Publications by authors named "Xing Ji"

84 Publications

RhoA/Rock activation represents a new mechanism for inactivating Wnt/β-catenin signaling in the aging-associated bone loss.

Cell Regen 2021 Mar 3;10(1). Epub 2021 Mar 3.

Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.

The Wnt/β-catenin signaling pathway appears to be particularly important for bone homeostasis, whereas nuclear accumulation of β-catenin requires the activation of Rac1, a member of the Rho small GTPase family. The aim of the present study was to investigate the role of RhoA/Rho kinase (Rock)-mediated Wnt/β-catenin signaling in the regulation of aging-associated bone loss. We find that Lrp5/6-dependent and Lrp5/6-independent RhoA/Rock activation by Wnt3a activates Jak1/2 to directly phosphorylate Gsk3β at Tyr216, resulting in Gsk3β activation and subsequent β-catenin destabilization. In line with these molecular events, RhoA loss- or gain-of-function in mouse embryonic limb bud ectoderms interacts genetically with Dkk1 gain-of-function to rescue the severe limb truncation phenotypes or to phenocopy the deletion of β-catenin, respectively. Likewise, RhoA loss-of-function in pre-osteoblasts robustly increases bone formation while gain-of-function decreases it. Importantly, high RhoA/Rock activity closely correlates with Jak and Gsk3β activities but inversely correlates with β-catenin signaling activity in bone marrow mesenchymal stromal cells from elderly male humans and mice, whereas systemic inhibition of Rock therefore activates the β-catenin signaling to antagonize aging-associated bone loss. Taken together, these results identify RhoA/Rock-dependent Gsk3β activation and subsequent β-catenin destabilization as a hitherto uncharacterized mechanism controlling limb outgrowth and bone homeostasis.
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http://dx.doi.org/10.1186/s13619-020-00071-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925793PMC
March 2021

Comparative intra-articular gene transfer of seven adeno-associated virus serotypes reveals that AAV2 mediates the most efficient transduction to mouse arthritic chondrocytes.

PLoS One 2020 15;15(12):e0243359. Epub 2020 Dec 15.

The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.

Osteoarthritis (OA) is the most common arthropathy, characterized by progressive degeneration of the articular cartilage. Currently, there are no disease-modifying approaches for OA treatment. Adeno-associated virus (AAV)-mediated gene therapy has recently become a potential treatment for OA due to its exceptional characteristics; however, the tropism and transduction efficiency of different AAV serotypes to articular joints and the safety profile of AAV applications are still unknown. The present study aims to screen an ideal AAV serotype to efficiently transfer genes to arthritic cartilage. AAV vectors of different serotypes expressing eGFP protein were injected into the knee joint cavities of mice, with all joint tissues collected 30 days after AAV injection. The transduction efficiency of AAVs was quantified by assessing the fluorescent intensities of eGFP in the cartilage of knee joints. Structural and morphological changes were analyzed by toluidine blue staining. Changes to ECM metabolism and pyroptosis of chondrocytes were determined by immunohistochemical staining. Fluorescence analysis of eGFP showed that eGFP was expressed in the cartilage of knee joints injected with each AAV vector. Quantification of eGFP intensity indicated that AAV2, 7 and 8 had the highest transduction efficiencies. Both toluidine blue staining and Mankin score showed that AAV6 aggravated cartilage degeneration. The analysis of key molecules in ECM metabolism suggested that AAV5 and 7 significantly reduced collagen type II, while AAV9 increased ADAMTS-4 but decreased MMP-19. In addition, transduction with AAV2, 5, 7 and 8 had no obvious effect on pyroptosis of chondrocytes. Comprehensive score analysis also showed that AAV2 had the highest score in intra-articular gene transfer. Collectively, our findings point to AAV2 as the best AAV serotype candidate for gene transfer on arthritic cartilage, resulting in minimal impact to ECM metabolism and pyroptosis of chondrocytes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737971PMC
January 2021

Erratum to "Identification of novel SMN1 subtle mutations using an allelic-specific RT-PCR" [Neuromuscular Disorders, 30(3) 2020, 219-226].

Neuromuscul Disord 2021 Jan 1;31(1):e1. Epub 2020 Dec 1.

Department of Genetic Counseling, Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Electronic address:

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http://dx.doi.org/10.1016/j.nmd.2020.11.006DOI Listing
January 2021

Steroid-resistant Nephrotic Syndrome in Children: A Mini-review on Genetic Mechanisms, Predictive Biomarkers and Pharmacotherapy Strategies.

Curr Pharm Des 2021 ;27(2):319-329

Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.

Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most frequent cause of chronic kidney disease in childhood. The etiology of SRNS remains largely unknown and no standardized treatment exists. Recent advances in genomics have helped to build understanding of the molecular mechanisms and pathogenesis of the disease. The genetic polymorphisms in genes encoding proteins which are involved in the pharmacokinetics and pharmacodynamics of glucocorticoids (GCs) partially account for the different responses between patients with nephrotic syndrome. More importantly, single-gene causation in podocytes-associated proteins was found in approximately 30% of SRNS patients. Some potential biomarkers have been tested for their abilities to discriminate against pediatric patients who are sensitive to GCs treatment and patients who are resistant to the same therapy. This article reviews the recent findings on genetic mechanisms, predictive biomarkers and current therapies for SRNS with the goal to improve the management of children with this syndrome.
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http://dx.doi.org/10.2174/1381612826666201102104412DOI Listing
January 2021

The role of Chinese clinical pharmacists in parenteral nutrition for children using the Screening Tool Risk on Nutrititional Status and Growth (STRONGkids).

