Publications by authors named "Fei Zou"

327 Publications

Permutation-based identification of important biomarkers for complex diseases via machine learning models.

Nat Commun 2021 05 21;12(1):3008. Epub 2021 May 21.

Department of Biostatistics and Department of Medicine, Columbia University, New York, NY, USA.

Study of human disease remains challenging due to convoluted disease etiologies and complex molecular mechanisms at genetic, genomic, and proteomic levels. Many machine learning-based methods have been developed and widely used to alleviate some analytic challenges in complex human disease studies. While enjoying the modeling flexibility and robustness, these model frameworks suffer from non-transparency and difficulty in interpreting each individual feature due to their sophisticated algorithms. However, identifying important biomarkers is a critical pursuit towards assisting researchers to establish novel hypotheses regarding prevention, diagnosis and treatment of complex human diseases. Herein, we propose a Permutation-based Feature Importance Test (PermFIT) for estimating and testing the feature importance, and for assisting interpretation of individual feature in complex frameworks, including deep neural networks, random forests, and support vector machines. PermFIT (available at https://github.com/SkadiEye/deepTL ) is implemented in a computationally efficient manner, without model refitting. We conduct extensive numerical studies under various scenarios, and show that PermFIT not only yields valid statistical inference, but also improves the prediction accuracy of machine learning models. With the application to the Cancer Genome Atlas kidney tumor data and the HITChip atlas data, PermFIT demonstrates its practical usage in identifying important biomarkers and boosting model prediction performance.
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http://dx.doi.org/10.1038/s41467-021-22756-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140109PMC
May 2021

Neurotrophic Factor Levels in the Serum and Cerebrospinal Fluid of Neonates Infected with Human Cytomegalovirus.

Microbiol Immunol 2021 May 21. Epub 2021 May 21.

Department of BioBank, Sheng Jing Hospital of China Medical University, Shenyang, P.R. China.

Human cytomegalovirus (HCMV) is most likely to damage the central nervous system (CNS) during early embryonic development; however, the early neurodevelopmental abnormalities caused by HCMV infection and the regulation of cytokines remain unclear. Therefore, we investigated neuronal factors in the serum and cerebrospinal fluid (CSF) of newborns infected with HCMV using protein microarray technology with a view to elucidating the changes in specific neuronal factors for use in the development of a reliable index for predicting CNS injury caused by HCMV infection. Serum and CSF were collected from four newborns with HCMV infection and CNS injury (HCMV-infected group) and from four newborns without CNS infection (control group). A protein microarray containing 29 kinds of CNS-related cytokines was used to identify differentially expressed neuronal factors in the serum and CSF of the HCMV-infected and control groups. The levels of the differentially expressed proteins were verified further in 30 CSF samples from an HCMV-infected group using ELISA. Between newborns in the HCMV-infected and control groups, the protein microarray analysis identified three differentially expressed neurotrophic factors in the CSF samples: Acrp30, MMP3, and IL-1α. No differential cytokine expression was seen in the serum. ELISA showed significantly higher expression levels of Acrp30 and MMP3 in the CSF of the 30 newborns with HCMV infection and CNS injury than those in the control group, whereas the expression of IL-1α was significantly lower. Our results demonstrate that changes in the expression levels of Acrp30, MMP3, and IL-1α in the CSF of newborns infected with HCMV may be related to the pathogenesis of CNS infection. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/1348-0421.12918DOI Listing
May 2021

Carbohydrate sulfotransferase 3 (CHST3) overexpression promotes cartilage endplate-derived stem cells (CESCs) to regulate molecular mechanisms related to repair of intervertebral disc degeneration by rat nucleus pulposus.

J Cell Mol Med 2021 May 16. Epub 2021 May 16.

Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China.

To investigate the regulatory effect of carbohydrate sulfotransferase 3 (CHST3) in cartilage endplate-derived stem cells (CESCs) on the molecular mechanism of intervertebral disc degeneration after nucleus pulposus repair in rats. We performed GO and KEGG analysis of GSE15227 database to select the differential genes CHST3 and CSPG4 in grade Ⅱ, Ⅲ and Ⅳ intervertebral disc degeneration, IHC and WB to detect the protein profile of CHST3 and CSPG4, Co-IP for the interaction between CHST3 and CSPG4. Then, immunofluorescence was applied to measure the level of CD90 and CD105, and flow cytometry indicated the level of CD73, CD90 and CD105 in CESCs. Next, Alizarin red staining, Alcian blue staining and TEM were performed to evaluate the effects of CESCs into osteoblasts and chondroblasts, respectively, CCK8 for the cell proliferation of osteoblasts and chondroblasts after induction for different times; cell cycle of osteoblasts or chondroblasts was measured by flow cytometry after induction, and WB for the measurement of specific biomarkers of OC and RUNX in osteoblasts and aggrecan, collagen II in chondroblasts. Finally, colony formation was applied to measure the cell proliferation of CESCs transfected with ov-CHST3 or sh-CHST3 when cocultured with bone marrow cells, WB for the protein expression of CHST3, CSPG4 and ELAVL1 in CSECs, transwell assay for the migration of CESCs to bone marrow cells, TEM image for the cellular characteristics of bone marrow cells, and WB for the protein profile of VCAN, VASP, NCAN and OFD1 in bone marrow cells. CHST3 and CSPG4 were differentially expressed and interacted in grade Ⅱ, Ⅲ and Ⅳ intervertebral disc degeneration; CD73, CD90 and CD105 were lowly expressed in CESCs, osteogenic or chondroblastic induction changed the characteristics, proliferation, cell cycle and specific biomarkers of osteoblasts and chondroblasts after 14 or 21 days,; CHST3 affected the cell proliferation, protein profile, migration and cellular features of cocultured CESCs or bone marrow cells. CHST3 overexpression promoted CESCs to regulate bone marrow cells through interaction with CSPG4 to repair the grade Ⅱ, Ⅲ and Ⅳ intervertebral disc degeneration.
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http://dx.doi.org/10.1111/jcmm.16440DOI Listing
May 2021

NLRP3 induces the autocrine secretion of IL-1β to promote epithelial-mesenchymal transition and metastasis in breast cancer.

Biochem Biophys Res Commun 2021 Jun 8;560:72-79. Epub 2021 May 8.

Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China. Electronic address:

Tumor metastasis is a leading cause of mortality in patients with breast cancer (BC). As a predominant component of inflammasome, Nod-like receptor protein 3 (NLRP3) was found to be required for tumor progression, while the role of NLRP3 in BC metastasis remains largely undefined. In current study, we found that invasive BC had aberrant upregulation of NLRP3 expression, especially in the claudin-low subtype. And higher expression of NLRP3 predicted poor survival of BC patients. Further investigation suggested that NLRP3 promotes the migration and invasion, as well as the metastasis of BC cells. Moreover, we revealed that NLRP3 induces the autocrine secretion of IL-1β to promote epithelial-mesenchymal transition via a Caspase-1-dependent manner. Hence, this study suggested that upregulation of NLRP3 in BC induces the autocrine secretion of IL-1β and promotes EMT and metastasis of BC cells.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.122DOI Listing
June 2021

The Short-Term to Midterm Follow-Up of Patients with Hirayama Disease After Anterior Cervical Discectomy and Fusion.

World Neurosurg 2021 Jun 31;150:e705-e713. Epub 2021 Mar 31.

Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China. Electronic address:

Objective: Surgical treatment is widely used to treat patients with Hirayama disease (HD). However, postoperative follow-up with abundant samples is still scarce. This study investigated short-term to midterm clinical outcomes after anterior cervical discectomy and fusion (ACDF) among patients with HD.

Methods: We enrolled 115 patients with HD who had undergone ACDF. Radiographic parameters included cervical lordosis (CL), sagittal vertical axis, segment lordosis (SL), T1 slope (T1S), T1S minus CL, range of motion (ROM), upper/lower adjacent segment ROM, and upper adjacent SL. Electrophysiologic parameters included the maximal compound muscle action potentials (CMAPs) of abductor digit minimi and abductor pollicis brevis, the latency of the ulnar nerve F reaction, and abnormal spontaneous action potentials. Clinical assessment included the selected brief-Michigan Hand Questionnaire and Odom scale.

Results: The average age was 19.5 ± 4.5 years. The mean follow-up time was 16.35 ± 9.21 months. CL, SL, and T1S increased, whereas sagittal vertical axis and ROM decreased at the final follow-up (P < 0.001). Upper adjacent SL, upper adjacent ROM, and lower adjacent ROM were stable after ACDF (P > 0.05). The maximal CMAPs of abductor digit minimi and the latency of the ulnar nerve F reaction improved bilaterally (P < 0.05), whereas there was no significance in the maximal CMAPs of abductor pollicis brevis (P > 0.05). Abnormal spontaneous action potentials reduced remarkably. The selected brief-Michigan Hand Questionnaire score increased after surgery (P < 0.001). The Odom scale showed a ratio of 79.1% (excellent and good ratio).

Conclusions: This study showed favorable radiologic, electrophysiologic, and clinical outcomes after ACDF among patients with HD.
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http://dx.doi.org/10.1016/j.wneu.2021.03.094DOI Listing
June 2021

On polygenic risk scores for complex traits prediction.

Biometrics 2021 Mar 31. Epub 2021 Mar 31.

Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.

Polygenic risk scores (PRS) have gained substantial attention for complex traits prediction in genome-wide association studies (GWAS). Motivated by the polygenic model of complex traits, we study the statistical properties of PRS under the high-dimensional but sparsity free setting where the triplet with being the sample size, the number of assayed single-nucleotide polymorphisms (SNPs), and the number of assayed causal SNPs, respectively. First, we derive asymptotic results on the out-of-sample (prediction) R-squared for PRS. These results help understand the widespread observed gap between the in-sample heritability (or partial R-squared due to the genetic features) estimate and the out-of-sample R-squared for most complex traits. Next, we investigate how features should be selected (e.g., by a p-value threshold) for constructing optimal PRS. We reveal that the optimal threshold depends largely on the genetic architecture underlying the complex trait and the sample size of the training GWAS, or the ratio. For highly polygenic traits with a large ratio, it is difficult to separate causal and null SNPs and stringent feature selection in principle often leads to poor PRS prediction. We numerically illustrate the theoretical results with intensive simulation studies and real data analysis on 33 complex traits with a wide range of genetic architectures in the UK Biobank database.
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http://dx.doi.org/10.1111/biom.13466DOI Listing
March 2021

Weakened Effective Connectivity Related to Electroacupuncture in Stroke Patients with Prolonged Flaccid Paralysis: An EEG Pilot Study.

Neural Plast 2021 9;2021:6641506. Epub 2021 Mar 9.

Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China.

Flaccid paralysis in the upper extremity is a severe motor impairment after stroke, which exists for weeks, months, or even years. Electroacupuncture treatment is one of the most widely used TCM therapeutic interventions for poststroke flaccid paralysis. However, the response to electroacupuncture in different durations of flaccid stage poststroke as well as in the topological configuration of the cortical network remains unclear. The objectives of this study are to explore the disruption of the cortical network in patients in different durations of flaccid stage and observe dynamic network reorganization during and after electroacupuncture. Resting-state networks were constructed from 18 subjects with flaccid upper extremity by partial directed coherence (PDC) analysis of multichannel EEG. They were allocated to three groups according to time after flaccid paralysis: the short-duration group (those with flaccidity for less than two months), the medium-duration group (those with flaccidity between two months and six months), and the long-duration group (those with flaccidity over six months). Compared with short-duration flaccid subjects, weakened effective connectivity was presented in medium-duration and long-duration groups before electroacupuncture. The long-duration group has no response in the cortical network during electroacupuncture. The global network measures of EEG data (sPDC, mPDC, and ) indicated that there was no significant difference among the three groups. These results suggested that the network connectivity reduced and weakly responded to electroacupuncture in patients with flaccid paralysis for over six months. These findings may help us to modulate the formulation of electroacupuncture treatment according to different durations of the flaccid upper extremity.
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http://dx.doi.org/10.1155/2021/6641506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969113PMC
March 2021

Testcrosses are an efficient strategy for identifying cis-regulatory variation: Bayesian analysis of allele-specific expression (BayesASE).

G3 (Bethesda) 2021 May;11(5)

Genetics Institute, University of Florida, Gainesville, FL 32608, USA.

Allelic imbalance (AI) occurs when alleles in a diploid individual are differentially expressed and indicates cis acting regulatory variation. What is the distribution of allelic effects in a natural population? Are all alleles the same? Are all alleles distinct? The approach described applies to any technology generating allele-specific sequence counts, for example for chromatin accessibility and can be applied generally including to comparisons between tissues or environments for the same genotype. Tests of allelic effect are generally performed by crossing individuals and comparing expression between alleles directly in the F1. However, a crossing scheme that compares alleles pairwise is a prohibitive cost for more than a handful of alleles as the number of crosses is at least (n2-n)/2 where n is the number of alleles. We show here that a testcross design followed by a hypothesis test of AI between testcrosses can be used to infer differences between nontester alleles, allowing n alleles to be compared with n crosses. Using a mouse data set where both testcrosses and direct comparisons have been performed, we show that the predicted differences between nontester alleles are validated at levels of over 90% when a parent-of-origin effect is present and of 60%-80% overall. Power considerations for a testcross, are similar to those in a reciprocal cross. In all applications, the testing for AI involves several complex bioinformatics steps. BayesASE is a complete bioinformatics pipeline that incorporates state-of-the-art error reduction techniques and a flexible Bayesian approach to estimating AI and formally comparing levels of AI between conditions. The modular structure of BayesASE has been packaged in Galaxy, made available in Nextflow and as a collection of scripts for the SLURM workload manager on github (https://github.com/McIntyre-Lab/BayesASE).
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http://dx.doi.org/10.1093/g3journal/jkab096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104932PMC
May 2021

Dynamic contrast-enhanced MRI of nasopharyngeal carcinoma: correlation of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters with hypoxia-inducible factor 1α expression and tumor grade/stage.

