Publications by authors named "Yanan Du"

158 Publications

Exendin-4 gene modification and microscaffold encapsulation promote self-persistence and antidiabetic activity of MSCs.

Sci Adv 2021 Jul 2;7(27). Epub 2021 Jul 2.

Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.

Mesenchymal stem cell (MSC)-based therapy to combat diabetic-associated metabolic disorders is hindered by impoverished cell survival and limited therapeutic effects under high glucose stress. Here, we genetically engineered MSCs with Exendin-4 (MSC-Ex-4), a glucagon-like peptide-1 (GLP-1) analog, and demonstrated their boosted cellular functions and antidiabetic efficacy in the type 2 diabetes mellitus (T2DM) mouse model. Mechanistically, MSC-Ex-4 achieved self-augmentation and improved survival under high glucose stress via autocrine activation of the GLP-1R-mediated AMPK signaling pathway. Meanwhile, MSC-Ex-4-secreted Exendin-4 suppressed senescence and apoptosis of pancreatic β cells through endocrine effects, while MSC-Ex-4-secreted bioactive factors (e.g., IGFBP2 and APOM) paracrinely augmented insulin sensitivity and decreased lipid accumulation in hepatocytes through PI3K-Akt activation. Furthermore, we encapsulated MSC-Ex-4 in 3D gelatin microscaffolds for single-dose administration to extend the therapeutic effect for 3 months. Together, our findings provide mechanistic insights into Exendin-4-mediated MSCs self-persistence and antidiabetic activity that offer more effective MSC-based therapy for T2DM.
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http://dx.doi.org/10.1126/sciadv.abi4379DOI Listing
July 2021

Targeted cell therapy for partial-thickness cartilage defects using membrane modified mesenchymal stem cells by transglutaminase 2.

Biomaterials 2021 Aug 27;275:120994. Epub 2021 Jun 27.

Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China; Arthritis Institute, Peking University, Beijing, 100044, China. Electronic address:

Unlike full-thickness cartilage defects (FCD), partial-thickness cartilage defects (PCD) may still have residual healthy cartilage tissue, and therefore, the conventional clinical treatments such as microfracture and autologous chondrocyte implantation (ACI) are so traumatic that they may not be the suitable therapies for PCD. Although intra-articular injection of mesenchymal stem cells (MSCs) is a minimally invasive treatment, its therapeutic efficacy is markedly limited due to anoikis caused by failure of cell colonization in the injured area. By modifying a functional polypeptide on the MSC plasma membrane and exploiting the high expression of transglutaminase 2 (TGase2) in the regions of injured cartilage, we achieved targeted recognition and capture of modified MSCs by injured articular chondrocytes (ACs). In the in vitro co-culture model, MSCs improved the function of injured ACs and enhanced the chondrogenic differentiation potential of MSCs. Results of in vitro study also revealed that the activation of the AKT/mTOR signaling pathway may play an important role in the treatment of injured ACs by MSCs. Further, membrane-modified MSCs exhibited a better therapeutic effect than wide-type MSCs in a rabbit model of PCD. Thus, this unique cell membrane modification strategy provides a new cell-based therapeutic approach for the early treatment of articular cartilage defects and other joint diseases.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120994DOI Listing
August 2021

Rapid, visual, and equipment-free point-of-care testing for Staphylococcus aureus by direct recombinase polymerase amplification with SYBR Green Ι.

Acta Biochim Biophys Sin (Shanghai) 2021 Jul 2. Epub 2021 Jul 2.

Biotechnology Research Institute, Shanghai Academy of Agricultural Sciences, Shanghai 201106, China.

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http://dx.doi.org/10.1093/abbs/gmab091DOI Listing
July 2021

Experimental Study on High-Speed Milling of SiCf/SiC Composites with PCD and CVD Diamond Tools.

Materials (Basel) 2021 Jun 22;14(13). Epub 2021 Jun 22.

College of Mechanical and Electrical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, China.

Silicon carbide fiber reinforced silicon carbide ceramic matrix composite (SiC/SiC composite) is characterized by a high strength-to-density ratio, high hardness, and high temperature resistance. However, due to the brittleness of the matrix material and the anisotropy of the reinforcing phase, it is a huge challenge for machining of the material. The milling method has advantages of a high material removal rate and applicability to complex surface geometry. However, no published literature on milling of SiC/SiC composite has been found up to now. In this paper, high-speed milling of SiC/SiC composites was carried out under dry conditions and cryogenic cooling using liquid nitrogen, respectively. Polycrystalline diamond (PCD) and chemical vapor deposition (CVD) diamond cutting tools were used for the milling work. The cutting performance of the two kinds of tools in high-speed milling of SiC/SiC composites was studied. Tool failure modes and mechanisms were analyzed. The effects of the cooling approach on tool wear and machined surface quality were also investigated. The experimental results showed that under identical cutting parameters and cooling approaches, the PCD tool yielded better cutting performance in terms of a longer tool life and better surface quality than that of the CVD diamond tool. In dry machining, the failure modes of the CVD diamond tool were a large area of spalling on the rake face, edge chipping and severe tool nose fracture, whereas for the PCD tool, only a small area of spalling around the tool nose took place. Compared to the dry machining, the wear magnitudes of both PCD and CVD diamond tools were decreased in cryogenic machining. Additionally, the surface quality also showed significant improvements. This study indicates that the PCD tool is highly suitable for machining of SiC/SiC composite, and that the cryogenic method can improve machining efficiency and surface quality.
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http://dx.doi.org/10.3390/ma14133470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269463PMC
June 2021

Underlying Topography Inversion Using Dual Polarimetric TomoSAR.

Sensors (Basel) 2021 Jun 15;21(12). Epub 2021 Jun 15.

School of Geography and Information Engineering, China University of Geosciences (Wuhan), Wuhan 430074, China.