Int J Clin Pharm 2020 Sep 29. Epub 2020 Sep 29.

Department of Pharmacy, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China.

Background The abuse and deficiency of nutritional support coexist in China, and clinical pharmacists have responsibilities to promote the rational use of drugs. Objective Apply the Screening Tool Risk on Nutritional Status and Growth to observe the influence of parenteral nutrition on children with an incarcerated hernia and educate physicians to promote the rational use of parenteral nutrition. Setting Department of General Surgery of Nanjing children's hospital. Method Patients were grouped according to the sores of Screening Tool Risk on Nutritional Status and Growth, and each group was then divided into subgroups according to receiving parenteral nutrition only (subgroup A) or no extra nutritional support (subgroup B). The clinical results were compared to ascertain whether parenteral nutrition was necessary, and the clinical pharmacists educated the physicians according to the results. One year later, the clinical results before and after education were compared. Main outcome measure Nutritional indicators (body weight, albumin, prealbumin, retinol binding protein), length of hospital stay after operation, hospitalization cost and incidence of adverse reactions. Results There were no significant differences in changes of nutritional indicators between the A and B subgroups of the score 1 and 2 groups. In the score 3 group, decreases of nutritional indicators were more pronounced in subgroup B than in subgroup A, and the length of hospital stay after operation was significantly shorter in subgroup A. The incidence of adverse reactions was significantly higher for those who received parenteral nutrition. One year after the clinical pharmacists educated the staff, the use of parenteral nutrition, hospitalization cost and incidence of adverse reactions significantly decreased. Conclusions Clinical pharmacists played an important role in improving the rational use of parenteral nutrition.
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http://dx.doi.org/10.1007/s11096-020-01156-4DOI Listing
September 2020

Malic Enzyme Couples Mitochondria with Aerobic Glycolysis in Osteoblasts.

Cell Rep 2020 09;32(10):108108

Translational Research Program in Pediatric Orthopedics, The Children's Hospital of Philadelphia, PA 19104, USA; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

The metabolic program of osteoblasts, the chief bone-making cells, remains incompletely understood. Here in murine calvarial cells, we establish that osteoblast differentiation under aerobic conditions is coupled with a marked increase in glucose consumption and lactate production but reduced oxygen consumption. As a result, aerobic glycolysis accounts for approximately 80% of the ATP production in mature osteoblasts. In vivo tracing with C-labeled glucose in the mouse shows that glucose in bone is readily metabolized to lactate but not organic acids in the TCA cycle. Glucose tracing in osteoblast cultures reveals that pyruvate is carboxylated to form malate integral to the malate-aspartate shuttle. RNA sequencing (RNA-seq) identifies Me2, encoding the mitochondrial NAD-dependent isoform of malic enzyme, as being specifically upregulated during osteoblast differentiation. Knockdown of Me2 markedly reduces the glycolytic flux and impairs osteoblast proliferation and differentiation. Thus, the mitochondrial malic enzyme functionally couples the mitochondria with aerobic glycolysis in osteoblasts.
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http://dx.doi.org/10.1016/j.celrep.2020.108108DOI Listing
September 2020

Whole Genome Low-Coverage Sequencing Concurrently Detecting Copy Number Variations and Their Underlying Complex Chromosomal Rearrangements by Systematic Breakpoint Mapping in Intellectual Deficiency/Developmental Delay Patients.

Front Genet 2020 6;11:616. Epub 2020 Jul 6.

Department of Pediatric Endocrinology and Genetic Metabolism, School of Medicine, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China.

Simple copy number variations (CNVs) detected by chromosomal microarray (CMA) can result from complex structural changes. Therefore, it is necessary to characterize potential structural changes that cause pathogenic CNVs. We applied whole-genome low-coverage sequencing (WGLCS) to concurrently detect pathogenic CNVs and their associated chromosomal rearrangements in 15 patients. All the patients had an average of 2-3 pathogenic CNVs involving 1-2 chromosomes. WGLCS identified all the 34 pathogenic CNVs found by microarray. By identifying chimeric read pairs, WGLCS mapped 70 breakpoints in these patients, of which 47 were finely mapped at the nucleotide level and confirmed by subsequent PCR amplification and Sanger sequencing of the junction fragments. In 15 patients, structural rearrangements were defined at molecular level in 13 patients. In 13 patients, WGLCS reveal no additional results in two patients. In another 11 patients, WGLCS revealed new breakpoints or finely mapped the genes disrupted by breakpoints or 1-6 bp microhomology and/or short insertion (4-70 bp) in the breakpoints junctions. However, structural changes in the other two patients still remained unclear after WGLCS was performed. The structural alteration identified in the 13 patients could be divided into the following categories: (1) interstitial inverted duplication with concomitant terminal deletion (inv dup del) (P1,P4,P9,P11); (2) the product of pericentric inversion (P5); (3) ring chromosome (P8); (4) interstitial duplication and/or triplication (P6, P7); and (5) +der(22)t(11;22) (P2,P15); (6) complex structural rearrangements (P3,P12,P14). WGLCS displayed the ability to discover CNVs and define breakpoints and its disrupted genes and its surrounding sequences in one experiment at base-pair-resolution, which help us to learn more about the mechanisms of formation of observed genomic rearrangements, and in which DNA replicative/repair mechanism might contribute to the formation of complex rearrangements in 11 patients. Clear karyotype at molecular level could help provide an accurate evaluation of recurrent risk and guide prenatal diagnosis or reproductive planning.
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http://dx.doi.org/10.3389/fgene.2020.00616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357533PMC
July 2020

L ARP7 Is a BRCA1 Ubiquitinase Substrate and Regulates Genome Stability and Tumorigenesis.