Ann Palliat Med 2021 Feb;10(2):2238-2253

Affiliated Cancer Hospital of Nanchang University, Nanchang, China; Department of Radiology, Jiangxi Provincial Cancer Hospital, Nanchang, China.

Background: Abnormal microangiogenesis and microenvironmental disturbances within the Nasopharyngeal carcinoma (NPC) can exacerbate tumor hypoxia, which may increase radiotherapy resistance and thus lead to poor prognosis in NPC patients. A non-invasive imaging technique, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which can reflect the tumor blood perfusion and angiogenesis status, was used to investigate the relationships of DCE-MRI parameters with hypoxia-inducible factor 1 alpha (HIF-1α) expression and tumor grades in NPC patients.

Methods: 42 treatment-naive patients with pathologically confirmed NPC were enrolled in this analysis. Plain magnetic resonance scans and DCE-MRI scans were performed before treatment, and post-processing was performed to calculate the relative enhancement (RE), maximum relative enhancement (MRE), maximum enhancement (ME), wash-in rate (WIR), wash-out rate (WOR), time to peak (TTP), and area under the curve (AUC). Immunohistochemistry was used to detect HIF-1α expression in electronasopharyngeal fiberoscopic specimens. The clinical grade/stage of NPC was jointly assessed by an experienced radiologist and a radiotherapist. The potential correlations of the DCE-MRI parameters with HIF-1α expression and clinical grades were analyzed. The statistical analysis was performed using SPSS 17.0 software package.

Results: Among DCE-MRI parameters, RE, ME, and MRE were associated with the positive expression of HIF-lα in NPC and could reflect the hypoxic status in the local microenvironment of the cancer foci in vivo. RE, ME, and MRE were significantly higher in the positive HIF-1α expression group than in the negative HIF-1α expression group (F=5.281, P=0.027; F=11.923, P=0.001; F=6.228, P=0.017). RE, ME, and MRE were significantly correlated with clinical grade (F=3.646, P=0.021; F=3.204, P=0.034, F=3.050, P=0.040) and T stage (F=6.578, P=0.001; F=3.540, P=0.023; F=4.384, P=0.010). The values of RE, MRE, and ME gradually increased as the clinical grade and T stage increased.

Conclusions: DCE-MRI is a valuable imaging technique for the noninvasive evaluation of hypoxia in NPC, the development of individualized treatment protocols, and the prediction of efficacy.
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http://dx.doi.org/10.21037/apm-21-303DOI Listing
February 2021

On kernel machine learning for propensity score estimation under complex confounding structures.

Pharm Stat 2021 Feb 22. Epub 2021 Feb 22.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Post marketing data offer rich information and cost-effective resources for physicians and policy-makers to address some critical scientific questions in clinical practice. However, the complex confounding structures (e.g., nonlinear and nonadditive interactions) embedded in these observational data often pose major analytical challenges for proper analysis to draw valid conclusions. Furthermore, often made available as electronic health records (EHRs), these data are usually massive with hundreds of thousands observational records, which introduce additional computational challenges. In this paper, for comparative effectiveness analysis, we propose a statistically robust yet computationally efficient propensity score (PS) approach to adjust for the complex confounding structures. Specifically, we propose a kernel-based machine learning method for flexibly and robustly PS modeling to obtain valid PS estimation from observational data with complex confounding structures. The estimated propensity score is then used in the second stage analysis to obtain the consistent average treatment effect estimate. An empirical variance estimator based on the bootstrap is adopted. A split-and-merge algorithm is further developed to reduce the computational workload of the proposed method for big data, and to obtain a valid variance estimator of the average treatment effect estimate as a by-product. As shown by extensive numerical studies and an application to postoperative pain EHR data comparative effectiveness analysis, the proposed approach consistently outperforms other competing methods, demonstrating its practical utility.
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http://dx.doi.org/10.1002/pst.2105DOI Listing
February 2021

The Impact of Electroacupuncture at Hegu, Shousanli, and Quchi Based on the Theory "Treating Flaccid Paralysis by Yangming Alone" on Stroke Patients' EEG: A Pilot Study.

Evid Based Complement Alternat Med 2020 24;2020:8839491. Epub 2020 Nov 24.

Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China.

Background: In China, electroacupuncture based on meridians theory "treating flaccid paralysis by alone" has been widely used for stroke rehabilitation in clinical practice. The aim of this study was to explore the electroencephalography change of electroacupuncture intervention on strokes patients with flaccid paralysis.

Methods: Twenty-three stroke patients with flaccid paralysis and six stroke patients with spasticity accepted electroacupuncture with the acupoints Hegu [LI4], Shousanli [LI10], and Quchi [LI11] for 20 minutes and their EEG data were recorded before, during, and after the electroacupuncture intervention.

Results: Compared with the baseline EEG signals before electroacupuncture, the ipsilesional and contralesional beta-band average power of patients with flaccid paralysis and spasticity were significantly increased during the needles retention stage and decreased slightly after removing the needles. The significant decrease of the ipsilesional and contralesional delta band average power in patients with flaccid paralysis occurred during the electroacupuncture stimulation, and they increased after the removal of the needles. The ipsilesional delta band average power of patients with spasticity significantly decreased during the electroacupuncture stimulation.

Conclusion: From this pilot electrophysiological study, we provided a possible electrophysiological mechanism of the curative effect of electroacupuncture for stroke rehabilitation.
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http://dx.doi.org/10.1155/2020/8839491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707989PMC
November 2020

MSC-Derived Exosomes Protect Vertebral Endplate Chondrocytes against Apoptosis and Calcification via the miR-31-5p/ATF6 Axis.

Mol Ther Nucleic Acids 2020 Dec 26;22:601-614. Epub 2020 Sep 26.

Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai 200040, China.