Underlying topography plays an important role in the national economic construction, military security, resource exploration and investigation. Since synthetic aperture radar tomography (TomoSAR) can achieve the three-dimensional imaging of forests, it has been widely used in underlying topography estimation. At present, there are two kinds of TomoSAR based on the applied datasets: single polarimetric TomoSAR (SP-TomoSAR) and fully polarimetric TomoSAR (FP-TomoSAR). However, SP-TomoSAR cannot obtain the underlying topography accurately due to the lack of enough observations. FP-TomoSAR can improve the estimation accuracy of underlying topography. However, it requires high-cost data acquisition for the large-scale application. Thus, this paper proposes the dual polarimetric TomoSAR (DP-TomoSAR) as another suitable candidate to estimate the underlying topography because of its wide swath and multiple polarimetric observations. Moreover, three frequently used spectral estimation algorithms, namely, Beamforming, Capon and MUSIC, are used in DP-TomoSAR. For validation, a series of simulated experiments was carried out, and the airborne P-band multiple polarimetric SAR data over the Lope, Gabon was also acquired to estimate the underlying topography. The results suggest that DP-TomoSAR in HH & HV combination is more suitable to estimate underlying topography over forest areas than other DP combinations. Moreover, the estimation accuracy of DP-TomoSAR is slightly lower than that of FP-TomoSAR but is higher than that of SP-TomoSAR.
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http://dx.doi.org/10.3390/s21124117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232797PMC
June 2021

Asporin inhibits collagen matrix-mediated intercellular mechanocommunications between fibroblasts during keloid progression.

FASEB J 2021 07;35(7):e21705

Department of Dermatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.

Keloids are fibrotic lesions that grow unceasingly and invasively and are driven by local mechanical stimuli. Unlike other fibrotic diseases and normal wound healing, keloids exhibit little transformation of dermal fibroblasts into α-SMA myofibroblasts. This study showed that asporin is the most strongly expressed gene in keloids and its gene-ontology terms relate strongly to ECM metabolism/organization. Experiments with human dermal cells (HDFs) showed that asporin overexpression/treatment abrogated the HDF ability to adopt a perpendicular orientation when subjected to stretching tension. It also induced calcification of the surrounding 3D collagen matrix. Asporin overexpression/treatment also prevented the HDFs from remodeling the surrounding 3D collagen matrix, leading to a disorganized network of thick, wavy collagen fibers that resembled keloid collagen architecture. This in turn impaired the ability of the HDFs to contract the collagen matrix. Asporin treatment also made the fibroblasts impervious to the fibrous collagen contraction of α-SMA myofibroblasts, which normally activates fibroblasts. Thus, by calcifying collagen, asporin prevents fibroblasts from linearly rearranging the surrounding collagen; this reduces both their mechanosensitivity and mechanosignaling to each other through the collagen network. This blocks fibroblast activation and differentiation into the mature myofibroblasts that efficiently remodel the extracellular matrix. Consequently, the fibroblasts remain immature, highly proliferative, and continue laying down abundant extracellular matrix, causing keloid growth and invasion. Notably, dermal injection of asporin-overexpressing HDFs into murine wounds recapitulated keloid collagen histopathological characteristics. Thus, disrupted interfibroblast mechanocommunication may promote keloid progression. Asporin may be a new diagnostic biomarker and therapeutic target for keloids.
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http://dx.doi.org/10.1096/fj.202100111RDOI Listing
July 2021

cIAP1/2 are involved in the radiosensitizing effect of birinapant on NSCLC cell line in vitro.

J Cell Mol Med 2021 May 3. Epub 2021 May 3.

Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

Tumour radioresistance is a major problem for cancer radiation therapy. To identify the underlying mechanisms of this resistance, we used human non-small cell lung cancer (NSCLC) cell lines and focused on the Inhibitor of Apoptosis Protein (IAP) family, which contributes to tumourigenesis and chemoresistance. We investigated the possible correlation between radioresistance in six NSCLC cell lines and IAP protein levels and tested the radiosensitizing effect of birinapant in vitro, a molecule that mimics the second mitochondria-derived activator of caspase. We found that birinapant-induced apoptosis and inhibited the proliferation of NSCLC cells after exposure to radiation. These effects were induced by birinapant downregulation of cIAP protein levels and changes of cIAP gene expression. Overall, birinapant can inhibit tumour growth of NSCLC cell lines to ironizing radiation and act as a promising strategy to overcome radioresistance in NSCLC.
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http://dx.doi.org/10.1111/jcmm.16526DOI Listing
May 2021

Increased Circulating T Follicular Helper Cells Induced IL-12/21 in Patients With Acute on Chronic Hepatitis B Liver Failure.

Front Immunol 2021 31;12:641362. Epub 2021 Mar 31.

Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objectives: T Follicular helper (Tfh) cells, recognized as a distinct CD4 T cell subset, mediate the development of long-lived humoral immunity B cell activation/differentiation. Tfh cells play an important role during hepatic viral infection, but its role in hepatitis B virus-related acute on chronic liver failure (HBV-ACLF) remains to be explored.

Materials And Methods: The frequency of Tfh cells, serum pro-inflammatory cytokine (IL-12, IL-21, IL-17 and TNF) levels and IgG/M levels were investigated in HBV-ACLF (n = 36), serious chronic hepatitis B (n = 21), moderate chronic hepatitis B patients (n = 32) and healthy control (HC) subjects (n = 10).

Results: Circulating Tfh cells were significantly increased in HBV-ACLF patients compared to other groups, correlating well with MELD score. However, the frequency of Tfh cells decreased in ameliorated HBV-ACLF patients. Furthermore, serum IL-12 and IL-21 levels were higher in HBV-ACLF patients, compared to other groups. Naïve CD4 T cells from HC subjects differentiate into Tfh cells following treatment with HBV-ACLF patients' serum, a process that can be blocked by IL-12/21 neutralizing antibodies. Tfh cells induced by HBV-ACLF patient's serum promoted the proliferation and IgG production of B cells . Moreover, circulating CD19 B cells, serum and liver IgG/M levels were significantly higher in HBV-ACLF patients, compared to other groups.

Conclusions: Our data demonstrated that there was a high frequency of Tfh cells and high levels of serum IL-12/21 in HBV-ACLF patients. Naïve CD4 T cells differentiate into Tfh cells in the presence of HBV-ACLF patients' serum rich in IL-12/21, which can be blocked by neutralizing IL-12/21 antibodies. These data may provide useful insights for both clinical and basic research in the treatment of HBV-ACLF.
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http://dx.doi.org/10.3389/fimmu.2021.641362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044369PMC
March 2021

Efficient endothelial and smooth muscle cell differentiation from human pluripotent stem cells through a simplified insulin-free culture system.