Cell Rep 2020 07;32(4):107974

Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address:

Attenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best-known tumor suppressors that promote homology recombination (HR) and arrest cell cycle. However, it remains ambiguous whether and how their E3 ligase activity regulates HR. Here, we demonstrate that upon genotoxic stress, BRCA1 together with BARD1 catalyzes the K48 polyubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degrades it through the 26S ubiquitin-proteasome pathway. Depleting LARP7 suppresses the expression of CDK1 complex, arrests the cell at the G2/M DNA damage checkpoint, and reduces BRCA2 phosphorylation, which thereby facilitates RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast cancer patients leads to chemoradiotherapy resistance both in vitro and in vivo. Altogether, this study unveils a mechanism by which BRCA1/BARD1 control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.
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http://dx.doi.org/10.1016/j.celrep.2020.107974DOI Listing
July 2020

Identification of novel SMN1 subtle mutations using an allelic-specific RT-PCR.

Neuromuscul Disord 2020 03 25;30(3):219-226. Epub 2019 Dec 25.

Department of Genetic Counseling, Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Electronic address:

Spinal muscular atrophy (SMA) is caused by homozygous deletions of the SMN1 gene in approximately 95% of patients. The remaining 5% of patients with SMA retain at least one copy of the SMN1 gene carrying insertions, deletions, or point mutations. Although molecular genetic testing for most SMA patients is quite easy, diagnosing "nondeletion" SMA patients is still compromised by the presence of a highly homologous SMN2 gene. In this study, we analyzed the SMN1/SMN2 copy number by quantitative PCR and multiplex ligation-dependent probe amplification (MLPA). Further, common primers for both SMN1 and SMN2 sequences were used to screen DNA intragenic mutations. To confirm whether the identified mutations occurred in SMN1 or SMN2, we improved the traditional RT-PCR method by only amplifying SMN1 transcripts using an allelic-specific PCR (AS-RT-PCR) strategy. We identified six SMN1 point mutations and small indels in 8 families, which included c.683T>A, c.22dupA, c.815A>G, c.19delG, c.551_552insA and c.401_402delAG. To the best of our knowledge, the latter three have never been previously reported. The most common mutation in Chinese patients is c.22dupA, which was identified in three families. In this work, we demonstrated AS-RT-PCR to be reliable for identifying SMN1 subtle mutations, especially the prevalent mutation c.22dupA in Chinese SMA patients. By reviewing published papers and summarizing reported SMN1 mutations, a distinct ethnic specificity was found in SMA patients from China. Our research extends the SMN1 mutation spectrum.
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http://dx.doi.org/10.1016/j.nmd.2019.11.010DOI Listing
March 2020

Phenotypic plasticity of carbon fixation stimulates cyanobacterial blooms at elevated CO.

Sci Adv 2020 02 19;6(8):eaax2926. Epub 2020 Feb 19.

Department of Freshwater and Marine Ecology, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, P.O. Box 94240, 1090 GE Amsterdam, Netherlands.

Although phenotypic plasticity is a widespread phenomenon, its implications for species responses to climate change are not well understood. For example, toxic cyanobacteria can form dense surface blooms threatening water quality in many eutrophic lakes, yet a theoretical framework to predict how phenotypic plasticity affects bloom development at elevated CO is still lacking. We measured phenotypic plasticity of the carbon fixation rates of the common bloom-forming cyanobacterium . Our results revealed a 1.8- to 5-fold increase in the maximum CO uptake rate of at elevated CO, which exceeds CO responses reported for other phytoplankton species. The observed plasticity was incorporated into a mathematical model to predict dynamic changes in cyanobacterial abundance. The model was successfully validated by laboratory experiments and predicts that acclimation to high CO will intensify blooms in eutrophic lakes. These results indicate that this harmful cyanobacterium is likely to benefit strongly from rising atmospheric CO.
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http://dx.doi.org/10.1126/sciadv.aax2926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030920PMC
February 2020

Super-enhancers: A new frontier for glioma treatment.

Biochim Biophys Acta Rev Cancer 2020 04 26;1873(2):188353. Epub 2020 Feb 26.

Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei 230601, China. Electronic address:

Glioma is the most common primary malignant tumor in the human brain. Although there are a variety of treatments, such as surgery, radiation and chemotherapy, glioma is still an incurable disease. Super-enhancers (SEs) are implicated in the control of tumor cell identity, and they promote oncogenic transcription, which supports tumor cells. Inhibition of the SE complex, which is required for the assembly and maintenance of SEs, may repress oncogenic transcription and impede tumor growth. In this review, we discuss the unique characteristics of SEs compared to typical enhancers, and we summarize the recent advances in the understanding of their properties and biological role in gene regulation. Additionally, we highlight that SE-driven lncRNAs, miRNAs and genes are involved in the malignant phenotype of glioma. Most importantly, the application of SE inhibitors in different cancer subtypes has introduced new directions in glioma treatment.
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http://dx.doi.org/10.1016/j.bbcan.2020.188353DOI Listing
April 2020

A Recurrent Variant in in Five Siblings with Severe Respiratory Disturbance after Birth.

Mol Syndromol 2020 Jan 5;10(5):286-290. Epub 2019 Jul 5.

Department of Pediatric Endocrinology and Genetics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China and Shanghai Institute for Pediatric Research, Shanghai, China.

Schaaf-Yang syndrome (SHFYNG) is caused by truncating mutations in the paternal allele of the gene located in the Prader-Willi syndrome region. We report 5 newborns affected with SHFYNG in one family. Trio exome analysis revealed a heterozygous c.1996dupC frameshift mutation in inherited from the unaffected father. The phenotypes showed strong resemblance, especially for severe respiratory disturbance requiring mechanical ventilation at birth. After discharge from the hospital, 4 of the patients died of respiratory insufficiency within 1 or 2 weeks after birth, and 1 child died after 110 days of aggravated apnea. Apnea or respiratory failure was the main cause of early death in this family. Respiratory distress is a common manifestation of SHFYNG, especially in patients with c.1996dupC mutations. Hypotonia is a main cause of respiratory disturbance, and we propose another possible cause affecting the respiratory center of the brain.
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http://dx.doi.org/10.1159/000501376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997796PMC
January 2020

Noninvasive prenatal diagnosis of cobalamin C (cblC) deficiency through target region sequencing of cell-free DNA in maternal plasma.

Prenat Diagn 2020 02 26;40(3):324-332. Epub 2019 Dec 26.

Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objective: This study aimed to validate the feasibility of haplotype-based noninvasive prenatal diagnosis (NIPD) of cobalamin C (cblC) deficiency.

Method: This method includes three steps: First, targeted sequencing was performed on 21 families affected by cblC deficiency (including the couples and probands). Second, parental haplotypes linked with the pathogenic variant were determined using the genotypes of trios. Then, the fetal haplotypes were inferred through a parental haplotype assisted hidden Markov model (HMM). The NIPD results were confirmed by using the invasive procedures.

Results: Twenty-one fetal genotypes were successfully inferred by NIPD including three compound heterozygotes with cblC deficiency, nine heterozygote carriers of cblC deficiency, and nine normal fetuses. The NIPD results were confirmed using the invasive procedures with 100% concordant rate.

Conclusion: This result has shown that haplotype-based NIPD of cblC deficiency has high concordant rate and indicated potential clinical utility as a pregnancy diagnosis method for high-risk carrier couples.
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http://dx.doi.org/10.1002/pd.5601DOI Listing
February 2020

A novel SCCmec type V variant in porcine MRSA ST398 from China.

J Antimicrob Chemother 2020 02;75(2):484-486

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.

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http://dx.doi.org/10.1093/jac/dkz445DOI Listing
February 2020

gen. nov. (Polyporaceae, Basidiomycota) evidenced by morphological characters and phylogenetic analyses with descriptions of four new species.

MycoKeys 2019 21;57:61-84. Epub 2019 Aug 21.

Institute of Microbiology, School of Ecology and Nature Conservation, Beijing Forestry University, Beijing 100083, China Beijing Forestry University Beijing China.

A new poroid wood-inhabiting fungal genus, gen. nov., is proposed on the basis of morphological characters and molecular evidence. The genus is characterized by an annual growth habit, effused-reflexed to pileate basidiocarps with pale yellowish brown to yellowish brown, concentrically zonate or sulcate, and velutinate pileal surface, a trimitic hyphal system with clamped generative hyphae, tissues turning to dark in KOH, oblong to broadly ellipsoid, hyaline, smooth, and slightly thick-walled basidiospores. Phylogenetic analysis based on ITS+nLSU sequences indicate that belongs to the core polyporoid clade. The combined ITS+nLSU+mtSSU+EF1-α+RPB2 sequences dataset of representative taxa in the Polyporaceae demonstrate that is grouped with but forms a monophyletic lineage. In addition, four new species of , , , , and are described.
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http://dx.doi.org/10.3897/mycokeys.57.38035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713667PMC
August 2019

Protein tyrosine phosphatase 11 acts through RhoA/ROCK to regulate eosinophil accumulation in the allergic airway.

FASEB J 2019 11 30;33(11):11706-11720. Epub 2019 Jul 30.

Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.