Apoptosis and calcification of endplate chondrocytes (EPCs) can exacerbate intervertebral disc degeneration (IVDD). Mesenchymal stem cell-derived exosomes (MSC-exosomes) are reported to have the therapeutic potential in IVDD. However, the effects and related mechanisms of MSC-exosomes on EPCs are still unclear. We aimed to investigate the role of MSC-exosomes on EPCs with a tert-butyl hydroperoxide (TBHP)-induced oxidative stress cell model and IVDD rat model. First, our study revealed that TBHP could result in apoptosis and calcification of EPCs, and MSC-exosomes could inhibit the detrimental effects. We also found that these protective effects were inhibited after miroRNA (miR)-31-5p levels were downregulated in MSC-exosomes. The target relationship between miR-31-5p and ATF6 was tested. miR-31-5p negatively regulated ATF6-related endoplasmic reticulum (ER) stress and inhibited apoptosis and calcification in EPCs. Our experiments indicated that sub-endplate injection of MSC-exosomes can ameliorate IVDD; however, after miR-31-5p levels were downregulated in MSC-exosomes, these protective effects were inhibited. In conclusion, MSC-exosomes reduced apoptosis and calcification in EPCs, and the underlying mechanism may be related to miR-31-5p/ATF6/ER stress pathway regulation.
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http://dx.doi.org/10.1016/j.omtn.2020.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569190PMC
December 2020

Absent atherosclerotic risk factors are associated with carotid stiffening quantified with ultrafast ultrasound imaging.

Eur Radiol 2021 May 17;31(5):3195-3206. Epub 2020 Oct 17.

Department of Ultrasound, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China.

Objectives: To evaluate carotid stiffening in participants without conventional cardiovascular risk factors (CVRFs) by using ultrafast pulse wave velocity (ufPWV).

Methods: The present study enrolled 517 participants without conventional CVRFs (CVRF-Free total population). Subjects in this population were defined as current non-smokers with untreated blood pressure < 140/90 mmHg, fasting blood glucose (FBG) < 7.0 mmol/L, total cholesterol (TC) < 6.2 mmol/L, low-density lipoprotein cholesterol < 4.1 mmol/L, and high-density lipoprotein cholesterol ≥ 1.0 mmol/L. Participants in the subgroup with optimal CVRFs (CVRF-Optimal subgroup; n = 188) were defined as having blood pressure < 120/80 mmHg, TC < 5.2 mmol/L, and FBG < 5.6 mmol/L. Clinical interviews, physical examinations, serum draw, carotid intima-media thickness (cIMT), and ufPWV were evaluated. Adjusted odds ratios (ORs) with 95% confidence intervals and ordinal logistic regression models were used.

Results: Carotid stiffening was present in 46.2-54.5% of CVRF-Free subjects. Age, male sex, and body mass index (BMI) were independently associated with carotid stiffening in both the CVRF-Free total population and CVRF-Optimal subgroup (OR for age = 1.10-1.11, OR for male sex = 2.65-7.19, OR for BMI = 1.34-1.62; p < 0.05). Carotid stiffening was associated with TC only in the CVRF-Free total population (OR for TC = 1.84; p = 0.034).

Conclusions: Many CVRF-Free individuals have carotid stiffening. ufPWV for atherosclerotic stiffening aids the assessment of early atherogenesis and may further clarify the true status of healthy adults without CVRFs.

Key Points: • CVRF-Optimal individuals have a lower carotid stiffness than CVRF-Free populations. • ufPWV is a quantitative predictor for the early assessment of AS. • Absent major CVRFs cannot be considered low risk for carotid stiffening and atherosclerosis.
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http://dx.doi.org/10.1007/s00330-020-07405-4DOI Listing
May 2021

MCU-dependent negative sorting of miR-4488 to extracellular vesicles enhances angiogenesis and promotes breast cancer metastatic colonization.

Oncogene 2020 11 16;39(46):6975-6989. Epub 2020 Oct 16.

Department of Occupational Health and Occupational Medicine, School of Public Health, Southern Medical University, 510515, Guangzhou, China.

Based on Stephen Paget's well-established theory, both cell-autonomous and non-cell-autonomous mechanisms are crucial for metastasis. Although the mitochondrial calcium uniporter (MCU) has been suggested to be involved in breast cancer (BC) progression via cell-autonomous mechanisms, whether it assists the metastasis of BC cells through non-cell-autonomous mechanisms remains unclear. This study aimed to demonstrate that the MCU regulates BC metastatic colonization via non-cell-autonomous mechanisms. The results suggested that extracellular vesicles (EVs) derived from MCU-downregulated MDA-MB-231 cells suppressed angiogenesis in the metastatic niche in a nude mouse model, thereby hindering the colonization of BC cells. Mechanistically, we revealed that the MCU negatively correlated with miR-4488 in EVs derived from BC cells. Significantly, miR-4488 was determined to suppress angiogenesis of vascular endothelial cells by directly targeting angiogenic CX3CL1. Furthermore, we identified miR-4488 as being significantly downregulated in serum EVs from patients with triple-negative BC. Hence, this study suggests that MCU-dependent negative sorting of miR-4488 to EVs enhances angiogenesis in the metastatic niche and, thus, favors the metastatic colonization of BC cells.
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http://dx.doi.org/10.1038/s41388-020-01514-6DOI Listing
November 2020

Melanocytes derived from mouse hair follicles: A novel study model to assess pigmentation disorders.

Pathol Res Pract 2020 Nov 28;216(11):153224. Epub 2020 Sep 28.

Department of Toxicology, School of Public Health, Jilin University, Changchun, China. Electronic address:

Melanocytes are the major cells responsible for skin and fair pigmentation in vertebrates. They localize to hair follicles(HFs) and the epidermis during embryonic development. A reduced number or dysfunction of melanocytes results in pigmentation disorders.Thus, methods for isolation, culture, and identification of melanocytes in mouse hair follicles provide an experimental basis for thestudy of of pigmentation disorders. In the current work, we harvested the melanocytes from the anagen phase dorsal skin of C57BL/6 mice.After its separation from the skin, the dermis was digested, and the HFs were released. HFs were then also digested, and the cells released from HFs were cultured in melanocyte growth medium. Immunofluorescence and immunohistochemistry staining were used to localize the distribution of melanocytes in HFs . Reverse transcription polymerase chain reaction was performed to detect the expression of specific melanocyte marker genes. Immunofluorescence, immunohistochemistry, flow cytometry, and western blot were carried out to detect the expression of marker proteins in cells. 3,4-Dihydroxy-L-phenylalanine (L-DOPA) staining was used to detect the pigmentation functionality of melaonocytes. Based on our results, we conclude that mature and functional melanocytes can be successfully obtained from theHFs, providing a cell model to study pigmentation disorders. The current findings provide novel insights for the treatment of pigmentation disorders by autologous cell transplantation. Further, we believe that issues related to skin damage, insufficient numbers of autologous cells, and autoimmune problems can be resolved in future though the use of functional melanocytes.
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http://dx.doi.org/10.1016/j.prp.2020.153224DOI Listing
November 2020

Exosome-Transported circRNA_0000253 Competitively Adsorbs MicroRNA-141-5p and Increases IDD.

