Publications by authors named "Zhihong Wu"

243 Publications

Proteomic changes of aqueous humor in proliferative diabetic retinopathy patients treated with different intravitreal anti-VEGF agents.

Exp Eye Res 2022 Jan 12:108942. Epub 2022 Jan 12.

Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China. Electronic address:

Anti-VEGF-based treatment have been regularly used in recent years in proliferative diabetic retinopathy (PDR) patients. However, some of these patients fail to respond effectively to anti-VEGF. Given that VEGF is not the sole factor influencing PDR pathogenesis and that different anti-VEGF pharmaceuticals are likely to differentially impact these underlying pathophysiological processes, we performed a prospective analysis of the protein profiles of the aqueous humor (AH) in PDR patients before and after treatment with three intravitreal anti-VEGF drugs (ranibizumab, aflibercept, and conbercept) to assess and compare the short-term impacts of these agents. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic methods were used to evaluate the AH protein profiles of PDR patients using paired pre- and 7 days post-anti-VEGF treatment samples (ranibizumab [IVR]: n = 10; conbercept [IVC]: n = 10; aflibercept [IVA]: n = 5). Gene ontology (GO) annotation, KEGG pathway analyses, and protein-protein interaction (PPI) networks were then used to explore the functional relevance of proteins that were differentially expressed between groups. Here, a total of 874 proteins from 25 patients (50 AH samples) were identified in the three patient groups. Different and common clusters of regulated proteins for each group were identified. We identified RARRES1, ALDH3A1, and RBP4 as being specifically regulated following treatment with all three tested anti-VEGF agents. We further found that VEGFR1, VEGFR2, APOM, hornerin, and HSP90B1 were differentially expressed in different anti-VEGF agent groups. In summary, we discovered that ALDH3A1 was a previously unreported protein that was related to angiogenesis and was differentially expressed in the three anti-VEGF treatment groups, suggesting that it may be a new target for PDR therapy. The described proteomic changes in the AH of PDR patients treated with different anti-VEGF agents provide novel targets which may explain the heterogeneity of anti-VEGF treatment responses in these patients, providing a robust foundation for future studies of PDR pathogenesis.
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http://dx.doi.org/10.1016/j.exer.2022.108942DOI Listing
January 2022

A genotype-first analysis in a cohort of Mullerian anomaly.

J Hum Genet 2022 Jan 13. Epub 2022 Jan 13.

Department of Obstetrics and Gynaecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.

Müllerian anomaly (M.A.) is a group of congenital anatomic abnormalities caused by aberrations of the development process of the Müllerian duct. M.A. can either be isolated or be involved in Mendelian syndromes, such as Dandy-Walker syndrome, Holt-Oram syndrome and Bardet-Biedl syndrome, which are often associated with both uterus and kidney malformations. In this study, we applied a genotype-first approach to analyze the whole-exome sequencing data of 492 patients with M.A. Six potential pathogenic variants were found in five genes previously related to female urogenital deformities (PKD1, SON, SALL1, BMPR1B, ITGA8), which are partially overlapping with our patients' phenotypes. We further identified eight incidental findings in seven genes related to Mendelian syndromes without known association with reproductive anomalies (TEK, COL11A1, ANKRD11, LEMD3, DLG5, SPTB, BMP2), which represent potential phenotype expansions of these genes.
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http://dx.doi.org/10.1038/s10038-021-00996-wDOI Listing
January 2022

Establishment of Human Pluripotent Stem Cell-Derived Skin Organoids Enabled Pathophysiological Model of SARS-CoV-2 Infection.

Adv Sci (Weinh) 2021 Dec 31:e2104192. Epub 2021 Dec 31.

Stem cell and Regenerative Medicine Lab, Department of Medical Science Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Translational Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.

Coronavirus disease 2019 (COVID-19) patients with impact on skin and hair loss are reported. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is detected in the skin of some patients; however, the detailed pathological features of skin tissues from patients infected with SARS-CoV-2 at a molecular level are limited. Especially, the ability of SARS-CoV-2 to infect skin cells and impact their function is not well understood. A proteome map of COVID-19 skin is established here and the susceptibility of human-induced pluripotent stem cell (hiPSC)-derived skin organoids with hair follicles and nervous system is investigated, to SARS-CoV-2 infection. It is shown that KRT17+ hair follicles can be infected by SARS-CoV-2 and are associated with the impaired development of hair follicles and epidermis. Different types of nervous system cells are also found to be infected, which can lead to neuron death. Findings from the present work provide evidence for the association between COVID-19 and hair loss. hiPSC-derived skin organoids are also presented as an experimental model which can be used to investigate the susceptibility of skin cells to SARS-CoV-2 infection and can help identify various pathological mechanisms and drug screening strategies.
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http://dx.doi.org/10.1002/advs.202104192DOI Listing
December 2021

Aberrant interaction between mutated ADAMTSL2 and LTBP4 is associated with adolescent idiopathic scoliosis.

Gene 2021 Dec 24;814:146126. Epub 2021 Dec 24.

Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address:

Adolescent idiopathic scoliosis (AIS) is a complex spinal deformity with a prevalence of 1%-3%. Genetic factors have been associated with the etiology of AIS. However, previous studies mainly focused on common single nucleotide polymorphisms which confer modest disease risk. Recently, rare variants in FBN1 and other extracellular matrix genes have been implicated in AIS, suggesting a potential overlapping disease etiology between AIS and hereditary connective tissue disorders (HCTD). In this study, we systematically analyzed rare variants in a set of HCTD-related genes in 302 AIS patients who underwent exome sequencing. We firstly focused on pathogenic variants based on a monogenic inheritance and identified nine disease-associated variants in FBN1, COL11A1, COL11A2 and TGFBR2. We then explored the potential interactions between variants in different genes based on the case-control statistics. We identified three ADAMTSL2-LTBP4 variant pairs in three AIS patients and none in controls. Furthermore, we revealed that the variant pairs identified in these genes could affect the interaction between ADAMTSL2 and LTBP4 and upregulate TGF-β signaling pathway in human fibroblasts. Our findings implicate that the aberrant interaction between mutated ADAMTSL2 and LTBP4 was associated with AIS.
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http://dx.doi.org/10.1016/j.gene.2021.146126DOI Listing
December 2021

National Rare Diseases Registry System (NRDRS): China's first nation-wide rare diseases demographic analyses.

Orphanet J Rare Dis 2021 Dec 18;16(1):515. Epub 2021 Dec 18.

The Administrative Group of National Rare Diseases Registry System of China, Beijing, 100730, China.

Background: China has made tremendous progresses in serving the needs of its people living with rare diseases in the past decade, especially over the last 5 years. The Chinese government's systematic approach included a series of coordinated initiatives, amongst these are: forming the Rare Disease Expert Committee (2016), funding the "Rare Diseases Cohort Study" (2016-2020), and publishing its first "Rare Disease Catalog" (2018). Herein, we present the National Rare Diseases Registry System (NRDRS)-China's first national rare diseases registry, and the analysis of cases registered in the first 5 years ending Dec 31, 2020.

Results: The total 62,590 cases covered 166 disease/disease types, forming 183 disease cohorts. The data from nearly 22% of them (13,947 cases) is also linked to valuable biological samples. The average age of definitive diagnosis was 30.88 years; 36.07% of cases were under 18 years of age. Regional distribution analysis showed 60% of cases were from the more developed, wealthier East and North China, suggesting the local availability of quality care and patients' financial status were key access factors. Finally, 82.04% of cases were registered from the five clinical departments: Neurology, Endocrine, Hematology, Cardiovascular, and Nephrology, suggesting that either these are most affected by rare diseases, or that there were disease non-specific ascertainment factors.

Conclusions: The preliminary analysis of the first 5-year's data provides unique and valuable insight on rare disease distribution in China, and higlights the directions for enhancing equity, scale and utility.
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http://dx.doi.org/10.1186/s13023-021-02130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684272PMC
December 2021

Serum metabolomics reveals dysregulation and diagnostic potential of oxylipins in tumor-induced osteomalacia.

J Clin Endocrinol Metab 2021 Dec 14. Epub 2021 Dec 14.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.

Context: Excessive production of fibroblast growth factor 23 (FGF23) by tumor was considered as the main pathogenesis in tumor-induced osteomalacia (TIO). Despite its importance to comprehensive understanding of pathogenesis and diagnosis, the regulation of systemic metabolism in TIO remains unclear.

Objectives: We aimed to systematically characterize the metabolome alteration associated with TIO.

Methods: By means of liquid chromatography-tandem mass spectrometry (LC-MS) based metabolomics, we analyzed the metabolic profile from 96 serum samples (32 initial diagnosis TIO patients, pairwise samples after tumor resection and 32 matched healthy control subjects). In order to screen and evaluate potential biomarkers, statistical analyses, pathway enrichment and receiver operating characteristic (ROC) were performed.

Results: Metabolomic profiling revealed distinct alterations between TIO and HC cohort. Differential metabolites were screened and conducted to functional clustering and annotation. Significantly enriched pathway was found involved in arachidonic acid metabolism. A combination of 5 oxylipins, 4-HDoHE, leukotriene B4, 5-HETE, 17-HETE and 9,10,13-TriHOME, demonstrated a high sensitivity and specificity panel for TIO prediction screened by random forest (RF) algorithm (AUC=0.951, 95% confidence interval, CI 0.827-1). Supported vector machine (SVM) model and partial least-squares (PLS) model were conducted to validate the predictive capabilities of the diagnostic panel.

Conclusions: Metabolite profiling of TIO altered significant compared with HC. A high sensitivity and specificity panel with 5 oxylipins were tested as diagnostic predictor. For the first time, we provide the global profile of metabolomes and identify potential diagnostic biomarkers of TIO. The present work may offer novel insights into the pathogenesis of TIO.
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http://dx.doi.org/10.1210/clinem/dgab885DOI Listing
December 2021

Time-Resolved Extracellular Matrix Atlas of the Developing Human Skin Dermis.

Front Cell Dev Biol 2021 26;9:783456. Epub 2021 Nov 26.

Stem Cell and Regenerative Medicine Lab, State Key Laboratory of Complex Severe and Rare Diseases, Department of Medical Science Research Center, Translational Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Skin aging is a physiological issue that is still relatively poorly understood. Studies have demonstrated that the dermal extracellular matrix (ECM) plays important roles in skin aging. However, the roles of the changes in ECM characteristics and the molecules that are secreted to the extracellular space and are involved in the formation of the dermal matrix from birth to old age remain unclear. To explore the way in which the ECM microenvironment supports the functions of skin development across different age groups is also poorly understood, we used a decellularization method and matrisome analysis to compare the composition, expression, and function of the dermal ECM in toddler, teenager, adult, and elderly skin. We found that the collagens, glycoproteins, proteoglycans, and regulatory factors that support skin development and interact with these core ECM proteins were differentially expressed at different ages. ECM expression markers occurring during the process of skin development were identified. In addition, our results elucidated the characteristics of ECM synthesis, response to skin development, and the features of the ECM that support epidermal stem cell growth the basement membrane during skin aging.
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http://dx.doi.org/10.3389/fcell.2021.783456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8661536PMC
November 2021

De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.

