Publications by authors named "Ling Qin"

756 Publications

Axl is related to inflammation in hemodialysis patients.

Mol Immunol 2021 Mar 2;133:146-153. Epub 2021 Mar 2.

Department of Nephrology & Rheumatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301, Middle Yanchang Road, Shanghai, 200072, China. Electronic address:

Background: Hemodialysis (HD) patients often develop chronic inflammation, which is associated with an increased risk of cardiovascular complications and mortality. Axl and its ligand, growth arrest 6 (Gas6), have been reported to play key roles in regulating the immune response. However, the function of Axl in HD patients has not been clarified.

Methods: In the present study, we enrolled 130 HD patients and 117 normal controls (NCs) and evaluated the levels of inflammatory markers, soluble Axl (sAxl), membrane Axl (mAxl), and Gas6 in all participants. The potential downstream cascades of Gas6-Axl signaling in HD patients were identified by quantitative real time polymerase chain reaction and western blotting.

Results: The levels of inflammatory cytokines-tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-plasma sAxl, and Gas6, were significantly increased in HD patients compared to NCs. Additionally, sAxl was positively associated with the inflammatory factor, interleukin-6 (IL-6), in HD patients. Moreover, we found that mAxl in CD14 mononuclear cells and CD19 B cells was increased upon HD. Furthermore, we discovered that the metalloproteinase ADAM17, also called TACE, contributed to the cleavage of mAxl into sAxl, and not ADAM10, in the peripheral blood mononuclear cells (PBMCs) of HD patients. The upregulation of Gas6-mAxl signaling caused the activation of the STAT1-SOCS3 pathway in the PBMCs of HD patients. After two years follow-up, patients with lower sAxl levels had longer survival time than those with higher sAxl levels.

Conclusion: Our results suggest that Axl may play a significant role in systemic inflammation in HD patients.
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http://dx.doi.org/10.1016/j.molimm.2021.02.024DOI Listing
March 2021

Synergistic effects of magnesium ions and simvastatin on attenuation of high-fat diet-induced bone loss.

Bioact Mater 2021 Aug 3;6(8):2511-2522. Epub 2021 Feb 3.

Musculoskeletal Research Laboratory of Department of Orthopedics & Traumatology and Innovative Orthopaedic Biomaterial & Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Introduction: Magnesium (Mg) has a prophylactic potential against the onset of hyperlipidemia. Similar to statin, Mg is recommended as lipid-lowering medication for hypercholesterolemia and concomitantly exhibits an association with increased bone mass. The combination of statin with Mg ions (Mg) may be able to alleviate the high-fat diet (HFD)-induced bone loss and reduce the side-effects of statin. This study aimed to explore the feasibility of combined Mg with simvastatin (SIM) for treating HFD-induced bone loss in mice and the involving mechanisms.

Materials And Methods: C57BL/6 male mice were fed with a HFD or a normal-fat diet (NFD). Mice were intraperitoneally injected SIM and/or orally received water with additional Mg until sacrificed. Enzyme-linked immunosorbent assay was performed to measure cytokines and cholesterol in serum and liver lysates. Bone mineral density (BMD) and microarchitecture were assessed by micro-computed tomography (μCT) in different groups. The adipogenesis in palmitate pre-treated HepG2 cells was performed under various treatments.

Results: μCT analysis showed that the trabecular bone mass was significantly lower in the HFD-fed group than that in NFD-fed group since week 8. The cortical thickness in HFD-fed group had a significant decrease at week 24, as compared with NFD-fed group. The combination of Mg and SIM significantly attenuated the trabecular bone loss in HFD-fed mice via arresting the osteoclast formation and bone resorption. Besides, such combination also reduced the hepatocytic synthesis of cholesterol and inhibited () mRNA expression in pre-osteoclasts.

Conclusions: The combination of Mg and SIM shows a synergistic effect on attenuating the HFD-induced bone loss. Our current formulation may be a cost-effective alternative treatment to be indicated for obesity-related bone loss.
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http://dx.doi.org/10.1016/j.bioactmat.2021.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889436PMC
August 2021

FOXO1 expression in chondrocytes modulates cartilage production and removal in fracture healing.

Bone 2021 Mar 1:115905. Epub 2021 Mar 1.

Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Fracture healing is a multistage process characterized by inflammation, cartilage formation, bone deposition, and remodeling. Chondrocytes are important in producing cartilage that forms the initial anlagen for the hard callus needed to stabilize the fracture site. We examined the role of FOXO1 by selective ablation of FOXO1 in chondrocytes mediated by Col2α1 driven Cre recombinase. Experimental mice with lineage-specific FOXO1 deletion (Col2α1CreFOXO1) and negative control littermates (Col2α1CreFOXO1) were used for in vivo, closed fracture studies. Unexpectedly, we found that in the early phases of fracture healing, FOXO1 deletion significantly increased the amount of cartilage formed, whereas, in later periods, FOXO1 deletion led to a greater loss of cartilage. FOXO1 was functionally important as its deletion in chondrocytes led to diminished bone formation on day 22. Mechanistically, the early effects of FOXO1 deletion were linked to increased proliferation of chondrocytes through enhanced expression of cell cycle genes that promote proliferation and reduced expression of those that inhibit it and increased expression of cartilage matrix genes. At later time points experimental mice with FOXO1 deletion had greater loss of cartilage, enhanced formation of osteoclasts, increased IL-6 and reduced numbers of M2 macrophages. These results identify FOXO1 as a transcription factor that regulates chondrocyte behavior by limiting the early expansion of cartilage and preventing rapid cartilage loss at later phases.
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http://dx.doi.org/10.1016/j.bone.2021.115905DOI Listing
March 2021

Sputum mast cell/basophil gene expression relates to inflammatory and clinical features of severe asthma.

J Allergy Clin Immunol 2021 Feb 18. Epub 2021 Feb 18.

National Health and Medical Research Council Centre for Research Excellence in Severe Asthma; The Priority Research Centre for Health Lungs, The University of Newcastle, Newcastle, NSW; School of Medicine and Public Health, The University of Newcastle, NSW. Electronic address:

Background: Mast cells (MCs) and basophils are important in asthma pathophysiology, however direct measurement is difficult, and clinical and inflammatory associations in severe asthma are poorly understood. Transcriptomic hallmarks of MCs/basophils may allow their measurement in sputum using gene expression.