Mol Ther Nucleic Acids 2020 Sep 31;21:1087-1099. Epub 2020 Jul 31.

Department of Orthopaedics, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address:

The pathogenesis of intervertebral disc degeneration (IDD) is complex, and a better understanding of IDD pathogenesis may provide a better method for the treatment of IDD. Exosomes are 40-100 nm nanosized vesicles that are released from many cell types into the extracellular space. We speculated that exosome-transported circular RNAs (circRNAs) could regulate IDD. Exosomes from different degenerative grades were isolated and added to nucleus pulposus cells (NPCs), and indicators of proliferation and apoptosis were detected. Based on the previous circRNA microarray results, the top 10 circRNAs were selected. PCR was performed to determine the circRNA with the maximum upregulation. Competing endogenous RNA (ceRNA) analysis was carried out, and the sponged microRNA (miRNA) was identified. Further functional verification of the selected circRNA was carried out in vivo and in vitro. NPCs of different degenerative grades secreted exosomes, which could regulate IDD. circRNA_0000253 was selected as having the maximum upregulation in degenerative NPC exosomes. ceRNA analysis showed that circRNA_0000253 could adsorb miRNA-141-5p to downregulate SIRT1. circRNA_0000253 was confirmed to increase IDD by adsorbing miRNA-141-5p and downregulating SIRT1 in vivo and in vitro. Exosomal circRNA_0000253 owns the maximum upregulation in degenerative NPC exosomes and could promote IDD by adsorbing miRNA-141-5p and downregulating SIRT1.
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http://dx.doi.org/10.1016/j.omtn.2020.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473879PMC
September 2020

MiR-122-5p and miR-326-3p promote cadmium-induced NRK-52E cell apoptosis by downregulating PLD1.

Environ Toxicol 2020 Dec 22;35(12):1334-1342. Epub 2020 Jul 22.

Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.

Cadmium is a toxic heavy metal distributed broadly in the environment and manufactory industry. Long-term exposure to cadmium, considered as a risk for kidney injury, leads to chronic kidney disease eventually. Phospholipase D1 (PLD1) promotes cell proliferation and inhibits apoptosis, and might be involved in cadmium-induced kidney injury. In this study, we used miRNA microarray assays and bioinformatics analysis to identify miRNAs, which may regulate PLD1 expression and exert an impact on cadmium-induced kidney injury. MiR-122-5p and miR-326-3p,selected as candidates, were explored for their regulatory functions in kidney injury, using NRK-52E cells. Both of these two miRNAs exhibited higher expression in kidneys of SD rats after exposure to cadmium for 6 weeks. Cadmium treatment also increased miR-122-5p and miR-326-3p and decreased PLD1 in NRK-52E cells. Both of miR-122-5p and miR-326-3p could downregulate PLD1 expression through targeting its 3'UTR and enhance cadmium-induced apoptosis, while inhibiting either of these two miRNAs could reverse such effects. In conclusion, our results suggest that miR-122-5p and miR-326-3p might enhance cadmium-induced NRK-52E cell apoptosis through downregulating PLD1 expression.
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http://dx.doi.org/10.1002/tox.22998DOI Listing
December 2020

Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX).

G3 (Bethesda) 2020 09 2;10(9):3165-3177. Epub 2020 Sep 2.

Department of Genetics, University of North Carolina, Chapel Hill, NC

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated ( < 0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.
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http://dx.doi.org/10.1534/g3.120.400975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466989PMC
September 2020

Effects of ecologically relevant concentrations of cadmium on locomotor activity and microbiota in zebrafish.

Chemosphere 2020 Oct 27;257:127220. Epub 2020 May 27.

Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China. Electronic address:

Cadmium (Cd) is widely spread in the aquatic environment, and its impact on humans and the ecosystem is an important issue in public health. However, its effects on zebrafish microbiota are still poorly understood. In this study, the potential developmental neurotoxicity and microbiota dysbiosis of ecologically relevant concentrations of Cd (0, 1.25, 2.5 and 5 μg/L) was evaluated by waterborne exposure for 7 days. The data showed that exposure to 5 μg/L of Cd significantly decreased survival rates and impaired locomotor activities. Uptake of Cd was enhanced with the increase of the concentration and duration of exposure. High-throughput sequencing analysis revealed a significant change in the richness and diversity of the microbiota of Cd-treated zebrafish. At the phylum level, the abundance of Proteobacteria increased, while that Firmicutes was significantly decreased after exposure to 5 μg/L Cd. At the genus level, there were significant changes in the abundances of several bacteria involved in the regulation of neurodegenerative diseases (Pseudomonas, Ruminococcaceae, Blautia, Bacteroides, Lactobacillus, Lachnospiraceae, and Phascolarctobacterium) in the Cd-treatment groups, as compared to the control group. In addition, the mRNA expression profiles of bdnf and genes involved in serotonin signaling and metabolism were changed in the Cd exposure groups. Together, these data suggest that Cd could be harmful to zebrafish health by inducing the microbiota changes, and the microbiota could serve as a potential target to protect against the adverse effects of Cd toxicity.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127220DOI Listing
October 2020

Pay-it-forward gonorrhoea and chlamydia testing among men who have sex with men in China: a randomised controlled trial.

Lancet Infect Dis 2020 08 28;20(8):976-982. Epub 2020 Apr 28.

University of North Carolina at Chapel Hill, Project-China, Guangzhou, China; London School of Hygiene and Tropical Medicine, London, UK. Electronic address:

Background: WHO recommends that men who have sex with men (MSM) receive gonorrhoea and chlamydia testing, but many evidence-based preventive services are unaffordable. The pay-it-forward strategy offers an individual a gift (eg, a test for sexually transmitted diseases) and then asks whether they would like to give a gift (eg, a future test) to another person. This study examined the effectiveness of a pay-it-forward programme to increase gonorrhoea and chlamydia testing among MSM in China.