NPJ Genom Med 2021 Dec 7;6(1):104. Epub 2021 Dec 7.

Department of Orthopedic Surgery, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.
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http://dx.doi.org/10.1038/s41525-021-00268-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651650PMC
December 2021

The Mutational Landscape of in Congenital Scoliosis and Adolescent Idiopathic Scoliosis.

Genes (Basel) 2021 11 12;12(11). Epub 2021 Nov 12.

State Key Laboratory of Complex Severe and Rare Diseases, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.

Depletion of is associated with both congenital scoliosis (CS) and adolescent idiopathic scoliosis (AIS) in zebrafish models. However, only one human variant of has been reported previously in a patient with AIS. In this study, we systemically investigated the variant landscape of in 583 patients with CS and 302 patients with AIS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study. We identified a total of four rare variants in CS and four variants in AIS, including one protein truncating variant (c.464_465delAC) in a patient with CS. We then explored the effects of these variants on protein expression and sub-cellular location. We confirmed that the c.464_465delAC variant causes loss-of-function (LoF) of . In addition, the c.353C>T and c.2290G>A variants identified in two patients with AIS led to reduced protein expression of PTK7 as compared to that of the wild type. In conclusion, LoF and hypomorphic variants are associated with CS and AIS, respectively.
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http://dx.doi.org/10.3390/genes12111791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619039PMC
November 2021

LRP5-Mediated Lipid Uptake Modulates Osteogenic Differentiation of Bone Marrow Mesenchymal Stromal Cells.

Front Cell Dev Biol 2021 2;9:766815. Epub 2021 Nov 2.

Medical Science Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Nutritional microenvironment determines the specification of progenitor cells, and lipid availability was found to modulate osteogenesis in skeletal progenitors. Here, we investigated the implications of lipid scarcity in the osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs) and the role of low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor transducing canonical Wnt/beta-catenin signals, in BMSC lipid uptake during osteogenesis. The osteogenic differentiation of murine BMSCs was suppressed by lipid scarcity and partially rescued by additional fatty acid treatment with oleate. The enhancement of osteogenesis by oleate was found to be dosage-dependent, along with the enhanced activation of beta-catenin and Wnt target genes. Conditional knockout (CKO) of gene in murine mesenchymal lineage using mice led to decreased bone quality and altered fat distribution . After ablation using adenoviral Cre-recombinase, the accumulation of lipid droplets in BMSC cytoplasm was significantly reduced, and the osteogenesis of BMSCs was suppressed. Moreover, the impaired osteogenesis due to either lipid scarcity or ablation could be rescued by recombinant Wnt3a protein, indicating that the osteogenesis induced by Wnt/beta-catenin signaling was independent of LRP5-mediated lipid uptake. In conclusion, lipid scarcity suppresses BMSC osteogenic differentiation. LRP5 plays a role in the uptake of lipids in BMSCs and therefore mediates osteogenic specification.
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http://dx.doi.org/10.3389/fcell.2021.766815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593169PMC
November 2021

Disruptive Variants Implicated in Congenital Vertebral Malformations.

Genes (Basel) 2021 10 14;12(10). Epub 2021 Oct 14.

Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.

Genetic perturbations in nicotinamide adenine dinucleotide de novo (NAD) synthesis pathway predispose individuals to congenital birth defects. The encodes the final enzyme in the de novo NAD synthesis pathway and, therefore, plays an important role in NAD metabolism and organ embryogenesis. Biallelic mutations in the gene have been reported to be causative of congenital organ defects known as VCRL syndrome (Vertebral-Cardiac-Renal-Limb syndrome). Here, we analyzed the genetic variants in in an exome-sequenced cohort consisting of patients with congenital vertebral malformations (CVMs). A total number of eight variants in , including two truncating variants and six missense variants, were identified in nine unrelated patients. All enrolled patients presented multiple organ defects, with the involvement of either the heart, kidney, limbs, or liver, as well as intraspinal deformities. An in vitro assay using COS-7 cells demonstrated either significantly reduced protein levels or disrupted enzymatic activity of the identified variants. Our findings demonstrated that functional variants in were involved in the complex genetic etiology of CVMs and provided further evidence for the causative variants in congenital NAD Deficiency Disorder.
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http://dx.doi.org/10.3390/genes12101615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535205PMC
October 2021

Machine learning in orthodontics: Challenges and perspectives.

Adv Clin Exp Med 2021 Oct;30(10):1065-1074

College of Computer Science, Sichuan University, Chengdu, China.

Artificial intelligence (AI) applications have significantly improved our everyday quality of life. The last decade has witnessed the emergence of up-and-coming applications in the field of dentistry. It is hopeful that AI, especially machine learning (ML), due to its powerful capacity for image processing and decision support systems, will find extensive application in orthodontics in the future. We performed a comprehensive literature review of the latest studies on the application of ML in orthodontic procedures, including diagnosis, decision-making and treatment. Machine learning models have been found to perform similar to or with even higher accuracy than humans in landmark identification, skeletal classification, bone age prediction, and tooth segmentation. Meanwhile, compared to human experts, ML algorithms allow for high agreement and stability in orthodontic decision-making procedures and treatment effect evaluation. However, current research on ML raises important questions regarding its interpretability and dataset sample reliability. Therefore, more collaboration between orthodontic professionals and technicians is urged to achieve a positive symbiosis between AI and the clinic.
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http://dx.doi.org/10.17219/acem/138702DOI Listing
October 2021

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients.

