Publications by authors named "Xiang Yan"

462 Publications

Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L.

Proc Natl Acad Sci U S A 2022 Jan;119(4)

Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229;

SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multidomain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L-associated human diseases.
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http://dx.doi.org/10.1073/pnas.2116550119DOI Listing
January 2022

Role of fibrosarcoma-induced CD11b myeloid cells and tumor necrosis factor-α in B cell responses.

Oncogene 2022 Jan 15. Epub 2022 Jan 15.

Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

The role of B cells in the anti-tumor immune response remains controversial. An increase in the number of B cells in the peripheral blood of some tumor patients has been associated with poor immunotherapy efficacy. However, the mechanism leading to the generation of these cells is not well-described. Using a fibrosarcoma model, we show that intraperitoneal administration of a xenogeneic antigen in tumor-bearing mice evokes large increases in antigen-specific serum immunoglobulin formation compared to tumor-naïve mice. An inability of tumor-bearing mice to induce enhanced antibody production after myeloid cell depletion suggests the antibody responses are CD11b myeloid cell-dependent. In vitro, CD11b myeloid cells promoted B cell proliferation, activation, and survival. High levels of tumor necrosis factor (TNF)-α were produced by CD11b cells, and TNF-α blockade inhibited B cell responses. CD11b cells appear to be important promoters of B cell responses and targeting B cells may increase the efficacy of immunotherapy in tumor-bearing hosts.
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http://dx.doi.org/10.1038/s41388-022-02187-zDOI Listing
January 2022

A real-world study of dacomitinib in later-line settings for advanced non-small cell lung cancer patients harboring EGFR mutations.

Cancer Med 2022 Jan 12. Epub 2022 Jan 12.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Objective: Dacomitinib has been approved for the first-line treatment of non-small cell lung cancer (NSCLC) carrying classical epidermal growth factor receptor (EGFR) mutations; however, real-world data on its later-line application are lacking.

Materials And Methods: Patients' data were retrospectively collected from the Chinese National Cancer Center and the PLA hospital between August 2019 and August 2021. Kaplan-Meier method and Log-rank test were utilized to assess progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox regression analysis was conducted to determine prognostic indicators.

Results: In total, 56 NSCLC patients harboring EGFR mutations treated with later-line single dacomitinib or combinatory dacomitinib were enrolled. A total of 53 patients (94.6%) had treatment-related adverse events; eight patients (14.3%) had grade 3 or 4 events. Among 49 evaluable patients, 26.5% (13 patients) had a confirmed partial response and 73.5% (36 patients) had disease control; the median duration of follow-up was 9.6 months (95% confidence interval [CI], 8.4-10.8 months), the median progression-free survival was 5.4 months (95% CI, 3.5-7.3 months), and the half-year, 1-year, and 2-year OS rate were 79.2%, 70.6%, and 64.1%, respectively. Univariate analysis suggested that smoking, line of dacomitinib, and interval between last EGFR-tyrosine kinase inhibitor (TKI) and dacomitinib were associated with PFS and OS; chemotherapy between last EGFR-TKI and dacomitinib, and EGFR-TKI generation followed by dacomitinib were respectively associated with PFS and OS; multivariate analysis indicated chemotherapy between last EGFR-TKI and dacomitinib negatively affect PFS, and smoking and third-generation EGFR-TKI followed by dacomitinib negatively affect OS.

Conclusions: This real-world study has shown that dacomitinib is active and well-tolerated in NSCLC patients harboring different EGFR mutations in later-line settings, even for those with brain metastases. Patients who benefited more from the first TKI were more likely to benefit from dacomitinib, and earlier application of dacomitinib after front-line TKI resistance may be considered.
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http://dx.doi.org/10.1002/cam4.4495DOI Listing
January 2022

Comprehensive omics analyses profile genesets related with tumor heterogeneity of multifocal glioblastomas and reveal LIF/CCL2 as biomarkers for mesenchymal subtype.

Theranostics 2022 1;12(1):459-473. Epub 2022 Jan 1.

Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Around 10%-20% patients with glioblastoma (GBM) are diagnosed with more than one tumor lesions or multifocal GBM (mGBM). However, the understanding on genetic, DNA methylomic, and transcriptomic characteristics of mGBM is still limited. In this study, we collected nine tumor foci from three mGBM patients followed by whole genome sequencing, whole genome bisulfite sequencing, RNA sequencing, and immunohistochemistry. The data were further examined using public GBM databases and GBM cell line. Analysis on genetic data confirmed common features of GBM, including gain of chr.7 and loss of chr.10, loss of critical tumor suppressors, high frequency of PDGFA and EGFR amplification. Through profiling DNA methylome of individual tumor foci, we found that promoter methylation status of genes involved in detection of chemical stimulus, immune response, and Hippo/YAP1 pathway was significantly changed in mGBM. Although both CNV and promoter methylation alteration were involved in heterogeneity of different tumor foci from same patients, more CNV events than promoter hypomethylation events were shared by different tumor foci, implying CNV were relatively earlier than promoter methylation alteration during evolution of different tumor foci from same mGBM. Moreover, different tumor foci from same mGBM assumed different molecular subtypes and mesenchymal subtype was prevalent in mGBM, which might explain the worse prognosis of mGBM than single GBM. Interestingly, we noticed that LIF and CCL2 was tightly correlated with mesenchymal subtype tumor focus in mGBM and predicted poor survival of GBM patients. Treatment with LIF and CCL2 produced mesenchymal-like transcriptome in GBM cells. Together, our work herein comprehensively profiled multi-omics features of mGBM and emphasized that components of extracellular microenvironment, such as LIF and CCL2, contributed to the evolution and prognosis of tumor foci in mGBM patients.
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http://dx.doi.org/10.7150/thno.65739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8690928PMC
January 2022

Distribution and transport characteristics of fine particulate matter in beijing with mobile lidar measurements from 2015 to 2018.