Biomaterials 2021 04 11;271:120713. Epub 2021 Feb 11.

Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China. Electronic address:

A major obstacle for using human pluripotent stem cells (hPSCs) derived vascular cells for cell therapy is the lack of simple, cost-saving, and scalable methods for cell production. Here we described a simplified and chemically defined medium (AATS) for endothelial cells (ECs) and smooth muscle cells (SMCs) differentiation. AATS medium does not contain insulin, enabling the rapid and highly efficient vascular mesoderm formation through accelerating metabolic and autophagy-enhanced mesoderm induction. Transcriptome profiling confirmed that hPSC-derived ECs and SMCs in the AATS medium closely resembled primary ECs and SMCs formed in vivo. ECs appeared to adhere and grow better in the AATS medium over other cell types, which allowed the purification of CD31CD144 double-positive cells. Furthermore, the AATS medium was compatible with 3D microscaffold (MS) culture, which may facilitate large-scale bioproduction of ECs. HPSC-derived ECs and SMCs in the AATS medium exhibited strong revascularization potential in treating murine ischemic models. Our study provided a cost-effective and efficient medium system to manufacture GMP compatible, off-the-shelf ECs, and SMCs to model human diseases and vascular repair.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120713DOI Listing
April 2021

ALT Flare Predicts Hepatocellular Carcinoma Among Antiviral Treated Patients With Chronic Hepatitis B: A Cross-Country Cohort Study.

Front Oncol 2020 21;10:615203. Epub 2021 Jan 21.

Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objectives: Alanine aminotransferase (ALT) level is one of the crucial indexes to evaluate disease status for chronic hepatitis B (CHB) patients. However, whether the ALT level after nucleos(t)ide analog (NA) treatment is associated with hepatocellular carcinoma (HCC) development remains unclear.

Materials And Methods: We evaluated the association between ALT level and HCC occurrence in NA-treated patients and investigated the predictive value of ALT flare for HCC. The associations between ALT level and HCC were analyzed by logistic regression and Cox proportional hazards models.

Results: There were 21,223 CHB patients at Ruijin Hospital of China and 16,737 CHB patients in the Optum electronic health records (EHR) in the United States (US) treated with NAs between 2010 and 2018. Among them, 8,152 and 4,893 patients who achieved a normal ALT value were included in the study cohorts, respectively. A significant positive dose-dependent correlation between the peak ALT level and HCC was identified in both cohorts. Within the China cohort, ALT flare was significantly associated with increased risks of HCC compared to normal ALT (HR 2.55, 95%CI 1.45-4.50). Stronger increased risks associated with ALT flare were observed in the US cohort (HR 7.62, 95%CI 4.85-11.98).

Conclusions: ALT flare is a strong predictor for HCC occurrence in the CHB patients treated with NAs. Elevation of ALT, especially ALT flare warrants close monitoring for early HCC detection.
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http://dx.doi.org/10.3389/fonc.2020.615203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859526PMC
January 2021

Multidimensional factors affecting care needs in daily living among community-dwelling older adults: A structural equation modelling approach.

J Nurs Manag 2021 Jul 21;29(5):1207-1219. Epub 2021 Feb 21.

School of Health and Caring Sciences, Linnaeus University, Växjö, Sweden.

Aims: To develop a model illustrating the factors that can influence care needs in daily living (CNDL) of older adults and the pathways between these.

Background: The care needs in community-dwelling older adults have increased sharply. A better understanding of the elderly's CNDL would thus help policymakers define which types of support and services should be given.

Methods: A multicentre study with structural equation modelling was conducted in this study. We recruited 3,448 community-dwelling older adults in China by using a stratified random cluster sampling technique.

Results: Physical and mental health was the strongest predictor of CNDL. Both age and living situation had positive effects on CNDL, while economic factors, social support and family support were the major risk factors for CNDL.

Conclusion: The presented model provides a better understanding of how to address CNDL in the targeted population. The older adults who are the oldest, low-income, non-empty nesters, and with poor self-rated health or the signs of loneliness should be firstly targeted for daily assistance.

Implications For Nursing Management: Using this model could provide health authorities and managers with the information of distinguishing between the priority group and the strategies for easing the caregiving burden in older adults care, and thus improving resource utilization.
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http://dx.doi.org/10.1111/jonm.13259DOI Listing
July 2021

Enhanced single-cell encapsulation in microfluidic devices: From droplet generation to single-cell analysis.

Biomicrofluidics 2020 Nov 22;14(6):061508. Epub 2020 Dec 22.

The State Key Laboratory of Chemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China.

Single-cell analysis to investigate cellular heterogeneity and cell-to-cell interactions is a crucial compartment to answer key questions in important biological mechanisms. Droplet-based microfluidics appears to be the ideal platform for such a purpose because the compartmentalization of single cells into microdroplets offers unique advantages of enhancing assay sensitivity, protecting cells against external stresses, allowing versatile and precise manipulations over tested samples, and providing a stable microenvironment for long-term cell proliferation and observation. The present Review aims to give a preliminary guidance for researchers from different backgrounds to explore the field of single-cell encapsulation and analysis. A comprehensive and introductory overview of the droplet formation mechanism, fabrication methods of microchips, and a myriad of passive and active encapsulation techniques to enhance single-cell encapsulation efficiency were presented. Meanwhile, common methods for single-cell analysis, especially for long-term cell proliferation, differentiation, and observation inside microcapsules, are briefly introduced. Finally, the major challenges faced in the field are illustrated, and potential prospects for future work are discussed.
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http://dx.doi.org/10.1063/5.0018785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758092PMC
November 2020

Radiosensitization Effect of AGuIX, a Gadolinium-Based Nanoparticle, in Nonsmall Cell Lung Cancer.

ACS Appl Mater Interfaces 2020 Dec 16;12(51):56874-56885. Epub 2020 Dec 16.

Institute Light and Mater, UMR5306, Lyon1 University-CNRS, Lyon University, 69100 Villeurbanne, France.