Front Endocrinol (Lausanne) 2021 13;12:711991. Epub 2021 Sep 13.

Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Purpose: Congenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms a candidate gene-based mutational burden analysis.

Methods: We retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis.

Results: In 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD ( [c.2329T>A, c.7131C>G], [c.731G>A], [c.1102delC], [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that ( = 0.005), ( = 0.006), ( = 0.021) and ( = 0.040) represented top genes enriched in GHD patients.

Conclusion: Our study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.
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http://dx.doi.org/10.3389/fendo.2021.711991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475633PMC
September 2021

Novel Variants Are Associated with Congenital Scoliosis.

Genes (Basel) 2021 07 24;12(8). Epub 2021 Jul 24.

Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.

encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic variants have been associated with Kallmann syndrome and hypogonadotropic hypogonadism. In our congenital scoliosis (CS) patient series of 424 sporadic CS patients under the framework of the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, we identified four unrelated patients harboring variants, including one frameshift and three missense variants. These variants were predicted to be deleterious by in silico prediction and conservation analysis. Signaling activities and expression levels of the mutated protein were evaluated in vitro and compared to that of the wild type (WT) . As a result, the overall protein expressions of c.2334dupC, c.2339T>C and c.1261A>G were reduced to 43.9%, 63.4% and 77.4%, respectively. By the reporter gene assay, we observed significantly reduced activity for c.2334dupC, c.2339T>C and c.1261A>G, indicating the diminished FGFR1 signaling pathway. In conclusion, variants identified in our patients led to only mild disruption to protein function, caused milder skeletal and cardiac phenotypes than those reported previously.
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http://dx.doi.org/10.3390/genes12081126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393897PMC
July 2021

ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies.

Front Mol Biosci 2021 9;8:703110. Epub 2021 Aug 9.

Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

ADAMTS5 is involved in the pathogenesis of OA. As the major aggrecanase-degrading articular cartilage matrix, ADAMTS5, has been regarded as a potential target for OA treatment. We here provide an updated insight on the regulation of ADAMTS5 and newly discovered therapeutic strategies for OA. Pathophysiological and molecular mechanisms underlying articular inflammation and mechanotransduction, as well as chondrocyte hypertrophy were discussed, and the role of ADAMTS5 in each biological process was reviewed, respectively. Senescence, inheritance, inflammation, and mechanical stress are involved in the overactivation of ADAMTS5, contributing to the pathogenesis of OA. Multiple molecular signaling pathways were observed to modulate ADAMTS5 expression, namely, Runx2, Fgf2, Notch, Wnt, NF-κB, YAP/TAZ, and the other inflammatory signaling pathways. Based on the fundamental understanding of ADAMTS5 in OA pathogenesis, monoclonal antibodies and small molecule inhibitors against ADAMTS5 were developed and proved to be beneficial pre-clinically both and . Recent novel RNA therapies demonstrated potentials in OA animal models. To sum up, ADAMTS5 inhibition and its signaling pathway-based modulations showed great potential in future therapeutic strategies for OA.
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http://dx.doi.org/10.3389/fmolb.2021.703110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381022PMC
August 2021

Uncovering Potential lncRNAs and mRNAs in the Progression From Acute Myocardial Infarction to Myocardial Fibrosis to Heart Failure.

Front Cardiovasc Med 2021 16;8:664044. Epub 2021 Jul 16.

Department of Cardiovasology, Shijiazhuang People's Hospital, Shijiazhuang, China.

Morbidity and mortality of heart failure (HF) post-myocardial infarction (MI) remain elevated. The aim of this study was to find potential long non-coding RNAs (lncRNAs) and mRNAs in the progression from acute myocardial infarction (AMI) to myocardial fibrosis (MF) to HF. Firstly, blood samples from AMI, MF, and HF patients were used for RNA sequencing. Secondly, differentially expressed lncRNAs and mRNAs were obtained in MF vs. AMI and HF vs. MF, followed by functional analysis of shared differentially expressed mRNAs between two groups. Thirdly, interaction networks of lncRNA-nearby targeted mRNA and lncRNA-co-expressed mRNA were constructed in MF vs. AMI and HF vs. MF. Finally, expression validation and diagnostic capability analysis of selected lncRNAs and mRNAs were performed. Several lncRNA-co-expressed/nearby targeted mRNA pairs including AC005392.3/AC007278.2-IL18R1, AL356356.1/AL137145.2-PFKFB3, and MKNK1-AS1/LINC01127-IL1R2 were identified. Several signaling pathways including TNF and cytokine-cytokine receptor interaction, fructose and mannose metabolism and HIF-1, hematopoietic cell lineage and fluid shear stress, and atherosclerosis and estrogen were selected. IL1R2, IRAK3, LRG1, and PLAC4 had a potential diagnostic value for both AMI and HF. Identified AC005392.3/AC007278.2-IL18R1, AL356356.1/AL137145.2-PFKFB3, and MKNK1-AS1/LINC01127-IL1R2 lncRNA-co-expressed/nearby targeted mRNA pairs may play crucial roles in the development of AMI, MF, and HF.
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http://dx.doi.org/10.3389/fcvm.2021.664044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322527PMC
July 2021

Bone mesenchymal stem cells stimulation by magnetic nanoparticles and a static magnetic field: release of exosomal miR-1260a improves osteogenesis and angiogenesis.