J Environ Sci (China) 2022 May 2;115:65-75. Epub 2021 Aug 2.

Key Laboratory of Environmental Optics and Technology, Anhui Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Hefei 230031, China.

Accurately quantifying the concentration and transport flux of atmospheric fine particulate matter (PM) is vital when attempting to thoroughly identify the pollution formation mechanism. In this study, the mobile lidar measurements in Beijing on heavily polluted days in December from 2015 to 2018 are presented. The lidar was mounted on a vehicle, which could perform measurements along designated routes. On the basis of mobile lidar measurements along closed circuits of the 6th Ring Road around Beijing, the spatial distribution and transport flux of PM in Beijing were determined with information of wind field. In the spatial distribution, both the concentration and transport of PM were revealed to be more significant in the southern section of Beijing. The regional transport layer at heights < 1.3 km plays an important role in pollution formation. The maximum transport flux reached 1600 μg/(m*sec) on 11 December 2016. With the aerosol boundary layer height determined from the image edge detection (IED) method, the inter-annual variations of the aerosol boundary layer height (ABLH) were also analysed. The ABLH decreased from 0.73 to 0.46 km during the same heavy pollution period from 2015 to 2018. Increasingly adverse aerosol boundary layer (ABL) meteorological factors, including lower ABLH, light winds, temperature inversions, and accumulated moisture, have become necessary for pollution formation in Beijing.
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http://dx.doi.org/10.1016/j.jes.2021.06.013DOI Listing
May 2022

Comparative analysis of the stellacyanins (SCs) family and focus on drought resistance of PtSC18 in Populus trichocarpa.

Gene 2022 Mar 23;813:146106. Epub 2021 Dec 23.

Laboratory of Modern Biotechnology, School of Forestry and Landscape Architecture, Anhui Agricultural University, Hefei 230036, China. Electronic address:

Stellacyanin (SC) is a type I (blue) copper protein, which plays a crucial role in plant growth and stress response. However, the comprehensive analysis and functional research of SCs in the woody plant is still lacking. Here, a total of 74 SCs were collected and identified from Arabidopsis, papaya, grape, rice and poplar. Bioinformatics was used to analyze the gene structure, protein structure and evolutionary relationship of 74 genes, especially 19 SCs in Populus trichocarpa. Based on the RNA-seq data, expression pattern of SCs in poplar under cold, high temperature, drought and salt stress were further analyzed. Subsequently, a key candidate gene PtSC18 that strongly responded to drought stress was screened. Subcellular localization experiment exhibited that PtSC18 was localized in the nucleus and plasma membrane. Overexpression of PtSC18 enhanced drought tolerance of transgenic Arabidopsis by improving water retention and reducing oxidative damage. Measurements of physiological indicators, including chlorophyll, HO, malondialdehyde content, peroxidase and catalase enzyme activities and electrical conductivity, all supported this conclusion. More importantly, PtSC18 enhanced the expression of some stress-related genes in transgenic Arabidopsis. Overall, our results lay a foundation for understanding the structure and function of PtSCs and provide useful gene resources for breeding through genetic engineering.
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http://dx.doi.org/10.1016/j.gene.2021.146106DOI Listing
March 2022

The moso bamboo WRKY transcription factor, PheWRKY86, regulates drought tolerance in transgenic plants.

Plant Physiol Biochem 2022 Jan 21;170:180-191. Epub 2021 Oct 21.

Laboratory of Modern Biotechnology, School of Forestry and Landscape Architecture, Anhui Agricultural University, Hefei, 230036, China. Electronic address:

PheWRKY86 is a member of the WRKY transcription factor family in moso bamboo (Phyllostachys edulis). Expression of PheWRKY86 is strongly induced by drought and abscisic acid (ABA) treatments. The PheWRKY86 protein localizes to the cell nucleus and is specifically able to bind to W-box elements. 35S:PheWRKY86 transgenic Arabidopsis and rice showed significantly improved tolerance to drought stress. 35S:PheWRKY86 transgenic plants exhibited better water retention and lower relative electrolyte leakage (REL) and malondialdehyde (MDA) compared to wild type plants. Moreover, 35S:PheWRKY86 transgenic lines showed higher sensitivity to ABA stress. The 35S:PheWRKY86 transgenic plants exhibited higher ABA levels relative to wild type, while also exhibiting a lower germination rate, root length and fresh weight compared to wild type. Further analysis showed that expression of some ABA-responsive genes was changed in the 35S:PheWRKY86 transgenic lines under drought conditions. Transient expression and yeast one-hybrid assays demonstrated that PheWRKY86 could bind to the W-box element in the promoter region of NCED1. Taken together, these results demonstrate that PheWRKY86 plays a positive role in drought tolerance by regulating NCED1 expression.
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http://dx.doi.org/10.1016/j.plaphy.2021.10.024DOI Listing
January 2022

GEPSdb: The Gene Expression Database of Poplar under Stress.