Radiotherapy is the main treatment for cancer patients. A major concern in radiotherapy is the radiation resistance of some tumors, such as human nonsmall cell lung cancer. However, the radiation dose delivered to the tumors is often limited by the possibility of collateral damage to surrounding healthy tissues. A new and efficient gadolinium-based nanoparticle, AGuIX, has recently been developed for magnetic resonance imaging-guided radiotherapy and has been proven to act as an efficient radiosensitizer. The amplified radiation effects of AGuIX nanoparticles appear to be due to the emission of low-energy photoelectrons and Auger electron interactions. We demonstrated that AGuIX nanoparticles exacerbated radiation-induced DNA double-strand break damage and reduced DNA repair in the H1299 nonsmall cell lung cancer cell line. Furthermore, we observed a significant improvement in tumor cell damage and growth suppression, under radiation therapy, with the AGuIX nanoparticles in a H1299 mouse xenograft model. This study paves the way for research into the radiosensitization mechanism of AGuIX nanoparticles and provides a scientific basis for the use of AGuIX nanoparticles as radiosensitizing drugs.
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http://dx.doi.org/10.1021/acsami.0c16548DOI Listing
December 2020

Feasibility of T1 mapping with histogram analysis for the diagnosis and staging of liver fibrosis: Preclinical results.

Magn Reson Imaging 2021 02 24;76:79-86. Epub 2020 Nov 24.

Department of Radiology, Third Affiliated Hospital of Soochow University, Changzhou & Changzhou First People's Hospital, Jiangsu 213200, China. Electronic address:

Purpose: To compare the diagnostic accuracy of parameters derived from the histogram analysis of precontrast, 10-min hepatobiliary phase (HBP) and 20-min HBP T1 maps for staging liver fibrosis (LF).

Methods: LF was induced in New Zealand white rabbits by subcutaneous injections of carbon tetrachloride for 4-16 weeks (n = 120), and 20 rabbits injected with saline served as controls. Precontrast, 10-min and 20-min HBP modified Look-Locker inversion recovery (MOLLI) T1 mapping was performed. Histogram analysis of T1 maps was performed, and the mean, median, skewness, kurtosis, entropy, inhomogeneity and 10th/25th/75th/90th percentiles of T1, T1 and T1 were derived. Quantitative histogram parameters were compared. For significant parameters, further receiver operating characteristic (ROC) analyses were performed to evaluate the potential diagnostic performance in differentiating LF stages.

Results: Finally, 17, 20, 21, 21 and 20 rabbits were included for the F0, F1, F2, F3, and F4 pathological grades of fibrosis, respectively. The mean/75th of T1, entropy of T1 and entropy/mean/median/10th of T1 demonstrated a significant good correlation with the LF stage (|r| = 0.543-0.866, all P < 0.05). The 75th of T1, entropy, and entropy were the three most reliable imaging markers in reflecting the stage of LF. The area under the ROC curve of entropy was larger than that of entropy (P < 0.05 for LF ≥ F2, ≥F3, and ≥ F4) and the 75th of T1 (P < 0.05 for LF ≥ F2 and ≥ F3) for staging LF.

Conclusion: Magnetic resonance histogram analysis of T1 maps, particularly the entropy derived from 20-min HBP T1 mapping, is promising for predicting the LF stage.
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http://dx.doi.org/10.1016/j.mri.2020.11.006DOI Listing
February 2021

Genetic Correlation Analysis and Transcriptome-wide Association Study Suggest the Overlapped Genetic Mechanism between Gout and Attention-deficit Hyperactivity Disorder: L'analyse de corrélation génétique et l'étude d'association à l'échelle du transcriptome suggèrent un mécanisme génétique superposé entre la goutte et le trouble de déficit de l'attention avec hyperactivité.

Can J Psychiatry 2020 Nov 6:706743720970844. Epub 2020 Nov 6.

Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.

Objectives: Gout is a common inflammatory arthritis, which is caused by hyperuricemia. Limited efforts have been paid to systematically explore the relationships between gout and common psychiatric disorders.

Methods: Genome-wide association study summary data of gout were obtained from the GeneATLAS, which contained 452,264 participants including 3,528 gout cases. Linkage disequilibrium score regression (LDSC) was first conducted to evaluate the genetic relationships between gout and 5 common psychiatric disorders. Transcriptome-wide association studies (TWAS) was then conducted to explore the potential biological mechanism underlying the observed genetic correlation between gout and attention-deficit hyperactivity disorder (ADHD). The Database for Annotation, Visualization and Integrated Discovery online functional annotation system was applied for pathway enrichment analysis and gene ontology enrichment analysis.

Results: LDSC analysis observed significant genetic correlation between gout and ADHD (genetic correlation coefficients = 0.29, standard error = 0.09 and value = 0.0015). Further TWAS of gout identified 105 genes with value < 0.05 in muscle skeleton and 228 genes with value < 0.05 in blood. TWAS of ADHD also detected 300 genes with value < 0.05 in blood. Further comparing the TWAS results identified 9 common candidate genes shared by gout and ADHD, such as ( = 0.0040; = 0.0226), ( = 0.0074; = 0.0460), and ( = 0.0349; = 0.03560).

Conclusion: We observed genetic correlation between gout and ADHD and identified multiple candidate genes for gout and ADHD.
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http://dx.doi.org/10.1177/0706743720970844DOI Listing
November 2020

Construction of Microunits by Adipose-Derived Mesenchymal Stem Cells Laden with Porous Microcryogels for Repairing an Acute Achilles Tendon Rupture in a Rat Model.

Int J Nanomedicine 2020 29;15:7155-7171. Epub 2020 Sep 29.

Department of Orthopedic Surgery, Key Laboratory of Musculoskeletal Trauma &war Injuries PLA, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Chinese PLA General Hospital, Beijing 100853, People's Republic of China.

Objective: Tissue engineering approaches seem to be an attractive therapy for tendon rupture. Novel injectable porous gelatin microcryogels (GMs) can promote cell attachment and proliferation, thus facilitating the repair potential for target tissue regeneration. The research objectives of this study were to assess the efficacy of tissue-like microunits constructed by multiple GMs laden with adipose-derived mesenchymal stem cells (ASCs) in accelerated tendon regeneration in a rat model.