Methods: We did a randomised controlled superiority trial at three HIV testing sites run by MSM community-based organisations in Guangzhou and Beijing, China. We included MSM aged 16 years or older who were seeking HIV testing and met indications for gonorrhoea and chlamydia testing. Restricted randomisation was done using computer-generated permuted blocks. 30 groups were randomised into three arms (1:1:1): a pay-it-forward arm in which men were offered free gonorrhoea and chlamydia testing and then asked whether they would like to donate for testing of prospective participants, a pay-what-you-want arm in which men were offered free testing and given the option to pay any desired amount for the test, and a standard-of-care arm in which testing was offered at ¥150 (US$22). There was no masking to arm assignment. The primary outcome was gonorrhoea and chlamydia test uptake ascertained by administrative records. We used generalised estimating equations to estimate intervention effects with one-sided 95% CIs and a prespecified superiority margin of 20%. The trial is registered with ClinicalTrials.gov, NCT03741725.

Findings: Between Dec 8, 2018, and Jan 19, 2019, 301 men were recruited and included in the analysis. 101 were randomly assigned to the pay-it-forward group, 100 to the pay-what-you-want group, and 100 to the standard-of-care group. Test uptake for gonorrhoea and chlamydia was 56% (57 of 101 participants) in the pay-it-forward arm, 46% (46 of 100 participants) in the pay-what-you-want arm, and 18% (18 of 100 participants) in the standard-of-care arm. The estimated difference in test uptake between the pay-it-forward and standard-of-care group was 38·4% (95% CI lower bound 28·4%). Among men in the pay-it-forward arm, 54 of 57 (95%) chose to donate to support testing for others.

Interpretation: The pay-it-forward strategy can increase gonorrhoea and chlamydia testing uptake among Chinese MSM and could be a useful tool for scaling up preventive services that carry a mandatory fee.

Funding: US National Institute of Health; Special Programme for Research and Training in Tropical Diseases, sponsored by UNICEF, UNDP, World Bank, and WHO; the National Key Research and Development Program of China; Doris Duke Charitable Foundation; and Social Entrepreneurship to Spur Health.
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http://dx.doi.org/10.1016/S1473-3099(20)30172-9DOI Listing
August 2020

Poly (ADP-ribose) polymerase 1 inhibition prevents neurodegeneration and promotes α-synuclein degradation via transcription factor EB-dependent autophagy in mutant α-synucleinA53T model of Parkinson's disease.

Aging Cell 2020 06 31;19(6):e13163. Epub 2020 May 31.

Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.

Poly (ADP-ribose) polymerase 1 (PARP1) is a master regulator of diverse biological processes such as DNA repair, oxidative stress, and apoptosis. PARP1 can be activated by aggregated α-synuclein, and this process in turn exacerbates toxicity of α-synuclein. This circle is closely linked to the evolution of Parkinson's disease (PD) that characterized by progressive neurodegeneration and motor deficits. Here, we reported the PARP1, as a novel upstream molecular of transcription factor EB (TFEB), participates in regulation of autophagy in α-synuclein aggregated cells and mice. PARP1 inhibition not only enhances the nuclear transcription of TFEB via SIRT1 mediated down-regulation of mTOR signaling but also reduces nuclear export of TFEB by attenuating the TFEB-CRM1 interaction. Our results revealed that PARP1 inhibition lessened the accumulation of α-synuclein in PD models. Also, oral administration of PARP1 inhibitor Veliparib prevented neurodegeneration and improved motor ability in α-synucleinA53T transgenic mice. These findings identify that PARP1 signaling pathway regulates TFEB-mediated autophagy, pointing to potential therapeutic strategy of PD via enhancing protein degradation systems.
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http://dx.doi.org/10.1111/acel.13163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294777PMC
June 2020

Internalization of the TAT-PBX1 fusion protein significantly enhances the proliferation of human hair follicle-derived mesenchymal stem cells and delays their senescence.

Biotechnol Lett 2020 Oct 20;42(10):1877-1885. Epub 2020 May 20.

Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.

Objectives: To express a TAT-PBX1 fusion protein using a prokaryotic expression system and to explore potential effects of TAT-PBX1 in the proliferation and senescence of human hair follicle-derived mesenchymal stem cells.

Results: The TAT-PBX1 fusion was produced in inclusion bodies and heterogenously expressed in Rosetta (DE3) cells. Immunofluorescence staining showed that TAT-PBX1 fusion proteins were internalized by human hair follicle-derived mesenchymal stem cells. The growth rate of cells was increased after treatment with more than 5.0 μg/mL of TAT-PBX1. The rate of senescence-associated β-galactosidase positive cells was reduced in the 10.0 μg/mL TAT-PBX1 group (28%) than the 0 μg/mL control group (60%). Cells treated with the TAT-PBX1 fusion protein showed higher expression of p-AKT (1.22-fold that of the control), which indicates that TAT-PBX1 activated AKT pathway after cellular uptake.

Conclusions: The TAT-PBX1 fusion protein increased the proliferation of hair follicle mesenchymal stem cells and delayed their senescence by activating the AKT pathway following internalization by cells.
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http://dx.doi.org/10.1007/s10529-020-02909-xDOI Listing
October 2020

MSC-derived exosomes attenuate cell death through suppressing AIF nucleus translocation and enhance cutaneous wound healing.

Stem Cell Res Ther 2020 05 11;11(1):174. Epub 2020 May 11.

Department of Toxicology, School of Public Health, Jilin University, No. 1163 Xinmin Street, Changchun, Jilin, 130021, China.

Background: Skin wounding is very common and may be slow to heal. Increasing evidence shows that exosomes derived from mesenchymal stem cells (MSCs) dramatically enhance skin wound healing in a paracrine manner. However, the mechanism underlying this phenomenon has not yet been elucidated. Thus, the objective of the present study was to identify the signaling pathways and paracrine factors by which MSC-derived exosomes promote de novo skin tissue regeneration in response to wound healing.

Methods: In vitro and in vivo skin wound healing models were created by treating immortalized human keratinocytes (HaCaT) with hydrogen peroxide (HO) and excising full-thickness mouse skin, respectively. Exosomes were extracted from human umbilical cord Wharton's jelly MSCs (hucMSC-Ex) by ultracentrifugation of cell culture supernatant.

Results: The hucMSC-Ex treatment significantly increased HaCaT cell proliferation and migration in a time- and dose-dependent manner, suppressed HaCaT apoptosis induced with HO by inhibiting nuclear translocation of apoptosis-inducing factor (AIF) and upregulating poly ADP ribose polymerase 1 (PARP-1) and poly (ADP-ribose) (PAR). The animal experiments showed that relative to hucMSCs, hucMSC-Ex attenuated full-thickness skin wounding by enhancing epidermal re-epithelialization and dermal angiogenesis.

Conclusions: These findings indicated that direct administration of hucMSC-Ex may effectively treat cutaneous wounding and could be of great value in clinical settings.
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http://dx.doi.org/10.1186/s13287-020-01616-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212595PMC
May 2020

Phospholipase D1 Ameliorates Apoptosis in Chronic Renal Toxicity Caused by Low-Dose Cadmium Exposure.