Plant Genome 2021 Dec 8:e20163. Epub 2021 Dec 8.

Laboratory of Modern Biotechnology, School of Forestry and Landscape Architecture, Anhui Agricultural Univ., Hefei, 230036, China.

As a model tree species, poplar (Populus L.) has important economic and ecological value. Here, we constructed the GEPSdb (Gene Expression Database of Poplar under Stress; http://gepsdb.ahau-edu.cn/), which is an integrated database of poplar gene expression profiles derived from RNA-seq and microarray library data. This database provides a comprehensive collection of gene expression data from poplar exposed to 14 types of environmental stress from 11 high-quality RNA-seq experiments and 51 microarray libraries. The GEPSdb includes 56 genes from previous literature that have been examined in poplar and functionally verified. By incorporating data from numerous expression analyses, GEPSdb provides a user-friendly web interface for querying, browsing, and visualizing the expression profiles of related genes. Consequently, GEPSdb can be used to link transcription data with phenotypes and can enhance our understanding of important biological processes and mechanisms underlying complex agronomic traits in poplar.
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http://dx.doi.org/10.1002/tpg2.20163DOI Listing
December 2021

Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity.

J Am Chem Soc 2021 12 3;143(49):20697-20709. Epub 2021 Dec 3.

Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.

The main protease (M) is a validated antiviral drug target of SARS-CoV-2. A number of M inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host proteases such as cathepsin L. In this study we describe the rational design of covalent SARS-CoV-2 M inhibitors with novel cysteine reactive warheads including dichloroacetamide, dibromoacetamide, tribromoacetamide, 2-bromo-2,2-dichloroacetamide, and 2-chloro-2,2-dibromoacetamide. The promising lead candidates (dichloroacetamide) and (tribromoacetamide) had not only potent enzymatic inhibition and antiviral activity but also significantly improved target specificity over caplain and cathepsins. Compared to , these new compounds did not inhibit the host cysteine proteases including calpain I, cathepsin B, cathepsin K, cathepsin L, and caspase-3. To the best of our knowledge, they are among the most selective covalent M inhibitors reported thus far. The cocrystal structures of SARS-CoV-2 M with and reaffirmed our design hypothesis, showing that both compounds form a covalent adduct with the catalytic C145. Overall, these novel compounds represent valuable chemical probes for target validation and drug candidates for further development as SARS-CoV-2 antivirals.
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http://dx.doi.org/10.1021/jacs.1c08060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672434PMC
December 2021

The phenotypic characteristics of patients with athelia and tooth agenesis.

Ann Transl Med 2021 Oct;9(20):1583

Department of Endodontics I, Stomatological Hospital of Xiamen Medical College, Xiamen, China.

Background: Although athelia, which is a congenital aplastic deformity of the nipple, is seldom reported in tooth agenesis patients, we observed athelia in 2 hypodontia patients. This study aimed to summarize the phenotypic characteristics of patients with athelia and tooth agenesis.

Methods: A database search was conducted for publications reporting on patients with athelia and tooth agenesis, and the phenotypes of such patients were recorded. Athelia-related syndromes were identified in the Online Mendelian Inheritance in Man (OMIM) database. The common symptoms and the causative genes were documented. Potential interactions between athelia-related genes and tooth agenesis-related genes were analyzed in the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database.

Results: We summarized the phenotypic characteristics of 8 previously reported patients. Deformities in hair, skin, and sweat glands were common in these patients. There were 23 nipple deformity-related syndromes reported. The most common symptoms included abnormalities of the head and neck, cardiovascular, genitourinary, and skeletal systems, and the skin, nails, and hair. Hypodontia was noted in association with 10 syndromes. A total of 16 genes were related to them, including , , and . The interaction found in the study suggests that nipple deformity-related genes potentially interact with tooth agenesis-related genes.

Conclusions: These results indicated that athelia might be related to hypodontia. Additional molecular genetics research is needed to fully elucidate the underlying relationship between athelia and tooth agenesis.
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http://dx.doi.org/10.21037/atm-21-5159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576720PMC
October 2021

Presenilin1 inhibits glioblastoma cell invasiveness via promoting Sortilin cleavage.

Cell Commun Signal 2021 11 15;19(1):112. Epub 2021 Nov 15.

Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 183# Xinqiao street, Shapingba District, Chongqing, 400037, China.

Background: Alzheimer's disease (AD) and glioblastoma are the most common and devastating diseases in the neurology and neurosurgery departments, respectively. Our previous research reports that the AD-related protein Presenilin1 represses cell proliferation by inhibiting the Wnt/β-catenin pathway in glioblastoma. However, the function of Presenilin1 and the underlying mechanism need to be further investigated.

Methods: The correlations of two genes were conducted on the R2 microarray platform and CGGA. Wound healing, Transwell assays and glioblastoma transplantation were performed to detect invasion ability. Phalloidin staining was employed to show cell morphology. Proximity ligation assays and protein docking assays were employed to detect two protein locations. We also employed western blotting to detect protein expression.

Results: We found that Presenilin1 clearly repressed the migration, invasion and mesenchymal transition of glioblastoma cells. Intriguingly, we observed that the expression of Presenilin1 was positively correlated with Sortilin, which is identified as a pro-invasion molecule in glioma. Furthermore, Presenilin1 interacted with Sortilin at the transmembrane domain and repressed Sortilin expression by cleaving it in glioblastoma cells. First, we found that Sortilin introduced the function of Presenilin1 in phosphorylating β-catenin and repressing invasion in glioblastoma cells. Last, Presenilin1 stimulation sharply suppressed the invasion and mesenchymal transition of glioblastoma in mouse subcutaneous and intracranial transplantation models.