J Nanobiotechnology 2021 Jul 13;19(1):209. Epub 2021 Jul 13.

Medical Science Research Center (MRC), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.

Background: The therapeutic potential of exosomes derived from stem cells has attracted increasing interest recently, because they can exert similar paracrine functions of stem cells and overcome the limitations of stem cells transplantation. Exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been confirmed to promote osteogenesis and angiogenesis. The magnetic nanoparticles (eg. FeO, γ-FeO) combined with a static magnetic field (SMF) has been commonly used to increase wound healing and bone regeneration. Hence, this study aims to evaluate whether exosomes derived from BMSCs preconditioned with a low dose of FeO nanoparticles with or without the SMF, exert superior pro-osteogenic and pro-angiogenic activities in bone regeneration and the underlying mechanisms involved.

Methods: Two novel types of exosomes derived from preconditioned BMSCs that fabricated by regulating the contents with the stimulation of magnetic nanoparticles and/or a SMF. Then, the new exosomes were isolated by ultracentrifugation and characterized. Afterwards, we conducted in vitro experiments in which we measured osteogenic differentiation, cell proliferation, cell migration, and tube formation, then established an in vivo critical-sized calvarial defect rat model. The miRNA expression profiles were compared among the exosomes to detect the potential mechanism of improving osteogenesis and angiogenesis. At last, the function of exosomal miRNA during bone regeneration was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro.

Results: 50 µg/mL FeO nanoparticles and a 100 mT SMF were chosen as the optimum magnetic conditions to fabricate two new exosomes, named BMSC-FeO-Exos and BMSC-FeO-SMF-Exos. They were both confirmed to enhance osteogenesis and angiogenesis in vitro and in vivo compared with BMSC-Exos, and BMSC-FeO-SMF-Exos had the most marked effect. The promotion effect was found to be related to the highly riched miR-1260a in BMSC-FeO-SMF-Exos. Furthermore, miR-1260a was verified to enhance osteogenesis and angiogenesis through inhibition of HDAC7 and COL4A2, respectively.

Conclusion: These results suggest that low doses of FeO nanoparticles combined with a SMF trigger exosomes to exert enhanced osteogenesis and angiogenesis and that targeting of HDAC7 and COL4A2 by exosomal miR-1260a plays a crucial role in this process. This work could provide a new protocol to promote bone regeneration for tissue engineering in the future.
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http://dx.doi.org/10.1186/s12951-021-00958-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278669PMC
July 2021

Expression Profiling and Functional Analysis of Circular RNAs in Inner Mongolian Cashmere Goat Hair Follicles.

Front Genet 2021 11;12:678825. Epub 2021 Jun 11.

College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China.

Background: Inner Mongolian cashmere goats have hair of excellent quality and high economic value, and the skin hair follicle traits of cashmere goats have a direct and important effect on cashmere yield and quality. Circular RNA has been studied in a variety of tissues and cells.

Result: In this study, high-throughput sequencing was used to obtain the expression profiles of circular RNA (circRNA) in the hair follicles of Inner Mongolian cashmere goats at different embryonic stages (45, 55, 65, and 75 days). A total of 21,784 circRNAs were identified. At the same time, the differentially expressed circRNA in the six comparison groups formed in the four stages were: d75vsd45, 59 upregulated and 33 downregulated DE circRNAs; d75vsd55, 61 upregulated and 102 downregulated DE circRNAs; d75vsd65, 32 upregulated and 33 downregulated DE circRNAs; d65vsd55, 67 upregulated and 169 downregulated DE circRNAs; d65vsd45, 96 upregulated and 63 downregulated DE circRNAs; and d55vsd45, 76 upregulated and 42 downregulated DE circRNAs. Six DE circRNA were randomly selected to verify the reliability of the sequencing results by quantitative RT-PCR. Subsequently, the circRNA corresponding host genes were analyzed by the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The results showed that the biological processes related to hair follicle growth and development enriched by GO mainly included hair follicle morphogenesis and cell development, and the signaling pathways related to hair follicle development included the Notch signaling pathway and NF-κB signaling pathway. We combined the DE circRNA of d75vsd45 with miRNA and mRNA databases (unpublished) to construct the regulatory network of circRNA-miRNA-mRNA, and formed a total of 102 pairs of circRNA-miRNA and 126 pairs of miRNA-mRNA interactions. The binding relationship of circRNA3236-chi-miR-27b-3p and circRNA3236-chi-miR-16b-3p was further verified by dual-luciferase reporter assays, and the results showed that circRNA3236 and chi-miR-27b-3p, and circRNA3236 and chi-miR-16b-3p have a targeted binding relationship.

Conclusion: To summarize, we established the expression profiling of circRNA in the fetal skin hair follicles of cashmere goats, and found that the host gene of circRNA may be involved in the development of hair follicles of cashmere goats. The regulatory network of circRNA-miRNA-mRNA was constructed and preliminarily verified using DE circRNAs.
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http://dx.doi.org/10.3389/fgene.2021.678825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226234PMC
June 2021

Deciphering the mutational signature of congenital limb malformations.

Mol Ther Nucleic Acids 2021 Jun 20;24:961-970. Epub 2021 Apr 20.

Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.