Objective: Develop and validate a sputum MC/basophil gene signature and investigate its relationship to inflammatory and clinical characteristics of severe asthma.

Methods: 134 candidate MC/basophil genes (identified by the Immunological Genome Project Consortium) were screened in sputum microarray for differential expression between controls (n=18), eosinophilic (n=29) and non-eosinophilic asthma (n=30). Candidate genes were validated by confirming correlation of gene expression with flow cytometry-quantified sputum MCs and basophils in a separate asthma cohort (n=20). The validated gene signature was measured in a severe asthma cohort (n=81), and inflammatory and clinical associations tested.

Results: Through microarray screening and subsequent validation, we found qPCR gene expression of 8 targets correlated with sputum MCs/basophils: TPSAB1/TPSB2, CPA3, ENO2, GATA2, KIT, GPR56, HDC, SOCS2. In severe asthma, MC/basophil genes were associated with eosinophilic airway inflammation (GATA2, TPSB2, CPA3, GPR56, HDC, SOCS2), blood eosinophils (TPSB2, CPA3, GATA2, SOCS2, FCER1A, HDC), FeNO (GATA2, SOCS2), decreased lung function (KIT, ENO2) and moderate exacerbation history (GATA2, SOCS2).

Conclusion: qPCR-based measures reflect varying sputum MC/basophil abundance, demonstrating associations of MCs/basophils with eosinophilic inflammation, spirometry and exacerbation history in severe asthma.
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http://dx.doi.org/10.1016/j.jaci.2021.01.033DOI Listing
February 2021

miR-139-5p promotes neovascularization in diabetic retinopathy by regulating the phosphatase and tensin homolog.

Arch Pharm Res 2021 Feb 20;44(2):205-218. Epub 2021 Feb 20.

Department of Endocrinology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, 266035, Shandong, People's Republic of China.

Pathological retinal neovascularization is a driver of the progression of diabetic retinopathy (DR). The present study sought to identify the microRNAs (miRNAs) that are differentially expressed during the progression of DR as well as to explore the specific regulatory mechanism of those miRNAs in retinal neovascularization. Using a microarray data set and a diabetic mouse model, it was determined that miR-139-5p was significantly upregulated during the progression of DR. The in vitro investigation revealed an elevation in the miR-139-5p level in both the high glucose (HG)-treated mouse retinal microvascular endothelial cells (mRMECs) and the HG-treated human RMECs (hRMECs). The miR-139-5p overexpression elevated cell migration, facilitated tube formation, and increased vascular endothelial growth factor (VEGF) protein level in the hRMECs. While the angiogenic effect of miR-139-5p overexpression was halted by an anti-VEGF antibody. Meanwhile, the miR-139-5p knockdown eliminated the VEGF-induced cell migration and tube formation in the hRMECs. The phosphatase and tensin homolog (PTEN) was the target gene of the miR-139-5p. PTEN overexpression removed the angiogenic effect of miR-139-5p overexpression, which led to reduced cell migration and tube formation. In the diabetic mice, the miR-139-5p antagomir effectively decreased the acellular capillaries and suppressed the formation of aberrant blood vessels in the retinal tissues. Taken together, miR-139-5p promotes retinal neovascularization by repressing PTEN expression.
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http://dx.doi.org/10.1007/s12272-021-01308-8DOI Listing
February 2021

Facile Fabrication of Flexible Pressure Sensor with Programmable Lattice Structure.

ACS Appl Mater Interfaces 2021 Mar 19;13(8):10388-10396. Epub 2021 Feb 19.

New Materials Institute, Department of Mechanical, Materials and Manufacturing Engineering, University of Nottingham Ningbo China, Ningbo 315100, China.

Flexible pressure sensors have attracted intense attention because of their widespread applications in electronic skin, human-machine interfaces, and healthcare monitoring. Conductive porous structures are always utilized as active layers to improve the sensor sensitivities. However, flexible pressure sensors derived from traditional foaming techniques have limited structure designability. Besides, random pore distribution causes difference in structure and signal repeatability between different samples even in one batch, therefore limiting the batch production capabilities. Herein, we introduce a structure designable lattice structure pressure sensor (LPS) produced by bottom-up digital light processing (DLP) 3D printing technique, which is capable of efficiently producing 55 high fidelity lattice structure models in 30 min. The LPS shows high sensitivity (1.02 kPa) with superior linearity over a wide pressure range (0.7 Pa to 160 kPa). By adjusting the design parameters such as lattice type and layer thickness, the electrical sensitivities and mechanical properties of LPS can be accurately controlled. In addition, the LPS endures up to 60000 compression cycles (at 10 kPa) without any obvious electrical signal degradation. This benefits from the firm carbon nanotubes (CNTs) coating derived from high-energy ultrasonic probe and the subsequent thermal curing process of UV-heat dual-curing photocurable resin. For practical applications, the LPS is used for real time pulse monitoring, voice recognition and Morse code communication. Furthermore, the LPS is also integrated to make a flexible 4 × 4 sensor arrays for detecting spatial pressure distribution and a flexible insole for foot pressure monitoring.
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http://dx.doi.org/10.1021/acsami.0c21407DOI Listing
March 2021

SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104;

Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific () and progenitor-specific ( and ) genes. Up-regulation of osteogenic genes (, , and ) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process.
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http://dx.doi.org/10.1073/pnas.2019152118DOI Listing
February 2021

Aberrant Auditory Steady-State Response of Awake Mice Induced by Chronic Interferon-α Treatment.

Front Pharmacol 2020 27;11:584425. Epub 2021 Jan 27.

Department of Physiology, China Medical Univeristy, Shenyang, China.