Conclusions: Our study reveals that Sortilin mediates the regulation of β-catenin by Presenilin1 and transduces the anti-invasive function of Presenilin1, which may provide novel therapeutic targets for glioblastoma treatment. Video Abstract.
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http://dx.doi.org/10.1186/s12964-021-00780-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594175PMC
November 2021

[Understanding the dual character of negative and positive results in acupuncture-moxibustion clinical trials in foreign countries].

Zhongguo Zhen Jiu 2021 Nov;41(11):1267-70

Sanya Maternal and Child Health Hospital.

The differences in the objective, starting point, disease spectrum and interventions of acupuncture-moxibustion clinical trials at home and abroad are collected. By taking two articles of acupuncture-moxibustion clinical trials in foreign countries accepted by as example, the reasons are analyzed on the dual character of negative and positive results obtained in acupuncture-moxibustion trials of foreign countries. The therapeutic regimens in acupuncture-moxibustion clinical trials in foreign countries are lack of TCM thinking, the manipulation of interventions have not displayed the basic principle of TCM in treatment of diseases, which is separated the theory from the practice in treatment with Chinese herbal medicine and acupuncture-moxibustion. Besides, the advantages in therapeutic effect of acupuncture-moxibustion have not been truly reflected. Regarding the dual character of negative and positive results in acupuncture-moxibustion clinical trials of foreign countries, it is suggested that acupuncture-moxibustion has not been thoroughly understood in foreign countries and its research content have not been in compliance with the theory of traditional acupuncture-moxibustion.
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http://dx.doi.org/10.13703/j.0255-2930.20200903-k0001DOI Listing
November 2021

Case Report: Osimertinib Followed by Osimertinib Plus Bevacizumab, Personalized Treatment Strategy for a Lung Cancer Patient With a Novel Exon 20 Insertion D770_N771insGT and Multiple Brain Metastases.

Front Oncol 2021 25;11:733276. Epub 2021 Oct 25.

Department of Oncology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are the standard of care for non-small cell lung cancer (NSCLC) patients with exon 19 deletion and L858R mutations. However, no EGFR TKI has been approved for NSCLC patients harboring insertion mutations in exon 20 (ex20ins), a subgroup of uncommon mutations resistant to first-generation EGFR TKIs. This unmet clinical challenge is further complicated by disease progression due to brain metastases (BMs), which limits the use of EGFR TKIs with low intracranial activity. Osimertinib, a third-generation EGFR TKI with high CNS activity, has demonstrated superior efficacy as a first-line treatment for -mutant NSCLC with or without BM. The VEGF pathway is a key mediator of cancer metastasis and resistance to EGFR TKIs. Accumulating evidence has demonstrated that the addition of anti-VEGF agents to EGFR TKIs provides an alternative treatment option for the clinical management of -mutant NSCLC. We herein report an NSCLC case with a novel ex20ins mutation D770_N771insGT and multiple brain metastases who briefly responded to first-line osimertinib treatment and subsequently achieved prolonged disease control with osimertinib plus bevacizumab as second-line treatment. Our case suggests that osimertinib in combination with bevacizumab may be an effective option for NSCLC patients with specific ex20ins mutations and brain metastases.
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http://dx.doi.org/10.3389/fonc.2021.733276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573166PMC
October 2021

Single Dose of SHR-1222, a Sclerostin Monoclonal Antibody, in Healthy Men and Postmenopausal Women With Low Bone Mass: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation, Phase I Study.

Front Pharmacol 2021 20;12:770073. Epub 2021 Oct 20.

National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.

SHR-1222 is a humanized monoclonal antibody targeting sclerostin and has the potential to promote bone formation and reduce bone resorption. This study was aimed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1222 in healthy men and postmenopausal women with low bone mass (BMD). It was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Subjects received SHR-1222 at 50, 100, 200, 300, and 400 mg sequentially or matching placebo subcutaneously. Totally, 50 subjects with low BMD were enrolled and randomly assigned; 10 received placebo and 40 received SHR-1222 (50 mg, n = 4; 100, 200, 300, or 400 mg, n = 9). The most common adverse events that occurred at least 10% higher in subjects with SHR-1222 treatment than those with placebo were decreased blood calcium, blood urine present, increased blood cholesterol, electrocardiogram T wave abnormal, urinary tract infection, increased blood pressure diastolic, and positive bacterial test. All the above adverse events were mild in severity and well resolved except one of increased blood cholesterol in a subject lost to follow-up. The serum SHR-1222 concentration increased in a dose-dependent manner. Administration of SHR-1222 upregulated the bone-formation markers N-terminal propeptide of type 1 procollagen, osteocalcin, and bone-specific alkaline phosphatase, while downregulated the bone-resorption marker β-C-telopeptide. The BMD at the lumbar spine notably rose after a single dose of SHR-1222. The largest increase occurred in the 400 mg cohort (3.8, 6.7, and 6.1% on day 29, 57, and 85, respectively; compared with 1.4, 0.8, and 1.0% in the placebo group). Although 10.0% of subjects receiving SHR-1222 tested positive for anti-SHR-1222 antibodies, no obvious effects of antibody formation were found on pharmacokinetics. Overall, SHR-1222 was well tolerated at doses from 50 to 400 mg and is a promising new remedy for osteoporosis. http://www.clinicaltrials.gov, NCT03870100.
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http://dx.doi.org/10.3389/fphar.2021.770073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564351PMC
October 2021

A Comparative Study of Marginalized Graph Kernel and Message-Passing Neural Network.