Methods: Through a series of experiments, such as isolation and identification of ASCs, scanning electron microscopy, mercury intrusion porosimetry (MIP), laser scanning confocal microscopy and the CCK-8 test, the biocompatibility of GMs was evaluated. In an in vivo study, 64 rat right transected Achilles tendons were randomly divided into four groups: the ASCs+GMs group (microunits aggregated by multiple ASC-laden GMs injected into the gap), the ASCs group ( injected into the gap), the GMs group (GMs injected into the gap) and the blank defect group (non-treated). At 2 and 4 weeks postoperatively, the healing tissue was harvested to evaluate the gross observation and scoring, biomechanical testing, histological staining and quantitative scoring. Gait analysis was performed over time. The 64 rats were randomly assigned into 4 groups: (1) micro-unit group (ASCs+GMs) containing ASC (10)-loaded 120 GMs in 60 μL DMEM; (2) cell control group (ASCs) containing 10 ASCs in 60 μL DMEM; (3) GM control group (GMs) containing 120 blank GMs in 60 μL DMEM; (4) blank defect group (Defect) containing 60 μL DMEM, which were injected into the defect sites. All animals were sacrificed at 2 and 4 weeks postsurgery (Table 1).

Results: In an in vitro study, GMs (from 126 μm to 348 μm) showed good porosities and a three-dimensional void structure with a good interpore connectivity of the micropores and exhibited excellent biocompatibility with ASCs. As the culture time elapsed, the extracellular matrix (ECM) secreted by ASCs encased the GMs, bound multiple microspheres together, and then formed active tendon tissue-engineering microunits. In animal experiments, the ASCs+GMs group and the ASCs group showed stimulatory effects on Achilles tendon healing. Moreover, the ASCs+GMs group was the best at improving the macroscopic appearance, histological morphology, Achilles functional index (AFI), and biomechanical properties of repair tissue without causing adverse immune reactions.

Conclusion: Porous GMs were conducive to promoting cell proliferation and facilitating ECM secretion. The ASCs-GMs matrices showed an obvious therapeutic efficiency for Achilles tendon rupture in rats.
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http://dx.doi.org/10.2147/IJN.S238399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535144PMC
November 2020

Consistent apparent Young's modulus of human embryonic stem cells and derived cell types stabilized by substrate stiffness regulation promotes lineage specificity maintenance.

Cell Regen 2020 Sep 3;9(1):15. Epub 2020 Sep 3.

Department of Biomedical Engineering, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, School of Medicine, Tsinghua University, Beijing, 100084, China.

Background: Apparent Young's modulus (AYM), which reflects the fundamental mechanical property of live cells measured by atomic force microscopy and is determined by substrate stiffness regulated cytoskeletal organization, has been investigated as potential indicators of cell fate in specific cell types. However, applying biophysical cues, such as modulating the substrate stiffness, to regulate AYM and thereby reflect and/or control stem cell lineage specificity for downstream applications, remains a primary challenge during in vitro stem cell expansion. Moreover, substrate stiffness could modulate cell heterogeneity in the single-cell stage and contribute to cell fate regulation, yet the indicative link between AYM and cell fate determination during in vitro dynamic cell expansion (from single-cell stage to multi-cell stage) has not been established.

Results: Here, we show that the AYM of cells changed dynamically during passaging and proliferation on substrates with different stiffness. Moreover, the same change in substrate stiffness caused different patterns of AYM change in epithelial and mesenchymal cell types. Embryonic stem cells and their derived progenitor cells exhibited distinguishing AYM changes in response to different substrate stiffness that had significant effects on their maintenance of pluripotency and/or lineage-specific characteristics. On substrates that were too rigid or too soft, fluctuations in AYM occurred during cell passaging and proliferation that led to a loss in lineage specificity. On a substrate with 'optimal' stiffness (i.e., 3.5 kPa), the AYM was maintained at a constant level that was consistent with the parental cells during passaging and proliferation and led to preservation of lineage specificity. The effects of substrate stiffness on AYM and downstream cell fate were correlated with intracellular cytoskeletal organization and nuclear/cytoplasmic localization of YAP.

Conclusions: In summary, this study suggests that optimal substrate stiffness regulated consistent AYM during passaging and proliferation reflects and contributes to hESCs and their derived progenitor cells lineage specificity maintenance, through the underlying mechanistic pathways of stiffness-induced cytoskeletal organization and the downstream YAP signaling. These findings highlighted the potential of AYM as an indicator to select suitable substrate stiffness for stem cell specificity maintenance during in vitro expansion for regenerative applications.
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http://dx.doi.org/10.1186/s13619-020-00054-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467757PMC
September 2020

The integrative analysis of DNA methylation and mRNA expression profiles confirmed the role of selenocompound metabolism pathway in Kashin-Beck disease.

Cell Cycle 2020 09 20;19(18):2351-2366. Epub 2020 Aug 20.

Department of Joint Surgery, The Red Cross Hospital of Xi'an Jiaotong University , Xi'an, China.

Kashin-Beck disease (KBD) is an endemic chronic osteochondropathy. The etiology of KBD remains unknown. In this study, we conducted an integrative analysis of genome-wide DNA methylation and mRNA expression profiles between KBD and normal controls to identify novel candidate genes and pathways for KBD. Articular cartilage samples from 17 grade III KBD patients and 17 healthy controls were used in this study. DNA methylation profiling of knee cartilage and mRNA expression profile data were obtained from our previous studies. InCroMAP was performed to integrative analysis of genome-wide DNA methylation profiles and mRNA expression profiles. Gene ontology (GO) enrichment analysis was conducted by online DAVID 6.7. The quantitative real-time polymerase chain reaction (qPCR), Western blot, immunohistochemistry (IHC), and lentiviral vector transfection were used to validate one of the identified pathways. We identified 298 common genes (such as COL4A1, HOXA13, TNFAIP6 and TGFBI), 36 GO terms (including collagen function, skeletal system development, growth factor), and 32 KEGG pathways associated with KBD (including Selenocompound metabolism pathway, PI3K-Akt signaling pathway, and TGF-beta signaling pathway). Our results suggest the dysfunction of many genes and pathways implicated in the pathogenesis of KBD, most importantly, both the integrative analysis and study in KBD cartilage highlighted the importance of selenocompound metabolism pathway in the pathogenesis of KBD for the first time.
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http://dx.doi.org/10.1080/15384101.2020.1807665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513840PMC
September 2020

TGase-Enhanced Microtissue Assembly in 3D-Printed-Template-Scaffold (3D-MAPS) for Large Tissue Defect Reparation.

