype, marginal expression, and insensitivity to upstream signals. Transcriptome profiling revealed that EIN3/EIL1 and PIFs additively and distinctly regulate a wide array of processes, including apical hook development. Together, our findings identify an integrated framework underlying the regulation of apical hook development and show that EIN3/EIL1 and PIFs fine-tune adaptive growth in response to hormone and light signals.
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http://dx.doi.org/10.1105/tpc.18.00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181014PMC
September 2018

A Small β-Carboline Derivative "B-9-3" Modulates TGF-β Signaling Pathway Causing Tumor Regression .

Front Pharmacol 2018 19;9:788. Epub 2018 Jul 19.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

Targeting tumor microenvironment (TME) is crucial in order to overcome the anti-cancer therapy resistance. In this study, we report the antitumor activity of a newly synthesized β-carboline derivative "B-9-3." Here, this small molecule showed a promising antitumor activity along with an enhanced immune response as reflected by a reduction of regulatory T cells and increased CD4+/CD8+ T cells. Further, B-9-3 decreased the number of myofibroblasts not only in the tumor but also in the lung suggesting an anti-metastatic action. The reduction of myofibroblasts was associated with lower expression of epithelial-to-mesenchymal transition markers and a decrease of phosphorylated SMAD2/3 complex indicating the implication of TGF-β signaling pathway in B-9-3's effect. The blockade of myofibroblasts induction by B-9-3 was also verified in human fibroblasts treated with TGF-β. To elucidate the mechanism of B-9-3's action on TGF-β pathway, first, we investigated the molecular interaction between B-9-3 and TGF-β receptors using docking method. Data showed a weak interaction of B-9-3 with the ATP-binding pocket of TGFβRI but a strong one with a ternary complex formed of extracellular domains of TGFβRI, TGFβRII, and TGF-β. In addition, the role of TGFβRI and TGFβRII in B-9-3's activity was explored . B-9-3 did not decrease any of the two receptors' protein level and only reduced phosphorylated SMAD2/3 suggesting that its effect was more probably due to its interaction with the ternary complex rather than decreasing the expression of TGF-β receptors or interfering with their ATP-binding domains. B-9-3 is a small active molecule which acts on the TGF-β signaling pathway and improves the TME to inhibit the proliferation and the metastasis of the tumor with the potential for clinical application.
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http://dx.doi.org/10.3389/fphar.2018.00788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063040PMC
July 2018

Ethylene signaling is critical for synergid cell functional specification and pollen tube attraction.

Plant J 2018 10 12;96(1):176-187. Epub 2018 Aug 12.

College of Life and Environmental Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai, 200234, China.

ETHYLENE INSENSITIVE 3 (EIN3) is a key regulator of ethylene signaling, and EIN3-BINDING F-BOX1 (EBF1) and EBF2 are responsible for EIN3 degradation. Previous reports have shown that the ebf1 ebf2 double homozygous mutant cannot be identified. In this study, the genetic analysis revealed that the ebf1 ebf2 female gametophyte is defective. The pollination experiment showed that ebf1 ebf2 ovules failed to attract pollen tubes. In female gametophyte/ovule, the synergid cell is responsible for pollen tube attraction. Observation of the pEIN3::EIN3-GFP transgenic lines showed that EIN3 signal was over-accumulated at the micropylar end of ebf1 ebf2 female gametophyte. The overexpression of stabilized EIN3 in synergid cell led to the defect of pollen tube guidance. These results suggested that the over-accumulated EIN3 in ebf1 ebf2 synergid cell blocks its pollen tube attraction which leads to the failure of ebf1 ebf2 homozygous plant. We identified that EIN3 directly activated the expression of a sugar transporter, SENESCENCE-ASSOCIATED GENE29 (SAG29/SWEET15). Overexpression of SAG29 in synergid cells blocked pollen tube attraction, suggesting that SAG29 might play a role in ethylene signaling to repel pollen tube entry. Taken together, our study reveals that strict control of ethylene signaling is critical for the synergid cell function during plant reproduction.
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http://dx.doi.org/10.1111/tpj.14027DOI Listing
October 2018

Ethylene-induced microtubule reorientation is essential for fast inhibition of root elongation in Arabidopsis.