J Chem Inf Model 2021 11 1;61(11):5414-5424. Epub 2021 Nov 1.

School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.

This work proposes a state-of-the-art hybrid kernel to calculate molecular similarity. Combined with Gaussian process models, the performance of the hybrid kernel in predicting molecular properties is comparable to that of the directed message-passing neural network (D-MPNN). The hybrid kernel consists of a marginalized graph kernel (MGK) and a radial basis function (RBF) kernel that operate on molecular graphs and global molecular features, respectively. Bayesian optimization was used to obtain the optimal hyperparameters for both models. The comparisons are performed on 11 publicly available data sets. Our results show that their performances are similar, their prediction errors are correlated, and the ensemble predictions of the two models perform better than either of them. Through principal component analysis, we found that the molecular embeddings of the hybrid kernel and the D-MPNN are also similar. The advantage of D-MPNN lies in the computational efficiency and scalability of large-scale data, while the advantage of the graph kernel models lies in the accurate uncertainty quantification.
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http://dx.doi.org/10.1021/acs.jcim.1c01118DOI Listing
November 2021

Screening strategy for islet autoantibodies in diabetes patients of different ages.

Diabetes Technol Ther 2021 Oct 27. Epub 2021 Oct 27.

The Second Xiangya Hospital of Central South University, Department of Metabolism & Endocrinology, Changsha, Hunan, China.

Background The detection of islet autoantibodies is essential for the accurate classification and diagnosis of diabetes mellitus (DM). The islet autoantibody distribution varies by age. However, screening strategies for DM patients with different onset ages remain lacking. Methods This cross-sectional study included 17 536 DM patients from 46 medical centers across China. The seroprevalence of glutamic acid decarboxylase autoantibody (GADA), insulinoma-associated-2 autoantibody (IA-2A), zinc transporter 8 autoantibody (ZnT8A) and insulin autoantibody (IAA) was determined in younger and older patients with type 1 DM (T1DM) (n=287 and 285, respectively), younger and older patients with latent autoimmune diabetes (LAD) (n=140 and 121, respectively), and younger and older patients with type 2 DM (T2DM) (n=200 in each group). Results The cutoff age between younger and older patients was 35 years using restricted cubic spline method (n = 17 536, adjusted R2 = 0.97, residual standard error = 1.32; P < 0.001). The seroprevalence rates of four islet autoantibodies were higher in patients aged 15-35 years than in those ≥ 35 years (GADA: 17% vs. 5.6%, IA-2A: 8.5% vs. 1.3%, ZnT8A: 6.3% vs. 2.3%, IAA: 2.2% vs. 1.0%). The prevalence of ZnT8A was higher in LAD patients than in T1DM patients, especially in older LAD patients. The results indicated that ZnT8A detection can increase the detection rate of older LAD patients from 70.2% (based on GADA detection alone) to 91.7%. Conclusions In patients stratified according to the cutoff age of 35 years, the optimal detection sequence should be GADA, IA-2A, and ZnT8A in younger patients and GADA, ZnT8A, and IA-2A in older patients, so as to reduce the screening cost while improving the detection rate. Particularly, the ZnT8A test is recommended in older patients to avoid a missed LAD diagnosis.
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http://dx.doi.org/10.1089/dia.2021.0177DOI Listing
October 2021

Author Correction: EEG microstate in obstructive sleep apnea patients.

Sci Rep 2021 Oct 21;11(1):21157. Epub 2021 Oct 21.

Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Kunming, 650500, China.

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http://dx.doi.org/10.1038/s41598-021-00538-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531393PMC
October 2021

Inhibition of SARS-CoV-2 polymerase by nucleotide analogs from a single-molecule perspective.

Elife 2021 10 7;10. Epub 2021 Oct 7.

Junior Research Group 2, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.

The absence of 'shovel-ready' anti-coronavirus drugs during vaccine development has exceedingly worsened the SARS-CoV-2 pandemic. Furthermore, new vaccine-resistant variants and coronavirus outbreaks may occur in the near future, and we must be ready to face this possibility. However, efficient antiviral drugs are still lacking to this day, due to our poor understanding of the mode of incorporation and mechanism of action of nucleotides analogs that target the coronavirus polymerase to impair its essential activity. Here, we characterize the impact of remdesivir (RDV, the only FDA-approved anti-coronavirus drug) and other nucleotide analogs (NAs) on RNA synthesis by the coronavirus polymerase using a high-throughput, single-molecule, magnetic-tweezers platform. We reveal that the location of the modification in the ribose or in the base dictates the catalytic pathway(s) used for its incorporation. We show that RDV incorporation does not terminate viral RNA synthesis, but leads the polymerase into backtrack as far as 30 nt, which may appear as termination in traditional ensemble assays. SARS-CoV-2 is able to evade the endogenously synthesized product of the viperin antiviral protein, ddhCTP, though the polymerase incorporates this NA well. This experimental paradigm is essential to the discovery and development of therapeutics targeting viral polymerases.
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http://dx.doi.org/10.7554/eLife.70968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497053PMC
October 2021

Genome and transcriptome analysis to understand the role diversification of cytochrome P450 gene under excess nitrogen treatment.