Biomed Res Int 2020 31;2020:7091053. Epub 2020 Mar 31.

Department of Occupational Health and Occupational Medicine, School of Public Health, Southern Medical University, Guangzhou 510515, China.

Exposure to cadmium (Cd), a common heavy metal used in industry, can result in long-term chronic toxicity. It has been well characterized that kidneys are the main organs that are targeted by toxicity, which can cause apoptosis, necrosis, and atrophy of renal tubular epithelial cells. However, the molecular mechanisms associated with Cd toxicity remain unclear. In this study, the expression of renal proteins in Sprague-Dawley rats exposed to chronic Cd was analyzed with iTRAQ proteomics. Bioinformatics analysis indicated that phospholipase D1 (PLD1) was significantly underexpressed and may correlate strongly with Cd-induced chronic kidney impairment. Previous studies have shown that PLD1 promotes cell proliferation and inhibits apoptosis, indicating that PLD1 may be implicated in the pathogenesis of kidney injury induced by Cd. Studies and all demonstrate that the mRNA and protein levels of PLD1 decrease significantly both in kidney tissue and in proximal tubular cell lines exposed to Cd. Overexpression of PLD1 and its downstream product PA could ameliorate Cd-induced apoptosis. Moreover, we identified that miR-122-5p was a regulatory miRNA of PLD1. miR-122-5p was overexpressed after Cd exposure and promoted cell apoptosis by downregulating PLD1 through binding the 3'UTR of the locus at 1761-1784 nt. In conclusion, our results indicated that PLD1 and its downstream PA were strongly implicated in Cd-induced chronic kidney impairment and could be a novel player in the defense against Cd-induced nephrotoxicity.
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http://dx.doi.org/10.1155/2020/7091053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150706PMC
January 2021

Semi-CAM: A semi-supervised deconvolution method for bulk transcriptomic data with partial marker gene information.

Sci Rep 2020 03 25;10(1):5434. Epub 2020 Mar 25.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Deconvolution of bulk transcriptomics data from mixed cell populations is vital to identify the cellular mechanism of complex diseases. Existing deconvolution approaches can be divided into two major groups: supervised and unsupervised methods. Supervised deconvolution methods use cell type-specific prior information including cell proportions, reference cell type-specific gene signatures, or marker genes for each cell type, which may not be available in practice. Unsupervised methods, such as non-negative matrix factorization (NMF) and Convex Analysis of Mixtures (CAM), in contrast, completely disregard prior information and thus are not efficient for data with partial cell type-specific information. In this paper, we propose a semi-supervised deconvolution method, semi-CAM, that extends CAM by utilizing marker information from partial cell types. Analysis of simulation and two benchmark data have demonstrated that semi-CAM outperforms CAM by yielding more accurate cell proportion estimations when markers from partial/all cell types are available. In addition, when markers from all cell types are available, semi-CAM achieves better or similar accuracy compared to the supervised method using signature genes, CIBERSORT, and the marker-based supervised methods semi-NMF and DSA. Furthermore, analysis of human chlamydia-infection data with bulk expression profiles from six cell types and prior marker information of only three cell types suggests that semi-CAM achieves more accurate cell proportion estimations than CAM.
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http://dx.doi.org/10.1038/s41598-020-62330-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096458PMC
March 2020

Job satisfaction, engagement, and burnout in the population of orthopedic surgeon and neurosurgeon trainees in mainland China.

Neurosurg Focus 2020 03;48(3):E3

4Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China; and.

Objective: In China, orthopedics and neurosurgery are among the most desired majors for medical students. However, little is known about the working and living status of specialists in these two fields. This study was aimed at evaluating job satisfaction, engagement, and burnout in the population of Chinese orthopedist and neurosurgeon trainees.

Methods: A nationwide online survey was administered in mainland China. Questionnaires were answered anonymously. Job satisfaction, engagement, and burnout were assessed using the Job Descriptive Index, the Utrecht Work Engagement Scale, and the Maslach Burnout Inventory, respectively.

Results: Data were collected from 643 orthopedist trainees and 690 neurosurgeon trainees. Orthopedists and neurosurgeons showed no statistical difference in terms of age, sex, job titles, and preference for working in tertiary hospitals. Orthopedists had a higher marriage rate (p < 0.01), a lower divorce rate (p = 0.017), relatively shorter working hours (p < 0.01), and a higher annual income (p = 0.023) than neurosurgeons. Approximately 40% of respondents experienced workplace violence in the last 5 years. Less than 10% of respondents were satisfied with their pay, and over 70% would not encourage their offspring to become a doctor. Orthopedists were more satisfied with their careers than neurosurgeons (p < 0.01) and had a higher level of work engagement (p < 0.01). In addition, a higher proportion of orthopedists were burnt out (p < 0.01) than neurosurgeons, though the difference between the two groups was not significant (p = 0.088). Multivariate regressions suggested that younger age (≤ 25 years old), being a senior trainee, getting divorced, working in a regional hospital, long working hours (≥ 71 hrs/wk), a low annual income (<¥100,000), sleeping < 6 hrs/day, and experience with workplace violence were significantly related to burnout for both groups.

Conclusions: Chinese orthopedic surgical and neurosurgical trainees are under significant stress. Orthopedic surgeons showed relatively optimistic data in their assessments of job satisfaction, engagement, and burnout. This study may provide valuable information for orthopedic and neurosurgical candidates considering either specialty as a career.
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http://dx.doi.org/10.3171/2019.12.FOCUS19830DOI Listing
March 2020

Preparation of antibacterial and osteoconductive 3D-printed PLGA/Cu(I)@ZIF-8 nanocomposite scaffolds for infected bone repair.

J Nanobiotechnology 2020 Feb 27;18(1):39. Epub 2020 Feb 27.

Department of Orthopaedics, Huashan Hospital, Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai, 200040, China.

Background: The repair of large bone defects is a great challenge in clinical practice. In this study, copper-loaded-ZIF-8 nanoparticles and poly (lactide-co-glycolide) (PLGA) were combined to fabricate porous PLGA/Cu(I)@ZIF-8 scaffolds using three-dimensional printing technology for infected bone repair.

Methods: The surface morphology of PLGA/Cu(I)@ZIF-8 scaffolds was investigated by transmission electron microscopy and scanning electron microscopy. The PLGA/Cu(I)@ZIF-8 scaffolds were co-cultured with bacteria to determine their antibacterial properties, and with murine mesenchymal stem cells (MSCs) to explore their biocompatibility and osteoconductive properties. The bioactivity of the PLGA/Cu(I)@ZIF-8 scaffolds was evaluated by incubating in simulated body fluid.