Patients receiving the cytokine immunotherapy of interferon-alpha (IFN-α) frequently present with depression. This is one of the excellent models to explore the action of peripheral cytokine on central nervous system (CNS) and to study the development of depression. The auditory steady-state response (ASSR), electroencephalogram (EEG) oscillations induced by periodic acoustic stimulation, is an effective approach to evaluate the neural function in mental illness including depression. The aim of the present study was to investigate the effect of IFN-α on the cortical ASSR and its correlation with depressive-like behavior. Chronic electrodes were implanted on the skull over the auditory cortex (AC) of male C57BL/6 mice. The animals were treated with daily injection of IFN-α or saline (vehicle) for three weeks. EEGs were recorded in AC of the same mouse before and after the injection treatment to monitor the changes of ASSR induced by IFN-α. Depressive-like behavior was analyzed in the forced swim test (FST). Immunohistochemical staining was used to examine the status of neuron and glia in the hippocampus and AC. Compared to pretreatment condition, injection of IFN-α significantly reduced the power of 40 Hz ASSR in the mouse AC from the second week. Such a decrease continued to the third week. The immobility times of FST were significantly increased by a 3-week treatment of IFN-α and the immobility time was negatively correlated with the power of 40 Hz ASSR. Astrocytes and microglia in the hippocampus and AC were activated by IFN-α, but the density of neuron was not significantly affected. Our results suggest that EEG measurement of ASSR may be used as a biomarker to monitor the CNS side effects of IFN-α treatment and to search a novel intervention with potential therapeutic implications.
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http://dx.doi.org/10.3389/fphar.2020.584425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873645PMC
January 2021

Overview of methods for enhancing bone regeneration in distraction osteogenesis: Potential roles of biometals.

J Orthop Translat 2021 Mar 2;27:110-118. Epub 2021 Feb 2.

Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong.

Background: Distraction osteogenesis (DO) is a functional tissue engineering approach that applies gradual mechanical traction on the bone tissues after osteotomy to stimulate bone regeneration. However, DO still has disadvantages that limit its clinical use, including long treatment duration.

Methods: Review the current methods of promoting bone formation and consolidation in DO with particular interest on biometal.

Results: Numerous approaches, including physical therapy, gene therapy, growth factor-based therapy, stem-cell-based therapy, and improved distraction devices, have been explored to reduce the DO treatment duration with some success. Nevertheless, no approach to date is widely accepted in clinical practice due to various reasons, such as high expense, short biologic half-life, and lack of effective delivery methods. Biometals, including calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), manganese (Mn), and cobalt (Co) have attracted attention in bone regeneration attributed to their biodegradability and bioactive components released during in vivo degradation.

Conclusion: This review summarizes the current therapies accelerating bone formation in DO and the beneficial role of biometals in bone regeneration, particularly focusing on the use of biometal Mg and its alloy in promoting bone formation in DO. Translational potential: The potential clinical applications using Mg-based devices to accelerate DO are promising. Mg stimulates expression of multiple intrinsic biological factors and the development of Mg as an implantable component in DO may be used to argument bone formation and consolidation in DO.
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http://dx.doi.org/10.1016/j.jot.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859169PMC
March 2021

Activin A promotes the development of acquired heterotopic ossification and is an effective target for disease attenuation in mice.

Sci Signal 2021 Feb 9;14(669). Epub 2021 Feb 9.

Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Heterotopic ossification (HO) is a common, potentially debilitating pathology that is instigated by inflammation caused by tissue damage or other insults, which is followed by chondrogenesis, osteogenesis, and extraskeletal bone accumulation. Current remedies are not very effective and have side effects, including the risk of triggering additional HO. The TGF-β family member activin A is produced by activated macrophages and other inflammatory cells and stimulates the intracellular effectors SMAD2 and SMAD3 (SMAD2/3). Because HO starts with inflammation and because SMAD2/3 activation is chondrogenic, we tested whether activin A stimulated HO development. Using mouse models of acquired intramuscular and subdermal HO, we found that blockage of endogenous activin A by a systemically administered neutralizing antibody reduced HO development and bone accumulation. Single-cell RNA-seq analysis and developmental trajectories showed that the antibody treatment reduced the recruitment of skeletal progenitors, many of which also expressed the gene encoding activin A (), to HO sites. Gain-of-function assays showed that activin A enhanced the chondrogenic differentiation of progenitor cells through SMAD2/3 signaling, and inclusion of activin A in HO-inducing implants enhanced HO development in vivo. Together, our data reveal that activin A is a critical upstream signaling stimulator of acquired HO in mice and could represent an effective therapeutic target against forms of this pathology in patients.
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http://dx.doi.org/10.1126/scisignal.abd0536DOI Listing
February 2021

Gli1 Defines a Subset of Fibro-adipogenic Progenitors that Promote Skeletal Muscle Regeneration With Less Fat Accumulation.

J Bone Miner Res 2021 Feb 2. Epub 2021 Feb 2.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Skeletal muscle has remarkable regenerative ability after injury. Mesenchymal fibro-adipogenic progenitors (FAPs) are necessary, active participants during this repair process, but the molecular signatures of these cells and their functional relevance remain largely unexplored. Here, using a lineage tracing mouse model (Gli1-CreER Tomato), we demonstrate that Gli1 marks a small subset of muscle-resident FAPs with elevated Hedgehog (Hh) signaling. Upon notexin muscle injury, these cells preferentially and rapidly expanded within FAPs. Ablation of Gli1+ cells using a DTA mouse model drastically reduced fibroblastic colony-forming unit (CFU-F) colonies generated by muscle cells and impaired muscle repair at 28 days. Pharmacologic manipulation revealed that Gli1+ FAPs rely on Hh signaling to increase the size of regenerating myofiber. Sorted Gli1+ FAPs displayed superior clonogenicity and reduced adipogenic differentiation ability in culture compared to sorted Gli1- FAPs. In a glycerol injury model, Gli1+ FAPs were less likely to give rise to muscle adipocytes compared to other FAPs. Further cell ablation and Hh activator/inhibitor treatments demonstrated their dual actions in enhancing myogenesis and reducing adipogenesis after injury. Examining single-cell RNA-sequencing dataset of FAPs from normal mice indicated that Gli1+ FAPs with increased Hh signaling provide trophic signals to myogenic cells while restrict their own adipogenic differentiation. Collectively, our findings identified a subpopulation of FAPs that play an essential role in skeletal muscle repair. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4265DOI Listing
February 2021

Tofacitinib Ameliorates Lipopolysaccharide-Induced Acute Kidney Injury by Blocking the JAK-STAT1/STAT3 Signaling Pathway.