Adv Healthc Mater 2020 09 16;9(18):e2000531. Epub 2020 Aug 16.

Department of Biomedical Engineering, School of Medicine Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China.

Engineering large and functional tissue constructs with complex structures (e.g., external ear or nose) for reparation and reconstruction of tissue defects remains one of the major challenges in regenerative medicine, which demands abundant cell sources, advanced biofabrication schemes, and satisfactory integration with the host for long-term efficacy post implantation. Here the 'Microtissue Assembly in 3D-Printed-template-Scaffold' (3D-MAPS), as a platform technology to rapidly fabricate centimeter-sized functional tissue constructs with complex structures, is developed. 3D-MAPS facilitates bottom-up assembly of large-scale manufactured microtissues within the 3D-printed hollow polymeric templates with pre-defined architectures. The assembly and fusion of 2×10 mesenchymal stem cell-based microtissues within the defined 3D-printed template is further enhanced by addition of a natural protein crosslinker (i.e., transglutaminase (TGase)), and thereby achieves construction of centimeter-sized tissue with high cell viability and mechanical stability in vitro within 30 min. Further in vivo implantation of the 3D-MAPS-fabricated ear-like tissue construct in rabbit models assisted by flap prefabrication technique results in increased structural vascular support and strengthened functional survival. Thus, the TGase-enhanced 3D-MAPS demonstrates its potential and feasibility as a powerful biofabrication platform for tissue engineering application.
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http://dx.doi.org/10.1002/adhm.202000531DOI Listing
September 2020

TGase-mediated cell membrane modification and targeted cell delivery to inflammatory endothelium.

Biomaterials 2021 02 6;269:120276. Epub 2020 Aug 6.

Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China. Electronic address:

Targeted cell delivery to lesion sites via minimally invasive approach remains an unmet need in regenerative medicine to endow controlled cell distribution and minimized side-effects. Current cell modification approaches to improve cell delivery tend to have adverse effects on cellular phenotype and functionality. Here, we rationally developed a facile and mild cell modification and targeted delivery strategy leveraging endogenous tissue transglutaminase (TGase) expressed on the surface of MSCs (Mesenchymal Stem Cells) and inflammatory endothelial cells (ECs). Cell modification by functional peptides was accomplished simply via TGase catalyzed cross-linking with naturally-expressed MSCs membrane proteins (e.g. Annexin II), without detectable disturbance of cellular viability and functionality. The modified functional peptides could facilitate adhesion of MSCs to inflammatory ECs (with up-regulated TGase expression compared with normal ECs) in vitro, as demonstrated by a one-fold increase of the MSC-EC adhesion force measured by atomic force microscopy (AFM) and by targeted delivery of modified MSC to inflammatory ECs in a flow chamber assay. When transplanted in vivo, modified MSCs demonstrated a dramatic increase in targeted efficiency to inflammatory endothelium compared with non-modified MSCs in both mice ear inflammation and acute/chronic liver injury models. The cell membrane modification strategy and targeted cell delivery mechanism described here can be readily extended for empowering cell engineering and cell therapy with multifaceted functionalities to combat refractory diseases.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120276DOI Listing
February 2021

Engineering 3D functional tissue constructs using self-assembling cell-laden microniches.

Acta Biomater 2020 09 6;114:170-182. Epub 2020 Aug 6.

Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing 100044, China; Arthritis Institute, Peking University, Beijing 100044, China. Electronic address:

Tissue engineering using traditional size fixed scaffolds and injectable biomaterials are faced with many limitations due to the difficulties of producing macroscopic functional tissues. In this study, 3D functional tissue constructs were developed by inducing self-assembly of microniches, which were cell-laden gelatin microcryogels. During self-assembly, the accumulation of extracellular matrix (ECM) components was found to strengthen cell-cell and cell-ECM interactions, leading to the construction of a 'native' microenvironment that better preserved cell viability and functions. MSCs grown in self-assembled constructs showed increased maintenance of stemness, reduced senescence and improved paracrine activity compared with cells grown in individual microniches without self-assembly. As an example of applying the self-assembled constructs in tissue regeneration, the constructs were used to induce in vivo articular cartilage repair and successfully regenerated hyaline-like cartilage tissue in the absence of other extrinsic factors. This unique approach of developing self-assembled 3D functional constructs holds great promise for the generation of tissue engineered organoids and repair of challenging tissue defects. STATEMENT OF SIGNIFICANCE: We developed 3D functional tissue constructs using a unique gelatin-based microscopic hydrogel (microcryogels). Mesenchymal stem cells (MSCs) were loaded into gelatin microcryogels to form microscopic cell-laden units (microniches), which were induced to undergo self-assembly using a specially designed 3D printed frame. Extracellular matrix accumulation among the microniches resulted in self-assembled macroscopic constructs with superior ability to maintain the phenotypic characteristics and stemness of MSCs, together with the suppression of senescence and enhanced paracrine function. As an example of application in tissue regeneration, the self-assembled constructs were shown to successfully repair articular cartilage defects without any other supplements. This unique strategy for developing 3D functional tissue constructs allows the optimisation of stem cell functions and construction of biomimetic tissue organoids.
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http://dx.doi.org/10.1016/j.actbio.2020.07.058DOI Listing
September 2020

Establishment of a porcine parvovirus (PPV) LAMP visual rapid detection method.

J Virol Methods 2020 10 1;284:113924. Epub 2020 Jul 1.

Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, 2901 Beidi Road, Shanghai, 201106, People's Republic of China; Key Laboratory of Agricultural Genetics and Breeding, Shanghai Academy of Agricultural Sciences, 2901 Beidi Road, Shanghai, 201106, People's Republic of China. Electronic address:

Porcine parvovirus (PPV) is one of the major causes of reproductive pig disease. Due to its serious nature, wide spread and consequent great damage to the swine industry, an effective, rapid and convenient method for its detection is needed. A loop-mediated isothermal amplification (LAMP) assay was established to detect PPV infection. Two pairs of primers were specifically designed to recognize the six different sequences of open reading frame1 (ORF1) gene. The optimized LAMP program was as follows: 50 min at 59 °C followed by 3 min at 80 °C.The amplified products were analyzed both by visual inspection after staining with SYBR Green I dye and by conventional agarose gel electrophoresis. Both methods showed the same sensitivity. The limit of detection (LOD) for PPV by LAMP was 10 copies, which is 100-fold lower than conventional PCR. Our LAMP assay did not cross-react with other viruses. We used the established LAMP system to test 1100 field samples and detected 660 positives. The LAMP detection method for PPV represents a visual, sensitive and rapid assay which can detect the virus in the field, offering an attractive alternative for the PPV detection methods currently in use.
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http://dx.doi.org/10.1016/j.jviromet.2020.113924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328634PMC
October 2020

Intra-articular Injection of Cell-laden 3D Microcryogels Empower Low-dose Cell Therapy for Osteoarthritis in a Rat Model.