Congenital limb malformations (CLMs) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study was to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely pathogenic single-nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified and as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p = 0.012) or more than one limb affected (p = 0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes.
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http://dx.doi.org/10.1016/j.omtn.2021.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141661PMC
June 2021

Arbuscular mycorrhizal trees influence the latitudinal beta-diversity gradient of tree communities in forests worldwide.

Nat Commun 2021 05 25;12(1):3137. Epub 2021 May 25.

School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.

Arbuscular mycorrhizal (AM) and ectomycorrhizal (EcM) associations are critical for host-tree performance. However, how mycorrhizal associations correlate with the latitudinal tree beta-diversity remains untested. Using a global dataset of 45 forest plots representing 2,804,270 trees across 3840 species, we test how AM and EcM trees contribute to total beta-diversity and its components (turnover and nestedness) of all trees. We find AM rather than EcM trees predominantly contribute to decreasing total beta-diversity and turnover and increasing nestedness with increasing latitude, probably because wide distributions of EcM trees do not generate strong compositional differences among localities. Environmental variables, especially temperature and precipitation, are strongly correlated with beta-diversity patterns for both AM trees and all trees rather than EcM trees. Results support our hypotheses that latitudinal beta-diversity patterns and environmental effects on these patterns are highly dependent on mycorrhizal types. Our findings highlight the importance of AM-dominated forests for conserving global forest biodiversity.
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http://dx.doi.org/10.1038/s41467-021-23236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149669PMC
May 2021

Factors and predictive model associated with perioperative complications after long fusion in the treatment of adult non-degenerative scoliosis.

BMC Musculoskelet Disord 2021 May 25;22(1):483. Epub 2021 May 25.

Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.

Introduction: Adult non-degenerative scoliosis accounts for 90% of spinal deformities in young adults. However, perioperative complications and related risk factors of long posterior instrumentation and fusion for the treatment of adult non-degenerative scoliosis have not been adequately studied.

Methods: We evaluated clinical and radiographical results from 146 patients with adult non-degenerative scoliosis who underwent long posterior instrumentation and fusion. Preoperative clinical data, intraoperative variables, and perioperative radiographic parameters were collected to analyze the risk factors for perioperative complications. Potential and independent risk factors for perioperative complications were evaluated by univariate analysis and logistic regression analysis.

Results: One hundred forty-six adult non-degenerative scoliosis patients were included in our study. There were 23 perioperative complications for 21 (14.4%) patients, eight of which were cardiopulmonary complications, two of which were infection, six of which were neurological complications, three of which were gastrointestinal complications, and four of which were incision-related complication. The independent risk factors for development of total perioperative complications included change in Cobb angle (odds ratio [OR] = 1.085, 95% CI = 1.035 ~ 1.137, P = 0.001) and spinal osteotomy (OR = 3.565, 95% CI = 1.039 ~ 12.236, P = 0.043). The independent risk factor for minor perioperative complications is change in Cobb angle (OR = 1.092, 95% CI = 1.023 ~ 1.165, P = 0.008). The independent risk factors for major perioperative complications are spinal osteotomy (OR = 4.475, 95% CI = 1.960 ~ 20.861, P = 0.036) and change in Cobb angle (OR = 1.106, 95% CI = 1.035 ~ 1.182, P = 0.003).

Conclusions: Our study indicate that change in Cobb angle and spinal osteotomy are independent risk factors for total perioperative complications after long-segment posterior instrumentation and fusion in adult non-degenerative scoliosis patients. Change in Cobb angle is an independent risk factor for minor perioperative complications. Change in Cobb angle and spinal osteotomy are independent risk factors for major perioperative complications.
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http://dx.doi.org/10.1186/s12891-021-04361-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152117PMC
May 2021

Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature.

J Genet Genomics 2021 05 22;48(5):396-402. Epub 2021 Mar 22.

Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China. Electronic address:

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations. Although the diagnostic utility of clinical genetic testing in short stature has been implicated, the genetic architecture and the utility of genomic studies such as exome sequencing (ES) in a sizable cohort of patients with short stature have not been investigated systematically. In this study, we recruited 561 individuals with short stature from two centers in China during a 4-year period. We performed ES for all patients and available parents. All patients were retrospectively divided into two groups: an isolated short stature group (group I, n = 257) and an apparently syndromic short stature group (group II, n = 304). Causal variants were identified in 135 of 561 (24.1%) patients. In group I, 29 of 257 (11.3%) of the patients were solved by variants in 24 genes. In group II, 106 of 304 (34.9%) patients were solved by variants in 57 genes. Genes involved in fundamental cellular process played an important role in the genetic architecture of syndromic short stature. Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.
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http://dx.doi.org/10.1016/j.jgg.2021.02.008DOI Listing
May 2021

Heterozygous Recurrent Mutations Inducing Dysfunction of Gene in Patients With Short Stature.

Front Cell Dev Biol 2021 14;9:661747. Epub 2021 Apr 14.

Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Purpose: ROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of in children with short stature and to identify the underlying molecular mechanisms.

Methods: We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of . We subsequently examined the changes in protein expression and subcellular location in caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a-ROR2 pathway was also examined.

Results: We identified 12 mutations in in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments . The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2.

Conclusion: We expanded the mutational spectrum of in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in might affect the expression of downstream Wnt5a-ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.
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http://dx.doi.org/10.3389/fcell.2021.661747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080376PMC
April 2021

Assessment on the Impact on Human Health, Environment, Water and Soil by Disposing Household Expired Drugs: A Cross-Sectional Study in China.