Biomed Res Int 2021 13;2021:8877056. Epub 2021 Jan 13.

Department of Physiology, China Medical University, Liaoning 110122, China.

Septic acute kidney injury (AKI) is the most common AKI syndrome in the intensive care unit (ICU), and it accounts for approximately half of AKI cases. Tofacitinib (TOFA) is a pan-Janus kinase (JAK) inhibitor that exhibits potent anti-inflammatory activity in rheumatoid arthritis. However, no study has examined the functional role of TOFA in septic AKI. In the present study, we investigated the protective effects of TOFA on septic AKI and the underlying mechanisms. A lipopolysaccharide- (LPS-) induced AKI model was established in C57BL/6 mice via an intraperitoneal injection of LPS (10 mg/kg). One hour after LPS challenge, the mice were orally administered TOFA (5, 10, or 15 mg/kg) every 6 h until sacrifice at 24 h. We found that TOFA significantly ameliorated LPS-induced renal histopathological changes and dysfunction. TOFA also suppressed the expression levels of proinflammatory cytokines (TNF-, IL-1, IL-6, and IFN-) and the parameters of oxidative stress (MDA, GSH, SOD, and CAT) in kidney tissues. These results may be associated with the inhibitory effect of TOFA on the JAK-STAT1/STAT3 pathway, which was significantly activated by LPS challenge. TOFA treatment also inhibited LPS-induced activation of the TLR4/NF-B pathway. In conclusion, we revealed that TOFA had a protective effect on LPS-induced AKI, and it may be a promising therapeutic agent for septic AKI.
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http://dx.doi.org/10.1155/2021/8877056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822662PMC
January 2021

Elevated inflammatory gene expression in intervertebral disc tissues in mice with ADAM8 inactivated.

Sci Rep 2021 Jan 19;11(1):1804. Epub 2021 Jan 19.

Department of Orthopedics, University of Maryland, Baltimore, MD, USA.

We found ADAM8 enzymatic activity elevated in degenerative human intervertebral disc (IVD). Here, we examined the discs in ADAM8-inactivation mice that carry a mutation preventing self-activation of the enzyme. Surprisingly, elevated gene expression for inflammatory markers (Cxcl1, IL6) was observed in injured discs of ADAM8 mutant mice, along with elevated expression of type 2 collagen gene (Col2a1), compared with wild type controls. Injured annulus fibrosus of mutant and wild type mice contained a higher proportion of large collagen fibers compared with intact discs, as documented by microscopic examination under circular polarized light. In the intact IVDs, Adam8 mouse AF contained lower proportion of yellow (intermediate) fiber than WT mice. This suggests that ADAM8 may regulate inflammation and collagen fiber assembly. The seemingly contradictory findings of elevated inflammatory markers in mutant mice and excessive ADAM8 activity in human degenerative discs suggest that ADAM8 may interact with other enzymatic and pro-inflammatory processes needed for tissue maintenance and repair. As a future therapeutic intervention to retard intervertebral disc degeneration, partial inhibition of ADAM8 proteolysis may be more desirable than complete inactivation of this enzyme.
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http://dx.doi.org/10.1038/s41598-021-81495-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815795PMC
January 2021

High TRAF3IP3 Level Predicts Poor Prognosis of Patients with Gliomas.

World Neurosurg 2021 Jan 12. Epub 2021 Jan 12.

Department of Oncology, The First People's Hospital of Chenzhou, Xiangnan University, Chenzhou, China.

Background: Tumor necrosis factor receptor-related factor 3 (TRAF3) interacting protein 3 (TRAF3IP3) is involved in the development of immune tissues and the immune response of the body. Downregulated expression of TRAF3IP3 in malignant melanoma can inhibit tumor growth. The role of TRAF3IP3 in glioma is unknown.

Methods: We used the Wilcoxon rank sum test to compare the expression of TRAF3IP3 in glioma and normal tissues based on The Cancer Genome Atlas and Genotype Tissue Expression. Logistics regression was used to evaluate the relationship between TRAF3IP3 and clinicopathologic characters. Gene set enrichment analysis and single-sample gene set enrichment analysis were conducted to annotate biological function of TRAF3IP3. We used Kaplan-Meier and Cox regression to evaluate the prognostic value of TRAF3IP3.

Results: We downloaded RNA-seq data of 670 gliomas and 1157 normal tissues. TRAF3IP3 was highly expressed in gliomas (P < 0.001). High expression of TRAF3IP3 and higher World Health Organization grade (odds ratio [OR], 3.57 [2.42-5.34 CI]; P < 0.001), wild-type isocitrate dehydrogenase status (OR, 4.79 [3.40-6.83 CI]; P < 0.001), 1p/19q non-codeletion (OR, 15.32 [9.23-27.01 CI]; P < 0.001), mutant epidermal growth factor receptor status (OR, 2.77 [1.65-4.81 CI]; P < 0.001), worse histologic type (OR, 3.64 [2.48-5.43 CI]; P < 0.001) and worse primary therapy outcome (OR, 2.29 [1.47-3.61 CI]; P < 0.001) were significantly correlated. Six signaling pathways were significantly enriched in the TRAF3IP3 high-expression phenotype group, including JAK-STAT, interferon-γ, apoptosis, P53, programmed cell death protein 1, and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). High expression of TRAF3IP3 was associated with worse progression-free survival (hazard ratio [HR], 2.39 (1.39-3.01); P < 0.001), disease-free survival (HR, 3.02 (2.27-4.01); P < 0.001) and overall survival (HR, 2.87 (2.20-3.75); P < 0.001).

Conclusions: TRAF3IP3 play an important role in the occurrence and development of glioma and may be a potential biomarker for the prognosis of glioma.
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http://dx.doi.org/10.1016/j.wneu.2021.01.006DOI Listing
January 2021

Targeting cartilage EGFR pathway for osteoarthritis treatment.