Cell Transplant 2020 Jan-Dec;29:963689720932142

Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China.

Intra-articular injection of mesenchymal stem cells (MSCs) in an osteoarthritic joint can help slow down cartilage destruction. However, cell survival and the efficiency of repair are generally low due to mechanical damage during injection and a high rate of cell loss. We, thus, investigated an improved strategy for cell delivery to an osteoarthritic joint through the use of three-dimensional (3D) microcryogels. MSCs were seeded into 3D microcryogels. The viability and proliferation of MSCs in microcryogels were determined over 5 d, and the phenotype of MSCs was confirmed through trilineage differentiation tests and flow cytometry. In Sprague Dawley rats with induced osteoarthritis (OA) of the knee joint, a single injection was made with the following groups: saline control, low-dose free MSCs (1 × 10 cells), high-dose free MSCs (1 × 10 cells), and microcryogels + MSCs (1 × 10 cells). Cartilage degeneration was evaluated by macroscopic examination, micro-computed tomographic analysis, and histology. MSCs grown in microcryogels exhibited optimal viability and proliferation at 3 d with stable maintenance of phenotype . Microcryogels seeded with MSCs were, therefore, primed for 3 d before being used for experiments. At 4 and 8 wk, the microcryogels + MSCs and high-dose free MSC groups had significantly higher International Cartilage Repair Society macroscopic scores, histological evidence of more proteoglycan deposition and less cartilage loss accompanied by a lower Mankin score, and minimal radiographic evidence of osteoarthritic changes in the joint compared to the other two groups. In conclusion, intra-articular injection of cell-laden 3D microcryogels containing a low dose of MSCs can achieve similar effects as a high dose of free MSCs for OA in a rat model. Primed MSCs in 3D microcryogels can be considered as an improved delivery strategy for cell therapy in treating OA that minimizes cell dose while retaining therapeutic efficacy.
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http://dx.doi.org/10.1177/0963689720932142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563831PMC
June 2021

Quantitative assessment of renal allograft pathologic changes: comparisons of mono-exponential and bi-exponential models using diffusion-weighted imaging.

Quant Imaging Med Surg 2020 Jun;10(6):1286-1297

Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China.

Background: Diffusion-weighted imaging (DWI) can noninvasively assess renal allograft pathologic changes that provide useful information for clinical management and prognostication. However, it is still unknown whether the bi-exponential model analysis of DWI signals is superior to that of the mono-exponential model.

Methods: Pathologic and DWI data from a total of 47 allografts were prospectively collected and analyzed. Kidney transplant interstitial fibrosis was quantified digitally. The severity of acute and chronic pathologic changes was semi-quantified by calculating the acute composite scores (ACS) and chronic composite score (CCS). Mono-exponential total apparent diffusion coefficient (ADCT), and the bi-exponential parameters of true diffusion (D) and perfusion fraction (fp) were acquired. The diagnostic performances of both mono-exponential and bi-exponential parameters were assessed and compared by calculating the area under the curve (AUC) from receiver-operating characteristic (ROC) curve analysis.

Results: ADCT, D, and fp were all significantly correlated with interstitial fibrosis, ACS, and CCS. Cortical fp discriminated mild from moderate and severe ACS with the largest AUC of 0.89 [95% confidence interval (CI), 0.77-0.96]. Noticeably, only cortical fp could differentiate severe ACS from mild-to-moderate ACS (P<0.001) with an AUC of 0.80 (95% CI, 0.65-0.90) and a sensitivity of 100% (95% CI, 66.4-100%). Strikingly, the joint use of D and fp in either the cortex or the medulla could achieve a sensitivity of 100% for identifying either mild or severe interstitial fibrosis. Meanwhile, the serial use of cortical D and cortical fp showed the largest specificity for identifying both mild [88.9% (95% CI, 70.8-97.6%)] and severe [84.4% (95% CI, 67.2-94.7%)] interstitial fibrosis. For identifying mild CCS, the AUC of medullary ADCT (0.90, 95% CI, 0.78-0.97) was similar to that of cortical D (0.81, 95% CI, 0.67-0.91) and fp (0.86, 95% CI, 0.73-0.94), but statistically larger than that of medullary D (P=0.005) and fp (P=0.01). Furthermore, the parallel use of cortical D and cortical fp could increase the sensitivity to 95.0% (95% CI, 75.1-99.9%), whereas serial use of medullary D and medullary fp could increase the specificity to 100% (95% CI, 87.2-100%). The AUCs for differentiating severe from mild and moderate CCS were statistically insignificant among all parameters in the cortex and medulla (P≥0.15).

Conclusions: Cortical fp was superior to the ADCT for identifying both mild and severe acute pathologic changes. Nevertheless, ADCT was equal to or better than single D or fp for evaluating chronic pathologic changes. Thus, both monoexponential and bi-exponential analysis of DWI images are complementary for evaluating kidney allograft pathologic changes, and the combined use of D and fp can increase the sensitivity and specificity for discriminating allograft pathologic changes severity.
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http://dx.doi.org/10.21037/qims-19-985aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276371PMC
June 2020

Comparison of Chondrocytes in Knee Osteoarthritis and Regulation by Scaffold Pore Size and Stiffness.

Tissue Eng Part A 2021 02 25;27(3-4):223-236. Epub 2020 Nov 25.

Arthritis Clinic and Research Center, Peking University People's Hospital, Peking University, Beijing, China.