Src homology domain 2-containing protein tyrosine phosphatase 2 (SHP2) participates in multiple cell functions including cell shape, movement, and differentiation. Therefore, we investigated the potential role of SHP2 in eosinophil recruitment into lungs in allergic airway inflammation and explored the underlying mechanism. Both SHP2 and Ras homolog family member A (RhoA) kinase were robustly activated in the airway eosinophils of children with allergic asthma and of a mouse model with allergic airway inflammation. Moreover, inhibition of SHP2 activity by its specific inhibitors reverses the dephosphorylation of p190-A Rho GTPase-activating protein and in turn attenuates RhoA/Rho-associated protein kinase (ROCK) signaling, resulting in the attenuation of eosinophil migration in response to platelet-activating factor stimulation. Specifically, deletion in myeloid cells did not affect the number and classification of circulating leukocytes but significantly attenuated the allergen-induced inflammatory cell, especially eosinophil, infiltration into lungs, and airway hyperreactivity. Notably, genetic interaction between and indicated that RhoA inactivation and deletion synergistically attenuated the allergen-induced eosinophil infiltration into lungs and airway hyperreactivity, whereas overexpression of active RhoA robustly restored the deletion-resultant attenuation of allergen-induced eosinophil recruitment into lungs and airway hyperreactivity as well. Thus, this study demonstrates that SHP2 RhoA/ROCK signaling regulates eosinophil recruitment in allergic airway inflammation and possibly in allergic asthma.-Xu, C., Wu, X., Lu, M., Tang, L., Yao, H., Wang, J., Ji, X., Hussain, M., Wu, J., Wu, X. Protein tyrosine phosphatase 11 acts through RhoA/ROCK to regulate eosinophil accumulation in the allergic airway.
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http://dx.doi.org/10.1096/fj.201900698RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902720PMC
November 2019

[Diagnosis of two cases from one family with Joubert syndrome caused by novel mutations of TCTN1 gene by whole exome sequencing].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Jul;36(7):686-689

Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.

Objective: To explore the pathogenesis of two fetuses from one family affected with Joubert syndrome (JS).

Methods: Whole exome sequencing was employed to screen potential mutations in both fetuses. Suspected mutations were verified by Sanger sequencing. Impact of intronic mutations on DNA transcription was validated by cDNA analysis.

Results: Two novel TCTN1 mutations, c.342-8A>G and c.1494+1G>A, were identified in exons 2 and 12, respectively.cDNA analysis confirmed the pathogenic nature of both mutations with interference of normal splicing resulting in production of truncated proteins.

Conclusion: The genetic etiology of the family affected with JS has been identified.Above findings have enriched the mutation spectrum of TCTN1gene and facilitated understanding of the genotype-phenotype correlation of JS.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.07.007DOI Listing
July 2019

Prenatal diagnosis of methylmalonic aciduria from amniotic fluid using genetic and biochemical approaches.

Prenat Diagn 2019 10 5;39(11):993-997. Epub 2019 Aug 5.

Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Objectives: This study reported the clinical prenatal diagnosis experience of families affected by methylmalonic acidemia (MMA) evaluated at a single prenatal diagnosis center over 8 years, and the reliability of a biochemical approach for prenatal diagnosis was analyzed.

Methods: Prenatal diagnosis data for 187 MMA families referred to our center from 2009 to 2016 were reviewed retrospectively. The results of the genetic analysis and biochemical approach were compared.

Results: A total of 41 MMA-affected pregnancies (21%) were identified. The biochemical analysis could identify the true status of 99.5% of fetuses. The diagnostic sensitivities of the propionylcarnitine (C3) level, the C3 to acetylcarnitine (C2) ratio (C3/C2), the methylmalonic acid, and methylcitrate levels in the amniotic fluid were 95.1%, 100%, 100%, and 82.9%, respectively, and the specificities were 98.7%, 99.3%, 97.4%, and 96.7%, respectively.

Conclusions: The biochemical analysis could be optionally used in the prenatal diagnosis of MMA, especially in cases where the genetic results are inconclusive. Among the four tested biochemical markers, C3/C2 appeared to be the most reliable.
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http://dx.doi.org/10.1002/pd.5519DOI Listing
October 2019

Adsorption of fluoride from aqueous solution by fly ash cenospheres modified with paper mill lime mud: Experimental and modeling.

Ecotoxicol Environ Saf 2019 Sep 15;180:366-373. Epub 2019 May 15.

State Key Laboratory of Geohazard Prevention and Geoenvironment Protection, Chengdu University of Technology, Chengdu, 610059, PR China; State Environmental Protection Key Laboratory of Synergetic Control and Joint Remediation for Soil & Water Pollution, Chengdu University of Technology, Chengdu, 610059, PR China. Electronic address:

Fluoride removal from aqueous solution by adsorption using fly ash cenospheres (FAC) modified with paper mill lime mud (LM) as composite adsorbent had been investigated. The characterization of FAC and composite adsorbent were analyzed by Scanning electron spectroscope (SEM), Energy dispersive spectrometer (EDS), Brunauer emmett teller (BET) and Fourier transform infrared (FTIR), which demonstrated that the porous structure of composite adsorbent was obtained after surface modification. Adsorption of fluoride on modified fly ash cenospheres was fitted with pseudo-second-order model and Langmuir model. Response surface methodology (RSM) was employed to investigate the effects of F concentration, pH, adsorbent dosage and temperature on the removal efficiency. Analysis of variance (ANOVA) was used to test the adequacy of the mathematical models. The Nonelectrostatic model of modified fly ash cenospheres adsorbing fluoride was built through the Generalized composite method, indicating that two inner-spherical complexes, ≡SF and ≡SOHF, were formed in the adsorption process by means of the ligand exchange and surface complexation. Optimization of the adsorption conditions enabled the realization of the practical needs for fluoride contaminated water.
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http://dx.doi.org/10.1016/j.ecoenv.2019.04.086DOI Listing
September 2019

[Genotypic and phenotypic analysis of a patient with de novo partial monosomy 18p and partial trisomy 18q].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 May;36(5):484-487

Xinhua Hospital, Medical School of Shanghai Jiao Tong University, Shanghai Institute for Pediatric Research, Shanghai 200092, China. Email:

Objective: To explore the genetic cause for a patient with intellectual disability, short stature and multiple congenital anomalies, and to correlate the result with the clinical phenotype.