Sci Transl Med 2021 Jan;13(576)

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor-α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.
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http://dx.doi.org/10.1126/scitranslmed.abb3946DOI Listing
January 2021

An impaired healing model of osteochondral defect in papain-induced arthritis.

J Orthop Translat 2021 Jan 22;26:101-110. Epub 2020 Sep 22.

Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.

Background: Osteochondral defects (OCD) are common in osteoarthritis (OA) and difficult to heal. Numerous tissue engineering approaches and novel biomaterials are developed to solve this challenging condition. Although most of the novel methods can successfully treat osteochondral defects in preclinical trials, their clinical application in OA patients is not satisfactory, due to a high spontaneous recovery rate of many preclinical animal models by ignoring the inflammatory environment. In this study, we developed a sustained osteochondral defect model in osteoarthritic rabbits and compared the cartilage and subchondral bone regeneration in normal and arthritic environments.

Methods: Rabbits were injected with papain (1.25%) in the right knee joints (OA group), and saline in the left knee joints (Non-OA group) at day 1 and day 3. One week later a cylindrical osteochondral defect of 3.2 mm in diameter and 3 mm depth was made in the femoral patellar groove. After 16 weeks, newly regenerated cartilage and bone inside the defect were evaluated by micro-CT, histomorphology and immunohistochemistry.

Results: One week after papain injection, extracellular matrix in the OA group demonstrated dramatically less safranin O staining intensity than in the non-OA group. Until 13 weeks of post-surgery, knee width remained significantly higher in the OA group than the non-OA control group. Sixteen weeks after surgery, the OA group had 11.3% lower International Cartilage Regeneration and Joint Preservation Society score and 32.5% lower O'Driscoll score than the non-OA group. There were less sulfated glycosaminoglycan and type II collagen but 74.1% more MMP-3 protein in the regenerated cartilage of the OA group compared with the non-OA group. As to the regenerated bone, bone volume fraction, trabecular thickness and trabecular number were all about 28% lower, while the bone mineral density was 26.7% higher in the OA group compared to the non-OA group. Dynamic histomorphometry parameters including percent labeled perimeter, mineral apposition rate and bone formation rate were lower in the OA group than in the non-OA group. Immunohistochemistry data showed that the OA group had 15.9% less type I collagen than the non-OA group.

Conclusion: The present study successfully established a non-self-healing osteochondral defect rabbit model in papain-induced OA, which was well simulating the clinical feature and pathology. In addition, we confirmed that both cartilage and subchondral bone regeneration were further impaired in arthritic environment.

The Translational Potential Of This Article: The present study provides an osteochondral defect in a small osteoarthritic model. This non-self-healing model and the evaluation protocol could be used to evaluate the efficacy and study the mechanism of newly developed biomaterials or tissue engineering methods preclinically; as methods tested in reliable preclinical models are expected to achieve improved success rate when tested clinically for treatment of OCD in OA patients.
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http://dx.doi.org/10.1016/j.jot.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773975PMC
January 2021

Biomaterials developed for facilitating healing outcome after anterior cruciate ligament reconstruction: Efficacy, surgical protocols, and assessments using preclinical animal models.

Biomaterials 2021 Feb 23;269:120625. Epub 2020 Dec 23.

Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Electronic address:

Anterior cruciate ligament (ACL) reconstruction is the recommended treatment for ACL tear in the American Academy of Orthopaedic Surgeons (AAOS) guideline. However, not a small number of cases failed because of the tunnel bone resorption, unsatisfactory bone-tendon integration, and graft degeneration. The biomaterials developed and designed for improving ACL reconstruction have been investigated for decades. According to the Food and Drug Administration (FDA) and the International Organization for Standardization (ISO) regulations, animal studies should be performed to prove the safety and bioeffect of materials before clinical trials. In this review, we first evaluated available biomaterials that can enhance the healing outcome after ACL reconstruction in animals and then discussed the animal models and assessments for testing applied materials. Furthermore, we identified the relevance and knowledge gaps between animal experimental studies and clinical expectations. Critical analyses and suggestions for future research were also provided to design the animal study connecting basic research and requirements for future clinical translation.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120625DOI Listing
February 2021

AChRs Degeneration at NMJ in Aging-Associated Sarcopenia-A Systematic Review.

Front Aging Neurosci 2020 10;12:597811. Epub 2020 Dec 10.

Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.

Sarcopenia is an aging process with a decline of skeletal muscle mass and function, which is a challenging public health problem with reduced quality of life in patients. The endplate, the post-synaptic part of the neuromuscular junction (NMJ), occupies 0.1% of the myofiber surface area only, but is composed of millions of acetylcholine receptors (AChRs) that are efficient in binding to acetylcholine (ACh) and triggering skeletal muscle contraction. This systematic review aims to examine aging-associated alterations of post-synaptic AChRs, including morphology, function and related gene expression. A systematic literature search was conducted in PubMed, Embase and Web of Science with relevant keywords by two independent reviewers. Original pre-clinical and clinical studies regarding AChRs changes during aging with available full text and written in English were included. Information was extracted from the included studies for further review. In total, 30 articles were included. Various parameters assessing AChRs alterations by radioassay, immunofluorescence, electrophysiology and mechanical test were reported. Endplate fragmentation and denervation were common in old skeletal muscles during aging. To ensure efficient NMJ transmission and force generation, type I or IIb muscle fibers tended to have increased ACh quanta releasing after electrical stimulations, while type IIa muscle fibers tended to have stronger binding between ACh and AChRs, but the overall function of AChRs was reduced during aging. Alterations of AChRs area depended on muscle type, species and the progress of muscle atrophy and type I muscles fibers tended to demonstrate enlarging AChRs areas. Myogenic regulator factors (MRFs) can regulate the expression of AChRs subunits, while decreased MRF4 may lead to expression changes of AChRs subunits during aging. Sarcoglycan-α can delay low-density lipoprotein receptor-related protein 4 (LRP4) degradation. This protein was increased in old muscles but still cannot suppress the degradation of LRP4. Investigating the role of these AChRs-related genes in the process of aging may provide a potential target to treat sarcopenia.
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http://dx.doi.org/10.3389/fnagi.2020.597811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759742PMC
December 2020

Determinants of estimated failure load in the distal radius after stroke: An HR-pQCT study.