Results: The results revealed that the PLGA/Cu(I)@ZIF-8 scaffolds had porosities of 80.04 ± 5.6% and exhibited good mechanical properties. When incubated with HO, Cu(I)@ZIF-8 nanoparticles resulted generated reactive oxygen species, which contributed to their antibacterial properties. The mMSCs cultured on the surface of PLGA/Cu(I)@ZIF-8 scaffolds were well-spread and adherent with a high proliferation rate, and staining with alkaline phosphatase and alizarin red was increased compared with the pure PLGA scaffolds. The mineralization assay showed an apatite-rich layer was formed on the surface of PLGA/Cu(I)@ZIF-8 scaffolds, while there was hardly any apatite on the surface of the PLGA scaffolds. Additionally, in vitro, Staphylococcus aureus cultured on the PLGA/Cu(I)@ZIF-8 scaffolds were almost all dead, while in vivo inflammatory cell infiltration and bacteria numbers were dramatically reduced in infected rats implanted with PLGA/[email protected] scaffolds.

Conclusion: All these findings demonstrate that PLGA/Cu(I)@ZIF-8 scaffolds possess excellent antibacterial and osteoconductive properties, as well as good biocompatibility and high bioactivity. This study suggests that the PLGA/Cu(I)@ZIF-8 scaffolds could be used as a promising biomaterial for bone tissue engineering, especially for infected bone repair.
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http://dx.doi.org/10.1186/s12951-020-00594-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045416PMC
February 2020

MicroRNA-101-3p Downregulates TLR2 Expression, Leading to Reduction in Cytokine Production by Treponema pallidum-Stimulated Macrophages.

J Invest Dermatol 2020 08 11;140(8):1566-1575.e1. Epub 2020 Jan 11.

Research Center, Dermatology Hospital, Southern Medical University, Guangzhou, China. Electronic address:

Treponema pallidum (Tp) infection-induced immune responses can cause tissue damage. However, the underlying mechanism by which Tp infection induces immune response is unclear. Recent studies suggest a regulatory role of microRNAs in host immunity. We assessed whether microRNAs also have a regulatory role in immune response to Tp infection in vitro. Our results showed that microRNA-101-3p (miR-101-3p) levels were significantly higher in peripheral blood mononuclear cells of patients with primary syphilis and those in the serofast state, whereas toll-like receptor (TLR) 2 levels were higher in patients with syphilis than in healthy controls. In vitro, stimulation of THP-1 cells with Tp increased miR-101-3p expression. Moreover, miR-101-3p reduced expression levels of TLR2 mRNA and protein in THP-1 cells via binding to the 3' untranslated region of TLR2. Likewise, miR-101-3p inhibited production of inflammatory cytokines, including IL-1β, IL-6, tumor necrosis factor-α, and IL-12, in Tp-stimulated macrophages. IL-1β and IL-6 mRNA expression levels were reduced by transfection of macrophages with a TLR2-specific small interfering RNA. Conversely, overexpression of TLR2 upregulated cytokine expression. Patients with secondary syphilis exhibited the highest levels of plasma IL-6, which were negatively correlated with miR-101-3p. In conclusion, Tp infection upregulates miR-101-3p expression, which in turn inhibits the TLR2 signaling pathway, leading to reduced cytokine production.
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http://dx.doi.org/10.1016/j.jid.2019.12.012DOI Listing
August 2020

SCDC: bulk gene expression deconvolution by multiple single-cell RNA sequencing references.

Brief Bioinform 2021 Jan;22(1):416-427

Recent advances in single-cell RNA sequencing (scRNA-seq) enable characterization of transcriptomic profiles with single-cell resolution and circumvent averaging artifacts associated with traditional bulk RNA sequencing (RNA-seq) data. Here, we propose SCDC, a deconvolution method for bulk RNA-seq that leverages cell-type specific gene expression profiles from multiple scRNA-seq reference datasets. SCDC adopts an ENSEMBLE method to integrate deconvolution results from different scRNA-seq datasets that are produced in different laboratories and at different times, implicitly addressing the problem of batch-effect confounding. SCDC is benchmarked against existing methods using both in silico generated pseudo-bulk samples and experimentally mixed cell lines, whose known cell-type compositions serve as ground truths. We show that SCDC outperforms existing methods with improved accuracy of cell-type decomposition under both settings. To illustrate how the ENSEMBLE framework performs in complex tissues under different scenarios, we further apply our method to a human pancreatic islet dataset and a mouse mammary gland dataset. SCDC returns results that are more consistent with experimental designs and that reproduce more significant associations between cell-type proportions and measured phenotypes.
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http://dx.doi.org/10.1093/bib/bbz166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820884PMC
January 2021

NANOG Attenuates Hair Follicle-Derived Mesenchymal Stem Cell Senescence by Upregulating PBX1 and Activating AKT Signaling.

Oxid Med Cell Longev 2019 4;2019:4286213. Epub 2019 Dec 4.

Department of Toxicology, School of Public Health, Jilin University, Changchun, China.

Stem cells derived from elderly donors or harvested by repeated subculture exhibit a marked decrease in proliferative capacity and multipotency, which not only compromises their therapeutic potential but also raises safety concerns for regenerative medicine. NANOG-a well-known core transcription factor-plays an important role in maintaining the self-renewal and pluripotency of stem cells. Unfortunately, the mechanism that NANOG delays mesenchymal stem cell (MSC) senescence is not well-known until now. In our study, we showed that both ectopic NANOG expression and PBX1 overexpression (i) significantly upregulated phosphorylated AKT (p-AKT) and PARP1; (ii) promoted cell proliferation, cell cycle progression, and osteogenesis; (iii) reduced the number of senescence-associated--galactosidase- (SA--gal-) positive cells; and (iv) downregulated the expression of p16, p53, and p21. Western blotting and dual-luciferase activity assays showed that ectopic NANOG expression significantly upregulated PBX1 expression and increased promoter activity. In contrast, knockdown by RNA interference in hair follicle- (HF-) derived MSCs that were ectopically expressing NANOG resulted in the significant downregulation of p-AKT and the upregulation of p16 and p21. Moreover, blocking AKT with the PI3K/AKT inhibitor LY294002 or knocking down via RNA interference significantly decreased PBX1 expression, while increasing p16 and p21 expression and the number of SA--gal-positive cells. In conclusion, our findings show that NANOG delays HF-MSC senescence by upregulating PBX1 and activating AKT signaling and that a feedback loop likely exists between PBX1 and AKT signaling.
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http://dx.doi.org/10.1155/2019/4286213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914946PMC
June 2020