Methods: Routine karyotyping analysis was carried out on GTG-banded metaphase chromosomes. Single nucleotide polymorphism (SNP) microarray was used to detect microdeletions or microduplications in the patient. Fluorescence in situ hybridization (FISH) was used to ascertain the origin of aberrant chromosomes.

Results: The karyotype of the patient was 46,XY,der(18), while both of his parents had a normal karyotype. SNP array identified a 1.23 Mb deletion at 18p11.32-pter (chr18: 136 227-1 370 501, hg19) and a 33.76 Mb duplication at 18q21.1-qter (chr18: 44 250 359-78 013 728, hg19) in the patient. Above finding was confirmed by dual-color FISH with one color for 18p and another for 18q. The patient presented with some common features of 18p deletion and 18q duplication including intellectual disability and growth retardation, in addition with some features of 18p deletion including pectus excavatum, short stature and growth hormone (GH) deficiency. The patient showed progressive improvement of stature with GH therapy. Comparison of patients with previously reported dup(18q)+del(18p) recombinations suggested that, even for patients with similar breakpoints, their phenotypes have ranged from normal to severe and there were no consistent findings.

Conclusion: As aberrations involving double chromosomal segments often result in phenotypic variability, it has been difficult to correlate the genotype of our patient with his phenotype.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.05.017DOI Listing
May 2019

Identifying occult maternal malignancies from 1.93 million pregnant women undergoing noninvasive prenatal screening tests.

Genet Med 2019 10 12;21(10):2293-2302. Epub 2019 Apr 12.

BGI Genomics, BGI-Shenzhen, Shenzhen, Guangdong, China.

Purpose: Multiple chromosomal aneuploidies may be associated with maternal malignancies and can cause failure of noninvasive prenatal screening (NIPS) tests. However, multiple chromosomal aneuploidies show poor specificity and selectivity for diagnosing maternal malignancies.

Methods: This multicenter retrospective analysis evaluated 639 pregnant women who tested positive for multiple chromosomal aneuploidies on initial NIPS test between January 2016 and December 2017. Women were assessed using genome profiling of copy-number variations, which was translated to cancer risk using a novel bioinformatics algorithm called the cancer detection pipeline (CDP). Sensitivity, specificity, and positive predictive value (PPV) of diagnosing maternal malignancies were compared for multiple chromosomal aneuploidies, the CDP model, and the combination of CDP and plasma tumor markers.

Results: Of the 639 subjects, 41 maternal malignant cancer cases were diagnosed. Multiple chromosomal aneuploidies predicted maternal malignancies with a PPV of 7.6%. Application of the CDP algorithm to women with multiple chromosomal aneuploidies allowed 34 of the 41 (83%) cancer cases to be identified, while excluding 422 of 501 (84.2%) of the false positive cases. Combining the CDP with plasma tumor marker testing gave PPV of 75.0%.

Conclusion: The CDP algorithm can diagnose occult maternal malignancies with a reasonable PPV in multiple chromosomal aneuploidies-positive pregnant women in NIPS tests. This performance can be further improved by incorporating findings for plasma tumor markers.
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http://dx.doi.org/10.1038/s41436-019-0510-5DOI Listing
October 2019

Genomic analysis of Staphylococcus aureus along a pork production chain and in the community, Shandong Province, China.

Int J Antimicrob Agents 2019 Jul 6;54(1):8-15. Epub 2019 Apr 6.

Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Animal Health and Antimicrobial Strategies, National Veterinary Institute (SVA), Uppsala, Sweden.

Livestock-associated meticillin-resistant Staphylococcus aureus (LA-MRSA) is an increasingly important public health concern worldwide; however, data on LA-MRSA from Asian countries is scarce. As such, a comprehensive molecular epidemiological survey of S. aureus along a pork production chain and in the community was undertaken in Shandong Province, China. spa typing and whole-genome sequencing were used to survey the occurrence and potential transmission of S. aureus in various sectors, including 899 porcine samples (snout or skin swabs, carcass swabs and pork portions), 845 human nasal samples and 239 environmental samples from commercial farms, a slaughterhouse, a pork wholesale market and the surrounding community. MRSA was detected in higher frequencies in samples from two commercial pig farms (pigs, 49%; farm workers, 64%; environmental samples, 16%) than in samples from the slaughterhouse (fatteners, 8.2%; carcasses, 1.1%; operation workers, 0%; environmental samples, 3.8%), the pork wholesale market (pork, 14%; sellers, 0%) and individuals in the community (6.8%). There were significant differences in population structures, antimicrobial susceptibility profiles, and the presence of resistance and virulence genes between human- and pig-associated isolates. The phylogenetic analysis confirmed the dissemination of LA-MRSA between various segments along the pork production chain. However, MRSA of the same sequence type was not found to be disseminated between the commercial farms and the surrounding communities. Furthermore, one MRSA ST398 was observed, and a novel CC9 variant ST3597 was detected within the chain. The high MRSA carriage rates and the emergence of a new MRSA CC9 variant identified in this study highlight the need for MRSA surveillance.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.03.022DOI Listing
July 2019

Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia: What Have We Learnt From the Genetic Variants of Drug Transporters.