Bone 2021 Mar 23;144:115831. Epub 2020 Dec 23.

Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong. Electronic address:

Bone health is often compromised after stroke and the distal radius is a common site of fragility fractures. The macro- and mircoproperties of bone tissue after stroke and their clinical correlates are understudied. The objectives of the study were to use High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) to investigate the bone properties at the distal radius, and to identify the correlates of estimated failure load for the distal radius in people with chronic stroke. This was a cross-sectional study of 64 people with stroke (age: 60.8 ± 7.7 years, stroke duration: 5.7 ± 3.9 years) and 64 age- and sex-matched controls. Bilateral bone structural, densitometric, geometric and strength parameters of the distal radius were measured using HR-pQCT. The architecture, stiffness and echo intensity of the bilateral biceps brachii muscle and brachial artery blood flow were evaluated using diagnostic ultrasound. Other outcomes included the Fugl-Meyer Motor Assessment (FMA), Motor Activity Log (MAL), and Composite Spasticity Scale (CSS). The results revealed a significant side (paretic vs non-paretic for the stroke group, non-dominant vs dominant for controls) by group (stroke vs control) interaction effect for estimated failure load, cortical area, cortical thickness, trabecular number and trabecular separation, and all volumetric density parameters. Post-hoc analysis showed percent side-to-side differences in bone outcomes were greater in the stroke group than the control group, with the exception of trabecular thickness and intracortical porosity. Among the HR-pQCT variables, percent side-to-side difference in trabecular volumetric bone mineral density contributed the most to the percent side-to-side difference in estimated failure load in the stroke group (R change = 0.334, β = 1.106). Stroke-related impairments (FMA, MAL, CSS) were found to be significant determinants of the percent side-to-side difference in estimated failure load (R change = 0.233, β = -0.480). This was the first study to examine bone microstructure post-stroke. We found that the paretic distal radius had compromised bone structural properties and lower estimated failure load compared to the non-paretic side. Motor impairment was a determinant of estimated bone strength at the distal radius and may be a potential intervention target for improving bone health post-stroke.
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http://dx.doi.org/10.1016/j.bone.2020.115831DOI Listing
March 2021

Association Between D-Dimer Level and In-Hospital Death of Pulmonary Embolism Patients.

Dose Response 2020 Oct-Dec;18(4):1559325820968430. Epub 2020 Dec 7.

Department of Cardiology, the First Hospital of Jilin University, Changchun, China.

To investigate whether D-dimer level could predict pulmonary embolism (PE) severity and in-hospital death, a total of 272 patients with PE were divided into a survival group (n = 249) and a death group (n = 23). Comparisons of patient characteristics between the 2 groups were performed using Mann-Whitney U test. Significant variables in univariate analysis were entered into multivariate logistic regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive value of D-dimer level alone or together with the simplified Pulmonary Embolism Severity Index (sPESI) for in-hospital death. Results showed that patients in the death group were significantly more likely to have hypotension (P = 0.008), tachycardia (P = 0.000), elevated D-dimer level (P = 0.003), and a higher sPESI (P = 0.002) than those in the survival group. Multivariable logistic regression analysis showed that D-dimer level was an independent predictor of in-hospital death (OR = 1.07; 95% CI, 1.003-1.143; P = 0.041). ROC curve analysis showed that when D-dimer level was 3.175 ng/ml, predicted death sensitivity and specificity were 0.913 and 0.357, respectively; and when combined with sPESI, specificity (0.838) and area under the curve (0.740) were increased. Thus, D-dimer level is associated with in-hospital death due to PE; and the combination with sPESI can improve the prediction level.
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http://dx.doi.org/10.1177/1559325820968430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724417PMC
December 2020

Neutrophilic asthma features increased airway classical monocytes.

Clin Exp Allergy 2021 Feb 1;51(2):305-317. Epub 2021 Jan 1.

Priority Research Centre for Healthy Lungs, The University of Newcastle, Newcastle, NSW, Australia.

Background: Monocytes and macrophages are critical innate immune cells of the airways. Despite their differing functions, few clinical studies discriminate between them and little is known about their regulation in asthma.

Objective: We aimed to distinguish and quantify macrophages, monocytes and monocyte subsets in induced sputum and blood and examine their relationship with inflammatory and clinical features of asthma.

Methods: We applied flow cytometry to distinguish macrophages, monocytes and subsets in sputum and blood (n = 53; 45 asthma, 8 non-asthma) and a second asthma sputum cohort (n = 26). Monocyte subsets were identified by surface CD14/CD16 (CD14 CD16 classical, CD14 CD16 intermediate and CD14 CD16 non-classical monocytes). Surface CD206, a marker of monocyte tissue differentiation, was measured in sputum. Relationship to airway inflammatory phenotype (neutrophilic n = 9, eosinophilic n = 14, paucigranulocytic n = 22) and asthma severity (severe n = 12, non-severe n = 33) was assessed.

Results: Flow cytometry- and microscope-quantified sputum differential cell proportions were significantly correlated. Sputum macrophage number was reduced (p = .036), while classical monocyte proportion was increased in asthma vs non-asthma (p = .032). Sputum classical monocyte number was significantly higher in neutrophilic vs paucigranulocytic asthma (p = .013). CD206 monocyte proportion and number were increased in neutrophilic vs eosinophilic asthma (p < .001, p = .013). Increased sputum classical and CD206 monocyte numbers in neutrophilic asthma were confirmed in the second cohort. Blood monocytes did not vary with airway inflammatory phenotype, but blood classical monocyte proportion and number were increased in severe vs non-severe asthma (p = .022, p = .011).