J Integr Plant Biol 2018 Sep 30;60(9):864-877. Epub 2018 Jun 30.

Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China.

Microtubule reorientation is a long-standing observation that has been implicated in regulating the inhibitory effect of ethylene on axial elongation of plant cells. However, the signaling mechanism underlying ethylene-induced microtubule reorientation has remained elusive. Here, we reveal, by live confocal imaging and kinetic root elongation assays, that the time courses of ethylene-induced microtubule reorientation and root elongation inhibition are highly correlated, and that microtubule reorientation is required for the full responsiveness of root elongation to ethylene treatment. Our genetic analysis demonstrated that the effect of ethylene on microtubule orientation and root elongation is mainly transduced through the canonical linear ethylene signaling pathway. By using pharmacological and genetic analyses, we demonstrate further that the TIR1/AFBs-Aux/IAAs-ARFs auxin signaling pathway, but not the ABP1-ROP6-RIC1 auxin signaling branch, is essential for ethylene-induced microtubule reorientation and root elongation inhibition. Together, these findings offer evidence for the functional significance and elucidate the signaling mechanism for ethylene-induced microtubule reorientation in fast root elongation inhibition in Arabidopsis.
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http://dx.doi.org/10.1111/jipb.12666DOI Listing
September 2018

IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo.

FASEB J 2018 09 3;32(9):4899-4916. Epub 2018 Apr 3.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

Vitiligo is a depigmentary disorder that develops as a result of the progressive disappearance of epidermal melanocytes. Stress can precipitate or exacerbate a skin disease through psychosomatic mechanisms. Stress exposure induces vitiligo-like symptoms in mice, as cellular damage to melanocytes causes synthetic pigment loss. Stress also increases IL-17, IL-1β, and antimelanocyte IgG in model mouse serum. Up-regulation of the IL-1β transcript in patients suggests its possible role in autoimmune pathogenesis of vitiligo. We demonstrate that IL-17 promoted IL-1β secretion from keratinocytes. Mitochondrial dysfunction, which can induce the excessive production of reactive oxygen species (ROS), is emerging as a mechanism that underlies various inflammatory and autoimmune diseases. In this study, we demonstrate that IL-17 inhibits melanogenesis of zebrafish, normal human epidermal melanocytes, and B16F10 cells. IL-17 increased mitochondrial dysfunction and ROS accumulation, which was related to autophagy induction. Autophagy is needed for autophagic apoptosis of B16F10 cells induced by IL-17. To inhibit ROS generation, B16F10 cells were pretreated with N-acetyl-l-cysteine (NAC), which inhibited autophagy. 3-Methyladenine (3-MA) also had an inhibiting effect on autophagy. NAC or 3-MA pretreatments inhibited IL-17-mediated cell apoptosis. In summary, IL-17 induces the cellular stress microenvironment in melanocytes to promote autophagic cell apoptosis in vitiligo.-Zhou, J., An, X., Dong, J., Wang, Y., Zhong, H., Duan, L., Ling, J., Ping, F., Shang, J. IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo.
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http://dx.doi.org/10.1096/fj.201701242RRDOI Listing
September 2018

Interleukin-22 participates in the inflammatory process of vitiligo.

Oncotarget 2017 Dec 24;8(65):109161-109174. Epub 2017 Nov 24.

School of Traditional Chinese Pharmacy, China Pharmaceutical University, NanJing 2111198, P.R. China.

Vitiligo is an acquired depigmentary skin inflammatory disorder. The pathogenesis of inflammatory skin disease involves the release of cytokines from keratinocytes, including interleukin (IL)-1β. IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22 has proinflammatory activities. Among skin cell populations only keratinocytes are the major targets of IL-22. In the present study, we demonstrated that IL-22 promoting IL-1β secretion from keratinocytes via the Reactive oxygen species (ROS)-NOD-like receptor family, pyrin domain containing 3 (NLRP3)-caspase-1 pathway. It inhibited the expression of protease-activated receptor-2 (PAR-2) of keratinocytes. However, IL-22 had no direct effect on normal human foreskin-derived epidermal melanocytes (NHEM). Considering the closely connection between keratinocytes and melanocytes, and the ability of keratinocytes to produce a plethora of cytokines, in the present work, we examined whether IL-22 could regulate melanocytes functions by keratinocytes participation. Keratinocytes were exposed to IL-22 and the conditional medium was collected. The effect of conditional medium on melanocytes was studied. The expressions of relative proteins were assessed by western blot. Influence of conditional medium on NHEM migration was assessed by Transwell method and the apoptosis by flow cytometry analysis. The IL-22-treating keratinocytes conditional medium inhibited melanogenesis and restrained the expressions of Rab GTPases of NHEM. In addition, the conditional medium suppressed melanocytes migration and induced apoptosis. Our results collectively indicated that IL-22 may potentiate IL-1β-mediated skin inflammation and result in participating in the inflammatory pathogenesis of vitiligo.
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http://dx.doi.org/10.18632/oncotarget.22644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752511PMC
December 2017