Curr Pharm Des 2019 ;25(6):627-634

Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.

Background: Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment.

Methods: We searched PubMed for citations published in English using the terms "methotrexate", "transporter", "acute lymphoblastic leukemia", "polymorphisms", and "therapeutic drug monitoring". The retrieval papers were critically reviewed and summarized according to the aims of this mini-review.

Results: Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied.

Conclusion: Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.
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http://dx.doi.org/10.2174/1381612825666190329141003DOI Listing
February 2020

Increased glycolysis mediates Wnt7b-induced bone formation.

FASEB J 2019 07 26;33(7):7810-7821. Epub 2019 Mar 26.

Department of Orthopedic Surgery, School of Medicine, Washington University, St. Louis, Missouri, USA.

Wingless/integrated (Wnt) signaling has emerged as a major mechanism for promoting bone formation and a target pathway for developing bone anabolic agents against osteoporosis. However, the downstream events mediating the potential therapeutic effect of Wnt proteins are not fully understood. Previous studies have indicated that increased glycolysis is associated with osteoblast differentiation in response to Wnt signaling, but direct genetic evidence for the importance of glucose metabolism in Wnt-induced bone formation is lacking. Here, we have generated compound transgenic mice to overexpress Wnt family member 7B (Wnt7b) transiently in the osteoblast lineage of postnatal mice, with or without concurrent deletion of the glucose transporter 1 (Glut1), also known as solute carrier family 2, facilitated glucose transporter member 1. Overexpression of Wnt7b in 1-mo-old mice for 1 wk markedly stimulated bone formation, but the effect was essentially abolished without Glut1, even though transient deletion of Glut1 itself did not affect normal bone accrual. Consistent with the results, Wnt7b increased Glut1 expression and glucose consumption in the primary culture of osteoblast lineage cells, and deletion of Glut1 diminished osteoblast differentiation . Thus, Wnt7b promotes bone formation in part through stimulating glucose metabolism in osteoblast lineage cells.-Chen, H., Ji, X., Lee, W.-C., Shi, Y., Li, B., Abel, E. D., Jiang, D., Huang, W., Long, F. Increased glycolysis mediates Wnt7b-induced bone formation.
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http://dx.doi.org/10.1096/fj.201900201RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593878PMC
July 2019

Copy number variation profile in noninvasive prenatal testing (NIPT) can identify co-existing maternal malignancies: Case reports and a literature review.

Taiwan J Obstet Gynecol 2018 Dec;57(6):871-877

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Objective: The coexistence of maternal malignancy and pregnancy has received increasing attention in Noninvasive prenatal testing (NIPT) studies. Malignancy in pregnant women potentially affects the copy number variation (CNV) profile in NIPT results. Only one case of hematologic cancer has been reported in a Hong-Kong pregnant women, and solid tumors have never been reported in pregnant Chinese women.

Case Report: The patients with dysgerminoma and cervical cancer showed aberrant chromosomal aneuploidies in NIPT and concordant patterns of genome disruption in tumor tissues. The genomic aberrations in the gastric cancer patient had similar copy number variation pattern of gastric cancer.

Conclusion: The findings in this study and the literature review further validate the effect of maternal malignancy on the copy number variation profile in NIPT data and strengthen the possibility of detecting malignant tumors with NIPT in the future.
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http://dx.doi.org/10.1016/j.tjog.2018.10.032DOI Listing
December 2018

Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance?

Drug Metab Rev 2018 08 16;50(3):369-397. Epub 2018 Sep 16.

a Department of Pharmacy , Children's Hospital of Nanjing Medical University , Nanjing , China.

There will be 642 million people worldwide by 2040 suffering from diabetes mellitus. Long-term multidrug therapy aims to achieve normal glycemia and minimize complications, and avoid severe hypoglycemic events. The appreciation of the drug-metabolizing enzymes and drug transporters as critical players in the treatment of diabetes has attracted much attention regarding their potential alterations in the pathogenesis of the disease. This review discusses pharmacokinetics-based alterations of cytochrome P450 enzymes, phase-II metabolizing enzymes, and membrane transporter proteins, as well as the potential mechanisms underlying these alterations. We also discuss the potential influences of altered enzymes and transporters on the disposition of commonly prescribed glucose-lowering medicines. Future studies should delve into the impact of altered drug-metabolizing enzymes and transporters on the progression toward abnormal glucose homeostasis.
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http://dx.doi.org/10.1080/03602532.2018.1497645DOI Listing
August 2018

Phylogeny and taxonomy of (Basidiomycota, Polyporales) with descriptions of two new species from western China.

MycoKeys 2018 31(37):57-71. Epub 2018 Jul 31.