Conclusion And Clinical Relevance: Flow cytometry allowed distinction of sputum macrophages, monocytes and subsets, revealing compartment-specific dysregulation of monocytes in asthma. We observed an increase in classical and CD206 monocytes in sputum in neutrophilic asthma, suggesting co-recruitment of monocytes and neutrophils to the airways in asthma. Our data suggest further investigation of how airway monocyte dysregulation impacts on asthma-related disease activity is merited.
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http://dx.doi.org/10.1111/cea.13811DOI Listing
February 2021

The DNA methylation of FOXO3 and TP53 as a blood biomarker of late-onset asthma.

J Transl Med 2020 12 9;18(1):467. Epub 2020 Dec 9.

Department of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Background: Late-onset asthma (LOA) is beginning to account for an increasing proportion of asthma patients, which is often underdiagnosed in the elderly. Studies on the possible relations between aging-related genes and LOA contribute to the diagnosis and treatment of LOA. Forkhead Box O3 (FOXO3) and TP53 are two classic aging-related genes. DNA methylation varies greatly with age which may play an important role in the pathogenesis of LOA. We supposed that the differentially methylated sites of FOXO3 and TP53 associated with clinical phenotypes of LOA may be useful biomarkers for the early screening of LOA.

Methods: The mRNA expression and DNA methylation of FOXO3 and TP53 in peripheral blood of 43 LOA patients (15 mild LOA, 15 moderate LOA and 13 severe LOA) and 60 healthy controls (HCs) were determined. The association of methylated sites with age was assessed by Cox regression to control the potential confounders. Then, the correlation between differentially methylated sites (DMSs; p-value < 0.05) and clinical lung function in LOA patients was evaluated. Next, candidate DMSs combining with age were evaluated to predict LOA by receiver operating characteristic (ROC) analysis and principal components analysis (PCA). Finally, HDM-stressed asthma model was constructed, and DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AZA) were used to determine the regulation of DNA methylation on the expression of FOXO3 and TP53.

Results: Compared with HCs, the mRNA expression and DNA methylation of FOXO3 and TP53 vary significantly in LOA patients. Besides, 8 DMSs from LOA patients were identified. Two of the DMSs, chr6:108882977 (FOXO3) and chr17:7591672 (TP53), were associated with the severity of LOA. The combination of the two DMSs and age could predict LOA with high accuracy (AUC values = 0.924). In HDM-stressed asthma model, DNA demethylation increased the expression of FOXO3 and P53.

Conclusions: The mRNA expression of FOXO3 and TP53 varies significantly in peripheral blood of LOA patients, which may be due to the regulation of DNA methylation. FOXO3 and TP53 methylation is a suitable blood biomarker to predict LOA, which may be useful targets for the risk diagnosis and clinical management of LOA.
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http://dx.doi.org/10.1186/s12967-020-02643-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726856PMC
December 2020

Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment.

Respiration 2020;99(12):1109-1121. Epub 2020 Dec 3.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia.

Background: Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking.

Objective: To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population.

Methods: We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma (n = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations.

Results: Of 546 participants, 61.9% had no exacerbations (n = 338), 29.6% had few exacerbations (n = 162), and 8.4% were exacerbation prone (n = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all p < 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV1 (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers.

Conclusion: EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.
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http://dx.doi.org/10.1159/000510793DOI Listing
December 2020

Magnesium-pretreated periosteum for promoting bone-tendon healing after anterior cruciate ligament reconstruction.

Biomaterials 2021 Jan 25;268:120576. Epub 2020 Nov 25.

Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, PR China. Electronic address:

Periosteum can improve tendon-bone healing when applied to wrap the tendon graft in both animal studies and clinical trials. As magnesium (Mg) ions can significantly elevate the levels of relevant cytokines involving in the osteogenic differentiation of periosteum-derived stem cells, the Mg-pretreated periosteum may be an innovative approach for enveloping the tendon graft. To test this hypothesis, we compared the effects of Mg-pretreated periosteum (M - P) and the stainless steel (SS)-pretreated periosteum (SS-P) in ACL reconstruction. We firstly found that the released Mg ions from the Mg implants were partially accumulated in periosteum, resulting in higher Mg/Ca ratio in the M - P compared to the SS-P. Additionally, the M - P showed significantly higher expression levels of calcitonin gene-related peptide (CGRP) and periostin than the SS-P due to the decrease in Cathepsin K (CTSK). Elevation of CGRP and periostin was beneficial for the osteogenic differentiation of periosteum-derived stem cells. More importantly, we demonstrated that the M - P remarkably increased the formation of fibrocartilage at the interface between the periosteum and tendon. Collectively, M - P group demonstrated significantly prevented peri-tunnel bone loss, more osseous ingrowth into the tendon graft and higher maximum load to failure as compared to the SS-P group. In summary, our study warrants further investigations for translating the current proof-of-concept findings to optimize the delivery of CGRP, periostin, and cells as novel practical therapeutic strategy for enhancing tendon-bone interface healing in patients undergoing ACL reconstruction.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120576DOI Listing
January 2021

Variable beam entrance Faraday cup system for pulsed electron beam current profile characterization.

Rev Sci Instrum 2020 Nov;91(11):113303

State Key Laboratory of Mechanical System and Vibration, Mechanical Engineering Department, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.

A high accuracy variable beam entrance Faraday cup (VBEFC) system is designed in this work. The presented VBEFC system is designed for the beam current profile measurement of the transient hollow cathode discharge (THCD) generated pulsed electron beam, which is a new source of high energy flux for metallic material processing. By proper designs of the beam entrance array, fast response electron collector, grounding, and shielding, this VBEFC system is capable of determining the radial profile and its temporal evolution of the THCD generated electron beam. The results of the electron beam current and current density distributions collected at varying radial locations and times under multiple voltages are presented in this paper. The experimental results show that both the amplitude and the current density of the THCD electron beam at a given radius always increased with the increase in the accelerating voltage, which is coincident with the self-focused propagation of the electron beam promoted by the voltage.
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http://dx.doi.org/10.1063/5.0019301DOI Listing
November 2020

Combination of magnesium ions and vitamin C alleviates synovitis and osteophyte formation in osteoarthritis of mice.

Bioact Mater 2021 May 10;6(5):1341-1352. Epub 2020 Nov 10.

Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.