In knee osteoarthritis (OA), there is more pronounced cartilage damage in the medial compartment ("lesion zone") than the lateral compartment ("remote zone"). This study fills a gap in the literature by conducting a systematic comparison of cartilage and chondrocyte characteristics from these two zones. It also investigates whether chondrocytes from the different zones respond distinctly to changes in the physical and mechanical microenvironment using three-dimensional porous scaffolds by changing stiffness and pore size. Cartilage was harvested from patients with end-stage varus knee OA. Cartilage from the lesion and remote zones were compared through histological and biomechanical assessments, and through proteomic and gene transcription analyses of chondrocytes. Gelatin scaffolds with varied pore sizes and stiffness were used to investigate microenvironmental regulation of chondrocytes from the two zones. Cartilage from the lesion and remote zones differed significantly ( < 0.05) in histological and biomechanical characteristics, as well as phenotype, protein, and gene expression of chondrocytes. Chondrocytes from both zones were sensitive to changes in the structural and mechanical properties of gelatin scaffolds. Of interest, although all chondrocytes better retained chondrocyte phenotype in stiffer scaffolds, those from the lesion and remote zones, respectively, preferred scaffolds with larger and smaller pores. Distinct variations exist in cartilage and chondrocyte characteristics in the lesion and remote zones of knee OA. Cells in these two zones respond differently to variations in the physical and mechanical microenvironment. Understanding and manipulating these differences will facilitate the development of more efficient and precise diagnostic and therapeutic approaches for knee OA.
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http://dx.doi.org/10.1089/ten.TEA.2020.0085DOI Listing
February 2021

Comparing GWAS and Brain Structure-Specific Gene Expression Profiles Identifies Psychiatric Disorder-Related Brain Structures at Different Developmental Stages.

Neurosci Bull 2020 09 30;36(9):1046-1050. Epub 2020 May 30.

Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.

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http://dx.doi.org/10.1007/s12264-020-00521-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475161PMC
September 2020

Matrix-transmitted paratensile signaling enables myofibroblast-fibroblast cross talk in fibrosis expansion.

Proc Natl Acad Sci U S A 2020 05 1;117(20):10832-10838. Epub 2020 May 1.

Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China;

While the concept of intercellular mechanical communication has been revealed, the mechanistic insights have been poorly evidenced in the context of myofibroblast-fibroblast interaction during fibrosis expansion. Here we report and systematically investigate the mechanical force-mediated myofibroblast-fibroblast cross talk via the fibrous matrix, which we termed paratensile signaling. Paratensile signaling enables instantaneous and long-range mechanotransduction via collagen fibers (less than 1 s over 70 μm) to activate a single fibroblast, which is intracellularly mediated by DDR2 and integrin signaling pathways in a calcium-dependent manner through the mechanosensitive Piezo1 ion channel. By correlating in vitro fibroblast foci growth models with mathematical modeling, we demonstrate that the single-cell-level spatiotemporal feature of paratensile signaling can be applied to elucidate the tissue-level fibrosis expansion and that blocking paratensile signaling can effectively attenuate the fibroblast to myofibroblast transition at the border of fibrotic and normal tissue. Our comprehensive investigation of paratensile signaling in fibrosis expansion broadens the understanding of cellular dynamics during fibrogenesis and inspires antifibrotic intervention strategies targeting paratensile signaling.
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http://dx.doi.org/10.1073/pnas.1910650117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245086PMC
May 2020

Adaptive Smoothness Constraint Ionospheric Tomography Algorithm.

Sensors (Basel) 2020 Apr 23;20(8). Epub 2020 Apr 23.

School of Geographical Sciences, Guangzhou University, Guangzhou 510006, China.

Ionospheric tomography reconstruction based on global navigation satellite system observations is usually an ill-posed problem. To resolve it, an adaptive smoothness constraint ionospheric tomography algorithm is proposed in this work. The new algorithm performs an adaptive adjustment for the constrained weight coefficients of the tomography system. The computational efficiency and the reconstructed quality of ionospheric imaging are improved by using the new algorithm. A numerical simulation experiment was conducted in order to validate the feasibility and superiority of the algorithm. The statistical results of the reconstructed errors and the comparisons of ionospheric profiles confirmed the superiority of the new algorithm. Finally, the new algorithm was successfully applied to reconstruct three-dimensional ionospheric images under geomagnetic quiet and geomagnetic disturbance conditions over Hunan province. The tomographic results are reasonable and consistent with the general behavior of the ionosphere. The positive and negative phase storm effects are found during geomagnetic storm occurrence.
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http://dx.doi.org/10.3390/s20082404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219507PMC
April 2020

A Heterotrimeric Dehydrogenase Complex Functions with 2 Distinct YcaO Proteins to Install 5 Azole Heterocycles into 35-Membered Sulfomycin Thiopeptides.

J Am Chem Soc 2020 05 24;142(18):8454-8463. Epub 2020 Apr 24.

State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.

Sulfomycins are sulfur-rich, ribosomally synthesized, and post-translationally modified peptides (RiPPs) that are characterized by a 35-membered macrocyclic ring system with a pyridine domain central to five azoles and additional dehydroamino acids. The pathway through which these large thiopeptide antibiotics are formed in remains elusive. Starting with the cloning of the biosynthetic gene cluster of sulfomycins, we here dissect a two-stage process in which an unusual dehydrogenase heterotrimer functions with two distinct YcaO proteins to install five azole heterocycles into the core peptide sequence of the precursor peptide. The first stage involves the activity of a typical cyclodehydratase complex composed of a didomain E1-YcaO protein and an F-protein partner to heterocyclize distant residues l-Cys2 and l-Thr9 and then the activity of the heterotrimeric dehydrogenase complex that converts the resulting azolines to azoles. In the second stage, this dehydrogenase complex associates with a discrete YcaO protein to form an atypical, four-component azole synthase complex, which is capable of sequentially converting residues l-Cys7, l-Thr5, and l-Ser12 to azoles in a distinct manner. During this process, an E1-like partner protein plays a critical role and functions through the two stages to mediate a variety of specific protein-protein interactions. This partner protein participates in the formation of the active dehydrogenase heterotrimer and the engagement of discrete YcaO activity to form the azole synthase heterotetramer. The findings in this study advance the understanding in the biosynthesis of different azole-containing RiPPs and set the stage for the discovery, engineering, and creation of new thiopeptides using genome mining and synthetic biology approaches.
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http://dx.doi.org/10.1021/jacs.0c02329DOI Listing
May 2020
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