Institute of Microbiology, Beijing Forestry University, Beijing 100083, China.

is a cosmopolitan genus of brown rot fungi. In this study, and are described as new species from western China, based on morphological and molecular evidence. has only been found on gymnosperms so far and is distinguished by pinkish-buff to clay-buff pileal surface and buff-yellow pore surface, azonate to faintly zonate pileus and ellipsoid to ovoid basidiospores (5-6.2 × 4.2-5.2 μm). is found on angiosperms and is characterised by pale-buff to clay-pink pileal surface, cream to light yellow pore surface, azonate to faintly zonate pileus, large pores (2-3 per mm) and small basidiospores (4.5-5 × 3-4.2 μm). The phylogeny of is reconstructed with multi-gene sequences including the internal transcribed spacer regions (ITS), the large subunit (nrLSU) and small subunit (nrSSU) of the nuclear ribosomal RNA gene, the small subunit of the mitochondrial rRNA gene (mtSSU), the translation elongation factor 1-α gene (EF-1α) and the second subunit of RNA polymerase II (RPB2). The results show that and formed two distinct lineages belonging to . Illustrated descriptions of the two new species are presented. An identification key to species of complex is provided.
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http://dx.doi.org/10.3897/mycokeys.37.26016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081469PMC
July 2018

Quantitative Analysis of Airway Tree in Low-dose Chest CT with a New Model-based Iterative Reconstruction Algorithm: Comparison to Adaptive Statistical Iterative Reconstruction in Routine-dose CT.

Acad Radiol 2018 12 13;25(12):1526-1532. Epub 2018 Jul 13.

Department of Radiology, The First Affiliated Hospital of Xi'an Jiaotong University, Yanta Western Road, Xi'an, Shannxi 710061, China. Electronic address:

Objective: We aimed to evaluate a new model-based iterative reconstruction (MBIRn) algorithm either with spatial resolution and noise reduction balance (MBIR) or spatial resolution preference (MBIR) for quantitative analysis of airway in low-dose chest computed tomography (CT) with a computer-aided detection (CAD) software, in comparison to adaptive statistical iterative reconstruction (ASIR) in routine-dose CT.

Methods: Thirty patients who underwent both the routine-dose (noise index [NI] = 14 HU) and low-dose (at 30% level with NI = 28 HU) CT examination for pulmonary disease were included. Image acquisition was performed with 120 kVp tube voltage and automatic tube current modulation. Routine-dose scans were reconstructed with ASIR, whereas low-dose scans were reconstructed with ASIR, MBIR, and MBIR. Airway dimensions of the right middle lobe bronchus from the four reconstructions were measured using CAD software. Two radiologists used a semiquantitative 5 scoring criteria (-2, inferior to; +2, superior to; -1 slightly inferior to; +1, slightly superior to; and 0, equal to ASIR in routine-dose CT) to rate the subjective image quality of MBIR and MBIR of airway trees. The paired t test and Wilcoxon signed-rank test were used for statistical comparison.

Results: The low-dose CT provided 70.76% dose reduction compared to the routine-dose CT (0.88 ± 0.83 mSv vs 3.01 ± 1.89 mSv). MBIR and MBIR with low-dose CT provided longer bronchial length measurements and were better in measurement variability and continuity and completeness of bronchial walls than ASIR in routine-dose CT (P < .05). MBIR was better for subjective noise and MBIR for showing distal branches CONCLUSIONS: MBIR and MBIR algorithms provide better airway quantification at 30% of the radiation dose, compared to ASIR at routine-dose CT.
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http://dx.doi.org/10.1016/j.acra.2018.03.021DOI Listing
December 2018

Chromosomal microarray analysis in developmental delay and intellectual disability with comorbid conditions.

BMC Med Genomics 2018 05 24;11(1):49. Epub 2018 May 24.

Department of Pediatric Endocrinology/Genetics, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, 1665 Kongjiang Road, Shanghai, 200092, China.

Background: Developmental delay (DD) and intellectual disability (ID) are frequently associated with a broad spectrum of additional phenotypes. Chromosomal microarray analysis (CMA) has been recommended as a first-tier test for DD/ID in general, whereas the diagnostic yield differs significantly among DD/ID patients with different comorbid conditions.

Methods: To investigate the genotype-phenotype correlation, we examined the characteristics of identified pathogenic copy number variations (pCNVs) and compared the diagnostic yields among patient subgroups with different co-occurring conditions.

Results: This study is a retrospective review of CMA results generated from a mixed cohort of 710 Chinese patients with DD/ID. A total of 247 pCNVs were identified in 201 patients (28%). A large portion of these pCNVs were copy number losses, and the size of copy number losses was generally smaller than gains. The diagnostic yields were significantly higher in subgroups with co-occurring congenital heart defects (55%), facial dysmorphism (39%), microcephaly (34%) or hypotonia (35%), whereas co-occurring conditions of skeletal malformation (26%), brain malformation (24%) or epilepsy (24%) did not alter the yield. In addition, the diagnostic yield nominally correlated with ID severity.

Conclusion: Varied yields exist in DD/ID patients with different phenotypic presentation. The presence of comorbid conditions can be among factors to consider when planning CMA.
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http://dx.doi.org/10.1186/s12920-018-0368-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968608PMC
May 2018