Risk Manag Healthc Policy 2021 23;14:1711-1721. Epub 2021 Apr 23.

Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.

Background: The household expired drugs disposal has been a huge public issue in many countries, including China, which may affect various side and toxic effects on human health and environment, water resources, and soil too. This paper explores the knowledge, attitude, and practice of Guangzhou city residents regarding household expired drugs and their effect on human health and provided the scientific pieces of evidence to carry out the long-term recovery mechanism for expired medicines.

Methods: An observational, cross-sectional study was conducted using a self-structured questionnaire. Descriptive analysis, including univariate and unconditional logistic regression models, was carried out to analyze the data.

Results: A total of 613 community residents with a 99.4% response rate enrolled for the study. More than half 60.2% of residents stated that expired drugs pollute the environment, soil, and water resources, where 81.2% of respondents knew that it would produce side effects or toxic effects. However, still, 71.6% of respondents disposed of directly into the trash bin or sink, and, only 24.8% had good practice that they use a designed recycling bin. Likewise, only 8.3% of respondents placed expired drugs into collection points nearly 3-5 times in a year, while 65.1% of participants never disposed of in the collection point, which found a worse practice.

Conclusion: Overall, the knowledge, attitude, and practice of Guangzhou residents regarding household expired drugs disposal were not ideal. To improve the resident's awareness about family expired drugs disposal, ensure the financial support for the recycling process, establish an accessible and acceptable recycling point, and introduce relevant laws and regulations for the long-term mechanism.
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http://dx.doi.org/10.2147/RMHP.S301910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079354PMC
April 2021

Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism.

Front Cell Dev Biol 2021 19;9:641133. Epub 2021 Mar 19.

Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

encodes the colony-stimulating factor 1 receptor which regulates the proliferation, differentiation, and biological activity of monocyte/macrophage lineages. Pathogenic variants in could lead to autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia or autosomal recessive skeletal dysplasia. In this study, we identified three heterozygous deleterious rare variants in from a congenital vertebral malformation (CVM) cohort. All of the three variants are located within the carboxy-terminal region of CSF1R protein and could lead to an increased stability of the protein. Therefore, we established a zebrafish model overexpressing . The zebrafish model exhibits CVM phenotypes such as hemivertebral and vertebral fusion. Furthermore, overexpression of the mutated mRNA depleted of the carboxy-terminus led to a higher proportion of zebrafish with vertebral malformations than wild-type CSF1R mRNA did ( = 0.03452), implicating a gain-of-function effect of the C-terminal variant. In conclusion, variants affecting the C-terminal of CSF1R could cause CVM though a potential gain-of-function mechanism.
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http://dx.doi.org/10.3389/fcell.2021.641133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017210PMC
March 2021

Chi-miR-370-3p regulates hair follicle morphogenesis of Inner Mongolian cashmere goats.

G3 (Bethesda) 2021 05;11(5)

College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, Inner Mongolia, China.

MicroRNAs (miRNAs), a class of 22 nucleotide (nt) noncoding RNAs, negatively regulate mRNA posttranscriptional modification in various biological processes. Morphogenesis of skin hair follicles in cashmere goats is a dynamic process involving many key signaling molecules, but the associated cellular biological mechanisms induced by these key signaling molecules have not been reported. In this study, differential expression, bioinformatics, and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on miRNA expression profiles of Inner Mongolian cashmere goats at 45, 55, and 65 days during the fetal period, and chi-miR-370-3p was identified and investigated further. Real-time fluorescence quantification (qRT-PCR), dual luciferase reporting, and Western blotting results showed that transforming growth factor beta receptor 2 (TGF-βR2) and fibroblast growth factor receptor 2 (FGFR2) were the target genes of chi-miR-370-3p. Chi-miR-370-3p also regulated the expression of TGF-βR2 and FGFR2 at mRNA and protein levels in epithelial cells and dermal fibroblasts. DNA staining, Cell Counting Kit-8, and fluorescein-labelled Annexin V results showed that chi-miR-370-3p inhibited the proliferation of epithelial cells and fibroblasts but had no effect on apoptosis. Cell scratch test results showed that chi-miR-370-3p promoted the migration of epithelial cells and fibroblasts. Chi-miR-370-3p inhibits the proliferation of epithelial cells and fibroblasts by targeting TGF-βR2 and FGFR2, thereby improving cell migration ability and ultimately regulating the fate of epithelial cells and dermal fibroblasts to develop the placode and dermal condensate, inducing hair follicle morphogenesis.
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http://dx.doi.org/10.1093/g3journal/jkab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104936PMC
May 2021

Whole-genome methylation analysis reveals novel epigenetic perturbations of congenital scoliosis.

Mol Ther Nucleic Acids 2021 Mar 10;23:1281-1287. Epub 2021 Feb 10.

Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.

Congenital scoliosis (CS) is a congenital disease caused by malformations of vertebrae. Recent studies demonstrated that DNA modification could contribute to the pathogenesis of disease. This study aims to identify epigenetic perturbations that may contribute to the pathogenesis of CS. Four CS patients with hemivertebra were enrolled and underwent spine correction operations. DNA was extracted from the hemivertebrae and spinal process collected from the specimen during the hemivertebra resection. Genome-wide DNA methylation profiling was examined at base-pair resolution using whole-genome bisulfite sequencing (WGBS). We identified 343 genes with hyper-differentially methylated regions (DMRs) and 222 genes with hypo-DMRs, respectively. These genes were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, calcium signaling pathway, and axon guidance in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and were enriched in positive regulation of cell morphogenesis involved in differentiation, regulation of cell morphogenesis involved in differentiation, and regulation of neuron projection development in Biological Process of Gene Ontology (GO-BP) terms. Hyper-DMR-related genes, including , , , , and and hypo DMR-related genes, including , , , , and , may contribute to the pathogenesis of hemivertebra. The aberrant DNA methylation may be associated with the formation of hemivertebra and congenital scoliosis.
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http://dx.doi.org/10.1016/j.omtn.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907230PMC
March 2021

The "Matrisome" reveals the characterization of skin keloid microenvironment.