BMC Plant Biol 2021 Oct 6;21(1):447. Epub 2021 Oct 6.

Laboratory of Modern Biotechnology, School of Forestry and Landscape Architecture, Anhui Agricultural University, Hefei, 230036, China.

Background: Panax notoginseng (Burk.) F. H. Chen (P. notoginseng) is a medicinal plant. Cytochrome P450 (CYP450) monooxygenase superfamily is involved in the synthesis of a variety of plant hormones. Studies have shown that CYP450 is involved in the synthesis of saponins, which are the main medicinal component of P. notoginseng. To date, the P. notoginseng CYP450 family has not been systematically studied, and its gene functions remain unclear.

Results: In this study, a total of 188 PnCYP genes were identified, these genes were divided into 41 subfamilies and clustered into 9 clans. Moreover, we identified 40 paralogous pairs, of which only two had Ka/Ks ratio greater than 1, demonstrating that most PnCYPs underwent purification selection during evolution. In chromosome mapping and gene replication analysis, 8 tandem duplication and 11 segmental duplication events demonstrated that PnCYP genes were continuously replicating during their evolution. Gene ontology (GO) analysis annotated the functions of 188 PnCYPs into 21 functional subclasses, suggesting the functional diversity of these gene families. Functional divergence analyzed the members of the three primitive branches of CYP51, CYP74 and CYP97 at the amino acid level, and found some critical amino acid sites. The expression pattern of PnCYP450 related to nitrogen treatment was studied using transcriptome sequencing data, 10 genes were significantly up-regulated and 37 genes were significantly down-regulated. Combined with transcriptome sequencing analysis, five potential functional genes were screened. Quantitative real-time PCR (qRT-PCR) indicated that these five genes were responded to methyl jasmonate (MEJA) and abscisic acid (ABA) treatment.

Conclusions: These results provide a valuable basis for comprehending the classification and biological functions of PnCYPs, and offer clues to study their biological functions in response to nitrogen treatment.
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http://dx.doi.org/10.1186/s12870-021-03224-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493724PMC
October 2021

Novel Inorganic Integrated Membrane Electrodes for Membrane Capacitive Deionization.

ACS Appl Mater Interfaces 2021 Oct 23;13(39):46537-46548. Epub 2021 Sep 23.

Department of Chemistry, Bar-Ilan University, Ramat-Gan 5290002, Israel.

In capacitive deionization (CDI), coion repulsion and Faradaic reactions during charging reduce the charge efficiency (CE), thus limiting the salt adsorption capacity (SAC) and energy efficiency. To overcome these issues, membrane CDI (MCDI) based on the enhanced permselectivity of the anode and cathode is proposed using the ion-exchange polymer as the independent membrane or coating. To develop a novel and cost-effective MCDI system, we fabricated an integrated membrane electrode using a thin layer of the inorganic ion-exchange material coated on the activated carbon (AC) electrode, which effectively improves the ion selectivity. Montmorillonite (MT, AlOSi) and hydrotalcite (HT, MgAl(CO)(OH)·4HO) were selected as the main active anion- and cation-exchange materials, respectively, for the cathode and anode. The HT-MT MCDI system employing HT-AC and MT-AC electrodes obtained a CE of 90.5% and an SAC of 15.8 mg g after 100 consecutive cycles (50 h); these values were considerably higher than those of the traditional CDI system employing pristine AC electrodes (initially, a CE of 55% and an SAC of 10.2 mg g, which attenuated continuously to zero, and even "inverted work" occurs after 50 h, i.e., desorption during charging and adsorption during discharging). The HT-MT MCDI system showed moderate tolerance to organic matters during desalination and retained 84% SAC and 89% CE after 70 cycles in 50-200 mg L sodium alginate. This study demonstrates a simple and cost-effective method for fabricating high-CE electrodes for desalination with great application potential.
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http://dx.doi.org/10.1021/acsami.1c10119DOI Listing
October 2021

Relationship between the sodium fluorescein yellow fluorescence boundary and the actual boundary of high-grade gliomas during surgical resection.

Br J Neurosurg 2021 Sep 20:1-8. Epub 2021 Sep 20.

Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

Objective: Resection of high-grade glioma with sodium fluorescein can improve the resection rate of the glioma and improve survival. However, it is unclear whether the yellow fluorescence boundary of the high-grade glioma is consistent with the actual boundary of the tumor. This study explores the yellow fluorescence boundary and the actual tumor boundary in high-grade glioma surgery.

Methods: This is a retrospective analysis of 10 patients with high-grade gliomas who underwent tumor visualization with sodium fluorescein. After staining of the tumor, random selections of both developed and non-developed yellow fluorescent border tissue at the fluorescence chromogenic boundary were made, followed by pathological examination. Claudin-5, an important component of the tight connections between vascular endothelial cells, was assessed by immunohistochemistry and qRT-PCR in the tumor and surrounding tissues in order to determine the tumor cell content of the tissue, blood-brain barrier damage, and vascular proliferation. The yellow fluorescence boundary was compared with the actual tumor boundary and the results analyzed.

Results: Tumor cells were still detected outside the yellow fluorescence boundary during high-grade glioma surgery ( <  0.05). Claudin-5 expression was higher in high-grade gliomas than in adjacent normal tissues ( < 0.05), while disconnected Claudin-5 expression was associated with intraoperative yellow fluorescence imaging ( = 0.67).