Ethylene promotes root hair growth through coordinated EIN3/EIL1 and RHD6/RSL1 activity in .

Proc Natl Acad Sci U S A 2017 12 12;114(52):13834-13839. Epub 2017 Dec 12.

Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China;

Root hairs are an extensive structure of root epidermal cells and are critical for nutrient acquisition, soil anchorage, and environmental interactions in sessile plants. The phytohormone ethylene (ET) promotes root hair growth and also mediates the effects of different signals that stimulate hair cell development. However, the molecular basis of ET-induced root hair growth remains poorly understood. Here, we show that ET-activated transcription factor ETHYLENE-INSENSITIVE 3 (EIN3) physically interacts with ROOT HAIR DEFECTIVE 6 (RHD6), a well-documented positive regulator of hair cells, and that the two factors directly coactivate the hair length-determining gene () to promote root hair elongation. Transcriptome analysis further revealed the parallel roles of the regulator pairs EIN3/EIL1 (EIN3-LIKE 1) and RHD6/RSL1 (RHD6-LIKE 1). EIN3/EIL1 and RHD6/RSL1 coordinately enhance root hair initiation by selectively regulating a subset of core root hair genes. Thus, our work reveals a key transcriptional complex consisting of EIN3/EIL1 and RHD6/RSL1 in the control of root hair initiation and elongation, and provides a molecular framework for the integration of environmental signals and intrinsic regulators in modulating plant organ development.
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http://dx.doi.org/10.1073/pnas.1711723115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748182PMC
December 2017

Downregulation of microRNA-448 improves isoflurane-induced learning and memory impairment in rats.

Mol Med Rep 2017 Aug 8;16(2):1578-1583. Epub 2017 Jun 8.

Laparoscopic Surgical Center and Sino‑American Minimally Invasive Surgical Center, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

The present study aimed to investigate the potential role of microRNA‑448 (miR‑448) in isoflurane-induced learning and memory impairment in rats. Sprague‑Dawley rats were used for the construction of isoflurane‑treated models. The Morris water maze test was used to evaluate the effects of isoflurane on rats regarding the following para-meters: Swimming speed, escape latency and time in original quadrant. Influences of isoflurane on neuron apoptosis and miR‑448 expression in rat hippocampus tissue were analyzed by flow cytometry and reverse transcription‑quantitative polymerase chain reaction, respectively. Furthermore, the effects of miR‑448 on the expression of cell apoptosis‑associated proteins were investigated by flow cytometry. The results demonstrated that isoflurane treatment induced higher escape latency and lower time spent in original quadrant compared with the control rats. In addition, isoflurane treatment induced neuron apoptosis and miR‑448 was highly expressed in the hippocampal tissue of isoflurane‑treated rats. Furthermore, Bcl‑x was significantly downregulated while caspase‑3 expression was upregulated by an miR‑448 inhibitor. Combined the results of the current study indicate that miR‑448 knockdown may have pivotal roles in improving isoflurane-induced learning and memory impairment via suppressing neuron apoptosis.
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http://dx.doi.org/10.3892/mmr.2017.6724DOI Listing
August 2017

Differential T cell homing to colon vs. small intestine is imprinted by local CD11c APCs that determine homing receptors.

J Leukoc Biol 2017 12 26;102(6):1381-1388. Epub 2017 Sep 26.

Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Mechanisms that imprint T cell homing to the small intestine have been well studied; however, those for homing to the colon are poorly understood. Recently, we found that these are distinct subcompartments of the gut mucosal immune system, which implies differential homing. Here, we show that colonic CD11c APCs imprint CD8 T cell preferential homing to the colon, in contrast to those from the small intestine that imprint CD8 T cell homing to the small intestine, and that the differences are related to the variable ability of APCs to induce α4β7-integrin and CCR9 expression on T cells. Colon APCs also expressed lower levels of retinoic acid-producing enzymes that are known to control the mucosal homing of T cells. These findings are the first to our knowledge to directly demonstrate that colon APCs imprint T cells to selectively home to the large bowel, which is critical for the design of successful T cell-based therapies and vaccines, such as colon cancer immunotherapy and HIV vaccines.
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http://dx.doi.org/10.1189/jlb.1A1116-463RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669635PMC
December 2017

Pyrazinamide and derivatives block ethylene biosynthesis by inhibiting ACC oxidase.

Nat Commun 2017 06 12;8:15758. Epub 2017 Jun 12.

Peking-Tsinghua Center for Life Sciences, Beijing 100871, China.

Ethylene is an important phytohormone that promotes the ripening of fruits and senescence of flowers thereby reducing their shelf lives. Specific ethylene biosynthesis inhibitors would help to decrease postharvest loss. Here, we identify pyrazinamide (PZA), a clinical drug used to treat tuberculosis, as an inhibitor of ethylene biosynthesis in Arabidopsis thaliana, using a chemical genetics approach. PZA is converted to pyrazinecarboxylic acid (POA) in plant cells, suppressing the activity of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO), the enzyme catalysing the final step of ethylene formation. The crystal structures of Arabidopsis ACO2 in complex with POA or 2-Picolinic Acid (2-PA), a POA-related compound, reveal that POA/2-PA bind at the active site of ACO, preventing the enzyme from interacting with its natural substrates. Our work suggests that PZA and its derivatives may be promising regulators of plant metabolism, in particular ethylene biosynthesis.
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http://dx.doi.org/10.1038/ncomms15758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472784PMC
June 2017

Paradoxical myeloid-derived suppressor cell reduction in the bone marrow of SIV chronically infected macaques.

PLoS Pathog 2017 May 12;13(5):e1006395. Epub 2017 May 12.

Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.

Myeloid derived suppressor cells (MDSCs), which suppress anti-tumor or anti-viral immune responses, are expanded in the peripheral blood and tissues of patients/animals with cancer or viral infectious diseases. We here show that in chronic SIV infection of Indian rhesus macaques, the frequency of MDSCs in the bone marrow (BM) was paradoxically and unexpectedly decreased, but increased in peripheral blood. Reduction of BM MDSCs was found in both CD14+MDSC and Lin-CD15+MDSC subsets. The reduction of MDSCs correlated with high plasma viral loads and low CD4+ T cell counts, suggesting that depletion of BM MDSCs was associated with SIV/AIDS disease progression. Of note, in SHIVSF162P4-infected macaques, which naturally control viral replication within a few months of infection, the frequency of MDSCs in the bone marrow was unchanged. To investigate the mechanisms by which BM MDSCs were reduced during chronic SIV infection, we tested several hypotheses: depletion due to viral infection, alterations in MDSC trafficking, and/or poor MDSC replenishment. We found that the possible mobilization of MDSCs from BM to peripheral tissues and the slow self-replenishment of MDSCs in the BM, along with the viral infection-induced depletion, all contribute to the observed BM MDSC reduction. We first demonstrate MDSC SIV infection in vivo. Correlation between BM CD14+MDSC reduction and CD8+ T cell activation in tissues is consistent with decreased immune suppression by MDSCs. Thus, depletion of BM MDSCs may contribute to the pathologic immune activation during chronic SIV infection and by extension HIV infection.
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http://dx.doi.org/10.1371/journal.ppat.1006395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448820PMC
May 2017

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy.

J Immunol 2017 05 27;198(9):3494-3506. Epub 2017 Mar 27.

Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that vaccination with low Ag dose selectively primes CD4 T cells of higher functional avidity, whereas CD8 T cell functional avidity was unrelated to vaccine dose in mice. Importantly, CD4 T cells of higher functional avidity induced by low-dose vaccinations showed higher cytokine release per cell and lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) compared with their lower-avidity CD4 counterparts. Notably, increased functional CD4 T cell avidity improved antiviral efficacy of CD8 T cells. These data suggest that potent adjuvants, such as cationic adjuvant formulation 09, render low-dose vaccination a feasible and promising approach for generating high-avidity T cells through vaccination.
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http://dx.doi.org/10.4049/jimmunol.1600965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392729PMC
May 2017

Signature motif-guided identification of receptors for peptide hormones essential for root meristem growth.

Cell Res 2016 06 27;26(6):674-85. Epub 2016 May 27.

Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China;

Peptide-mediated cell-to-cell signaling has crucial roles in coordination and definition of cellular functions in plants. Peptide-receptor matching is important for understanding the mechanisms underlying peptide-mediated signaling. Here we report the structure-guided identification of root meristem growth factor (RGF) receptors important for plant development. An assay based on a signature ligand recognition motif (Arg-x-Arg) conserved in a subfamily of leucine-rich repeat receptor kinases (LRR-RKs) identified the functionally uncharacterized LRR-RK At4g26540 as a receptor of RGF1 (RGFR1). We further solved the crystal structure of RGF1 in complex with the LRR domain of RGFR1 at a resolution of 2.6 Å, which reveals that the Arg-x-Gly-Gly (RxGG) motif is responsible for specific recognition of the sulfate group of RGF1 by RGFR1. Based on the RxGG motif, we identified additional four RGFRs. Participation of the five RGFRs in RGF-induced signaling is supported by biochemical and genetic data. We also offer evidence showing that SERKs function as co-receptors for RGFs. Taken together, our study identifies RGF receptors and co-receptors that can link RGF signals with their downstream components and provides a proof of principle for structure-based matching of LRR-RKs with their peptide ligands.
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http://dx.doi.org/10.1038/cr.2016.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897187PMC
June 2016

High-efficiency broadband anti-Stokes emission from Yb3+-doped bulk crystals.

Opt Lett 2016 May;41(10):2141-4

We investigate the broadband anti-Stokes emission (BASE) from Yb3+-doped crystals with a laser diode (LD) pumping at 940 nm. Our experiment reveals that Yb3+-doped crystals with random cracks are able to generate bright BASE at room temperature and atmospheric pressure. By examining the various characteristics of the crystals and the emitted light, we supply a theory for interpreting the underlying physics for this variety of BASE. In particular, we take into consideration the effects of energy migration, avalanche process, and charge-transfer luminescence. This represents the first time, to the best of our knowledge, that BASE was obtained from Yb3+-doped bulk crystals with a high optical-optical efficiency.
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http://dx.doi.org/10.1364/OL.41.002141DOI Listing
May 2016

Interleukin-15 Constrains Mucosal T Helper 17 Cell Generation: Influence of Mononuclear Phagocytes.

PLoS One 2015 23;10(11):e0143001. Epub 2015 Nov 23.

Vaccine Branch, Center for Cancer Research, National Institute of Health, Bethesda, Maryland, United States of America.

Interleukin (IL)-15 has multiple roles in innate and adaptive immunity, especially regarding CD8+ T cells and natural killer cells. However, the role of IL-15 in regulating differentiation of T helper cell subsets and mononuclear phagocytes (MPs) in different tissues in vivo is unknown. Here we report that IL-15 indirectly regulates Th17 but not other Th subsets in the intestinal lamina propria (LP), apparently through effects on MPs. Th17 cells in the LP were more prevalent in IL-15 KO mice than their wild-type counterparts, and less prevalent in IL-15 transgenic mice than their wild-type littermates, even co-caged. MPs from the LP of these mice were sufficient to mimic the in vivo finding in vitro by skewing of cocultured wild type OVA-specific CD4+ T cells. However, production of IL-15 or lack thereof by these MPs was not sufficient to explain the skewing, as addition or blockade of IL-15 in the cultures had no effect. Rather, a skewing of the relative proportion of CD11b+, CD103+ and double positive LP MP subsets in transgenic and KO could explain the differences in Th17 cells. Thus, IL-15 may influence MP subsets in the gut in a novel way that alters the frequency of LP Th17 cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143001PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658142PMC
June 2016