FASEB J 2021 04;35(4):e21237

Stem Cell and Regenerative Medicine Lab, Department of Medical Science Research Center, Translational Medicine Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Keloids are fibroproliferative dermal tumors of unknown origin that are characterized by the overabundant accumulation of extracellular matrix (ECM) components. The mechanism of keloid formation has remained unclear because of a poor understanding of its molecular basis. In this study, the dermal ECM components of keloids were identified and the pathological features of keloid formation were characterized using large-scale quantitative proteomic analyses of decellularized keloid biomatrix scaffolds. We identified a total of 267 dermal core ECM and ECM-associated proteins that were differentially expressed between patients with keloids and healthy controls. Skin mechanical properties and biological processes including protease activity, wound healing, and adhesion were disordered in keloids. The integrated network analysis of the upregulated ECM proteins revealed multiple signaling pathways involved in these processes that may lead to keloid formation. Our findings may improve the scientific basis of keloid treatment and provide new ideas for the establishment of keloid models.
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http://dx.doi.org/10.1096/fj.202001660RRDOI Listing
April 2021

Transplantation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Improves Cartilage Repair in a Rabbit Model.

Biomed Res Int 2021 25;2021:6380141. Epub 2021 Feb 25.

Medical Research Center, Chinese Academy of Medical College & Peking Union Medical College Hospital, Beijing, China.

The aim of this study was to investigate the therapeutic efficacy and safety of transplanting human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in the treatment of cartilage injury. First, the articular cartilage defect model in rabbits was constructed. Then, the identified hUCB-MSCs and rabbit bone marrow stem cells (rBM-MSCs) were transplanted into the bone defect, respectively, and the cartilage repair effect was observed by hematoxylin-eosin (HE) staining and immunohistochemistry. Besides, the glycosaminoglycan (GAG) content and biomechanics of the restoration area were also evaluated. In our study, hUCB-MSCs and rBM-MSCs exhibited typical MSC characteristics, with positive expressions of CD73, CD105, and CD90 and negative for CD45, CD34, CD14, and HLA-DR. After the transplantation of hUCB-MSCs and rBM-MSCs, the overall quality of cartilage tissue was significantly improved, and the recipients did not show significant side effects in general. However, the expression of matrix metalloproteinase-13 (MMP-13) in the de novo tissues of the hUCB-MSCs and rBM-MSCs groups was both increased, indicating that the novel tissues may have some potential osteoarthritic changes. In conclusion, our results suggest the therapeutic effect of hUCB-MSCs transplantation in cartilage regeneration, providing a promising future in the clinical treatment of cartilage injury.
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http://dx.doi.org/10.1155/2021/6380141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932770PMC
May 2021

Comparative proteomics analysis for identifying the lipid metabolism related pathways in patients with Klippel-Feil syndrome.

Ann Transl Med 2021 Feb;9(3):255

Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Background: Klippel-Feil syndrome (KFS) represents the rare and complex deformity characterized by congenital defects in the formation or segmentation of the cervical vertebrae. There is a wide gap in understanding the detailed mechanisms of KFS because of its rarity, heterogeneity, small pedigrees, and the broad spectrum of anomalies.

Methods: We recruited eight patients of Chinese Han ethnicity with KFS, five patients with congenital scoliosis (CS) who presented with congenital fusion of the thoracic or lumbar spine and without known syndrome or cervical deformity, and seven healthy controls. Proteomic analysis by data-independent acquisition (DIA) was performed to identify the differential proteome among the three matched groups and the data were analyzed by bioinformatics tools including Gene Ontology (GO) categories and Ingenuity Pathway Analysis (IPA) database, to explore differentially abundant proteins (DAPs) and canonical pathways involved in the pathogenesis of KFS.

Results: A total of 49 DAPs were detected between KFS patients and the controls, and moreover, 192 DAPs were identified between patients with KFS and patients with CS. Fifteen DAPs that were common in both comparisons were considered as candidate biomarkers for KFS, including membrane primary amine oxidase, noelin, galectin-3-binding protein, cadherin-5, glyceraldehyde-3-phosphate dehydrogenase, peroxiredoxin-1, CD109 antigen, and eight immunoglobulins. Furthermore, the same significant canonical pathways of LXR/RXR activation and FXR/RXR activation were observed in both comparisons. Seven of DAPs were apolipoproteins related to these pathways that are involved in lipid metabolism.

Conclusions: This study provides the first proteomic profile for understanding the pathogenesis and identifying predictive biomarkers of KFS. We detected 15 DAPs that were common in both comparisons as candidate predictive biomarkers of KFS. The lipid metabolism-related canonical pathways of LXR/RXR and FXR/RXR activation together with seven differentially abundant apolipoproteins may play significant roles in the etiology of KFS and provide possible pathogenesis correlation between KFS and CS.
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http://dx.doi.org/10.21037/atm-20-5155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940892PMC
February 2021
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