Conclusions: There is a difference between the yellow fluorescence boundary and the actual boundary of the tumor in high-grade glioma, and there are glioma cell infiltrations in the brain tissue of the undeveloped yellow fluorescent border. To ensure patient recovery and function, it is recommended that tumor resection be expanded based on yellow fluorescence visualization. Claudin-5 is overall up-regulated in high-grade gliomas, but some Claudin-5 expression is disconnected. This Claudin-5 expression pattern may be related to the development of yellow fluorescence.
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http://dx.doi.org/10.1080/02688697.2021.1976392DOI Listing
September 2021

[Corrigendum] Effect of Yi Guan Jian decoction on differentiation of bone marrow mesenchymal stem cells into hepatocyte‑like cells in dimethylnitrosamine‑induced liver cirrhosis in mice.

Mol Med Rep 2021 Nov 20;24(5). Epub 2021 Sep 20.

Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.

Following the publication of the above article, an interested reader to the authors' attention that there appeared to be several duplications of data panels featured within Figs. 1‑3. After having consulted their original data, the authors have realized that a number of the data panels were inadvertently assembled incorrectly in these figures. The corrected versions of Fig. 1A (showing the correct data for the NC‑2W and NC‑4W experiments), Fig. 1B (including the correct data for the C‑4W, M‑2W, NC‑2W and NC‑4W experiments), Fig. 2 (showing the correct data for the YGD‑2W experiment), Fig. 3A (NC‑3W data panel corrected), Fig. 3B (HGF‑1W and NC‑3W data panels corrected) and Fig. 3C (C‑4W data panel corrected) are shown on the next four pages. All these corrections were approved by all authors. The authors regret that these errors were not resolved before the publication of the paper, thank the Editor of for granting them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published in 15: 613‑626, 2017; DOI: 10.3892/mmr.2016.6083].
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http://dx.doi.org/10.3892/mmr.2021.12448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477171PMC
November 2021

Analogs of microgravity: the function of Schlemm's canal, intraocular pressure and autonomic nervous during the head-down tilt test in healthy subjects.

Int J Ophthalmol 2021 18;14(9):1419-1423. Epub 2021 Sep 18.

Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.

Aim: To evaluate the ocular outcomes and to elucidate possible mechanisms underlying intraocular pressure (IOP) change following the head-down tilt (HDT) test.

Methods: The study included 21 participants at the Department of Ophthalmology of Tongji Hospital. Subjects received the test of I-care tonometry, enhanced depth imaging optical coherence tomography and heart rate variability (HRV) analysis before and after 15min HDT test. The lumen area of Schlemm's canal (SCAR), IOP, HRV were calculated.

Results: IOP increased significantly after 20° head down position from 14.0±3.0 to 17.0±3.3 mm Hg (<0.001). SCAR decreased from 13449.0±5454.9 µm at sitting condition to 9576.6±4130.9 µm post 15min HDT test. High frequency (HF) indices increased significantly from 1462±865 Hz at baseline to 2128±824 Hz. Heart rate (HR) decreased significantly from 76±11.48 to 70±11.52 bpm after the HDT. The linear regression analysis showed that the difference of HF and SCAR significantly correlated with each other during the HDT ( =20%, =0.04).

Conclusion: These outcomes perform the first evidence of the activation of autonomic nervous system of HDT may cause the collapse of Schlemm's canal lumen, which in turn leading to the increased IOP.
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http://dx.doi.org/10.18240/ijo.2021.09.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403865PMC
September 2021

Multiple root canals in the maxillary molar: an unusual case report.

BMC Oral Health 2021 08 30;21(1):423. Epub 2021 Aug 30.

Endodontics Department of Stomatological Hospital of Xiamen Medical College, Xiamen, 361008, China.

Background: The objective of this report was to highlight the importance of using a dental operating microscope (DOM) to locate supernumerary canals and diagnose variations in root canals using cone-beam computed tomographic (CBCT) images.

Case Presentation: A 35-year-old Chinese female had repeated swelling in the upper right posterior maxilla for 3 months and was referred to evaluate symptomatic apical periodontitis and mesotaurodonts for upper right first permanent molar and upper right second permanent molar. Root canal therapy was proposed and conducted with the use of DOM and CBCT.

Conclusions: Proper diagnosis and careful clinicoradiological examination are necessary, and it is essential to reinforce the knowledge of the rare morphology of root canals for clinicians.
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http://dx.doi.org/10.1186/s12903-021-01771-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404290PMC
August 2021

EEG microstate in obstructive sleep apnea patients.

Sci Rep 2021 08 25;11(1):17178. Epub 2021 Aug 25.

Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Kunming, 650500, China.

Obstructive sleep apnea (OSA) is a common sleep respiratory disease. Previous studies have found that the wakefulness electroencephalogram (EEG) of OSA patients has changed, such as increased EEG power. However, whether the microstates reflecting the transient state of the brain is abnormal is unclear during obstructive hypopnea (OH). We investigated the microstates of sleep EEG in 100 OSA patients. Then correlation analysis was carried out between microstate parameters and EEG markers of sleep disturbance, such as power spectrum, sample entropy and detrended fluctuation analysis (DFA). OSA_OH patients showed that the microstate C increased presence and the microstate D decreased presence compared to OSA_withoutOH patients and controls. The fifth microstate E appeared during N1-OH, but the probability of other microstates transferring to microstate E was small. According to the correlation analysis, OSA_OH patients in N1-OH showed that the microstate D was positively correlated with delta power, and negatively correlated with beta and alpha power; the transition probability of the microstate B → C and E → C was positively correlated with alpha power. In other sleep stages, the microstate parameters were not correlated with power, sample entropy and FDA. We might interpret that the abnormal transition of brain active areas of OSA patients in N1-OH stage leads to abnormal microstates, which might be related to the change of alpha activity in the cortex.
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http://dx.doi.org/10.1038/s41598-021-95749-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387348PMC
August 2021

Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir.

ACS Pharmacol Transl Sci 2021 Aug 9;4(4):1408-1421. Epub 2021 Jun 9.

Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.

SARS-CoV-2 main protease (M) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. M is highly conserved among all seven human coronaviruses, with certain M inhibitors having broad-spectrum antiviral activity. In this study, we designed two hybrid inhibitors and based on the superimposed X-ray crystal structures of SARS-CoV-2 M with GC-376, telaprevir, and boceprevir. Both and showed potent binding and enzymatic inhibition against the M's from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP M assay results show that and inhibited the intracellular protease activity of SARS-CoV-2 M. In addition, and had potent antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, with being more potent than GC-376 in inhibiting SARS-CoV-2. Selectivity profiling revealed that and had an improved selectivity index over that of GC-376 against host cysteine proteases calpain I and cathepsin L, but not cathepsin K. The X-ray crystal structures of SARS-CoV-2 M with and were both solved at 1.9 Å, which validated our design hypothesis. Overall, hybrid inhibitors and are promising candidates to be further developed as broad-spectrum coronavirus antivirals.
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http://dx.doi.org/10.1021/acsptsci.1c00099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204911PMC
August 2021

Geniposide-Loaded Liposomes for Brain Targeting: Development, Evaluation, and In Vivo Studies.

AAPS PharmSciTech 2021 Aug 18;22(7):222. Epub 2021 Aug 18.

Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, No.1688, Meiling Road, Wanli District, Nanchang, Jiangxi, ,330004, People's Republic of China.

Geniposide (GE) possesses excellent neuroprotective effects but with poor brain targeting and short half-life. Liposome was considered to have great potential for brain diseases. Therefore, this research aimed to develop a geniposide liposome (GE-LP) as a brain delivery system for cerebral ischemia reperfusion injury (CIRI) therapy and evaluate its characterization, pharmacokinetics, brain targeting, and neuroprotective effects in vivo. Then, a reverse-phase evaporation method was applied to develop the GE-LP and optimize the formulation. Notably, the GE-LP had suitable size, which was 223.8 nm. Subsequently, the pharmacokinetic behavior of GE solution and GE-LP in mice plasma was investigated, and the brain targeting was also researched. The results showed that GE in plasma of GE-LP displayed three folds longer distribution half-life and a higher bioavailability and brain targeting compared to GE solution. In vivo neuroprotective effects was evaluated through the middle cerebral artery occlusion (MCAO) rat model, and GE-LP exhibited a stronger tendency in preventing the injury of CIRI, which can significantly improve neurological deficits. Overall, this study demonstrates GE-LP as a new formulation with ease of preparation, sustained release, and high brain targeting, which has significant development prospects on CIRI; this is expected to improve the efficacy of GE and reduce the frequency of administration.
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http://dx.doi.org/10.1208/s12249-021-02093-9DOI Listing
August 2021

The TCP transcription factor PeTCP10 modulates salt tolerance in transgenic Arabidopsis.

Plant Cell Rep 2021 Oct 14;40(10):1971-1987. Epub 2021 Aug 14.

Laboratory of Modern Biotechnology, School of Forestry and Landscape Architecture, Anhui Agricultural University, Hefei, 230036, China.

Key Message: PeTCP10 can be induced by salt stresses and play important regulation roles in salt stresses response in transgenic Arabidopsis. Salt stress is one of the major adverse environmental factors that affect normal plant development and growth. PeTCP10, a Class I TCP member, was markedly expressed in moso bamboo mature leaf, root and stem under normal conditions and also induced by salt stress. Overexpressed PeTCP10 was found to enhance salt tolerance of transgenic Arabidopsis at the vegetative growth stage. It was also found capable to increase relative water content, while decreasing relative electrolyte leakage and Na accumulation of transgenic Arabidopsis versus wild-type (WT) plants at high-salt conditions. In addition, it improved antioxidant capacity of transgenic Arabidopsis plants by promoting catalase activity and enhanced their HO tolerance. In contrast to WT plants, transcriptome analysis demonstrated that multiple genes related to abscisic acid, salt and HO response were induced after NaCl treatment in transgenic plants. Meanwhile, overexpressed PeTCP10 improved the tolerance of abscisic acid. Moreover, luciferase reporter assay results showed that PeTCP10 is able to directly activate the expression of BT2 in transgenic plants. In contrary, the germination rates of transgenic plants were significantly lower than those of WT plants under high-NaCl conditions. Both primary root length and survival rate at the seedling stage are also found lower in transgenic plants than in WT plants. It is concluded that overexpressed PeTCP10 enhances salt stress tolerance of transgenic plants at the vegetative growth stage, and it also improves salt sensitiveness in both germination and seedling stages. These research results will contribute to further understand the functions of TCPs in abiotic stress response.
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http://dx.doi.org/10.1007/s00299-021-02765-7DOI Listing
October 2021
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