Introduction: We previously demonstrated that magnesium ions (Mg) was a novel therapeutic alternative for osteoarthritis (OA) through promoting the hypoxia inducible factor-1α (HIF-1α)-mediated cartilage matrix synthesis. However, oxidative stress can inhibit the expression of HIF-1α, amplify the inflammation that potentially impairs the therapeutic efficacy of Mg in OA. Vitamin (VC), a potent antioxidant, may enhance the efficacy of Mg in OA treatment. This study aims to investigate the efficacy of combination of Mg and VC on alleviating joint destruction and pain in OA.

Material And Methods: Anterior cruciate ligament transection with partial medial meniscectomy induced mice OA model were randomly received intra-articular injection of either saline, MgCl (0.5 mol/L), VC (3 mg/ml) or MgCl (0.5 mol/L) plus VC (3 mg/ml) at week 2 post-operation, twice weekly, for 2 weeks. Joint pain and pathological changes were assessed by gait analysis, histology, western blotting and micro-CT.

Results: Mg and VC showed additive effects to significantly alleviate the joint destruction and pain. The efficacy of this combined therapy could sustain for 3 months after the last injection. We demonstrated that VC enhanced the promotive effect of Mg on HIF-1α expression in cartilage. Additionally, combination of Mg and VC markedly promoted the M2 polarization of macrophages in synovium. Furthermore, combination of Mg and VC inhibited osteophyte formation and expressions of pain-related neuropeptides.

Conclusions: Intra-articular administration of Mg and VC additively alleviates joint destruction and pain in OA. Our current formulation may be a cost-effective alternative treatment for OA.
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http://dx.doi.org/10.1016/j.bioactmat.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658330PMC
May 2021

Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss.

J Clin Invest 2021 Jan;131(2)

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Bone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts. Alterations in this relationship can lead to pathologic bone loss such as osteoporosis. It is well known that osteogenic cells support osteoclastogenesis via production of RANKL. Interestingly, our recently identified bone marrow mesenchymal cell population-marrow adipogenic lineage precursors (MALPs) that form a multidimensional cell network in bone-was computationally demonstrated to be the most interactive with monocyte-macrophage lineage cells through high and specific expression of several osteoclast regulatory factors, including RANKL. Using an adipocyte-specific Adipoq-Cre to label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase in trabecular bone mass in long bones and vertebrae starting from 1 month of age, while their cortical bone appears normal. This phenotype was accompanied by diminished osteoclast number and attenuated bone formation at the trabecular bone surface. Reduced RANKL signaling in calvarial MALPs abolished osteolytic lesions after LPS injections. Furthermore, in ovariectomized mice, elevated bone resorption was partially attenuated by RANKL deficiency in MALPs. In summary, our studies identified MALPs as a critical player in controlling bone remodeling during normal bone metabolism and pathological bone loss in a RANKL-dependent fashion.
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http://dx.doi.org/10.1172/JCI140214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810488PMC
January 2021

Ssu72 Regulates Fungal Development, Aflatoxin Biosynthesis and Pathogenicity in .

Toxins (Basel) 2020 11 13;12(11). Epub 2020 Nov 13.

Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

The RNA polymerase II (Pol II) transcription process is coordinated by the reversible phosphorylation of its largest subunit-carboxy terminal domain (CTD). Ssu72 is identified as a CTD phosphatase with specificity for phosphorylation of Ser5 and Ser7 and plays critical roles in regulation of transcription cycle in eukaryotes. However, the biofunction of Ssu72 is still unknown in , which is a plant pathogenic fungus and produces one of the most toxic mycotoxins-aflatoxin. Here, we identified a putative phosphatase Ssu72 and investigated the function of Ssu72 in . Deletion of resulted in severe defects in vegetative growth, conidiation and sclerotia formation. Additionally, we found that phosphatase Ssu72 positively regulates aflatoxin production through regulating expression of aflatoxin biosynthesis cluster genes. Notably, seeds infection assays indicated that phosphatase Ssu72 is crucial for pathogenicity of . Furthermore, the Δ mutant exhibited more sensitivity to osmotic and oxidative stresses. Taken together, our study suggests that the putative phosphatase Ssu72 is involved in fungal development, aflatoxin production and pathogenicity in , and may provide a novel strategy to prevent the contamination of this pathogenic fungus.
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http://dx.doi.org/10.3390/toxins12110717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696088PMC
November 2020

Genome-Wide Gene Expression Profiles Analysis Reveal Novel Insights into Drought Stress in Foxtail Millet ( L.).

Int J Mol Sci 2020 Nov 12;21(22). Epub 2020 Nov 12.

Key Laboratory of Crop Epigenetic Regulation and Development in Hunan Province, College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.

Foxtail millet ( (L.) P. Beauv) is an important food and forage crop because of its health benefits and adaptation to drought stress; however, reports of transcriptomic analysis of genes responding to re-watering after drought stress in foxtail millet are rare. The present study evaluated physiological parameters, such as proline content, p5cs enzyme activity, anti-oxidation enzyme activities, and investigated gene expression patterns using RNA sequencing of the drought-tolerant foxtail millet variety (Jigu 16) treated with drought stress and rehydration. The results indicated that drought stress-responsive genes were related to many multiple metabolic processes, such as photosynthesis, signal transduction, phenylpropanoid biosynthesis, starch and sucrose metabolism, and osmotic adjustment. Furthermore, the Δ1-pyrroline-5-carboxylate synthetase genes, and , were remarkably upregulated in foxtail millet under drought stress conditions. Foxtail millet can also recover well on rehydration after drought stress through gene regulation. Our data demonstrate that recovery on rehydration primarily involves proline metabolism, sugar metabolism, hormone signal transduction, water transport, and detoxification, plus reversal of the expression direction of most drought-responsive genes. Our results provided a detailed description of the comparative transcriptome response of foxtail millet variety Jigu 16 under drought and rehydration environments. Furthermore, we identify as an important gene likely involved in the drought tolerance of foxtail millet.
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http://dx.doi.org/10.3390/ijms21228520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696101PMC
November 2020

The causal effect of interleukin-17 on the risk of psoriatic arthritis: a Mendelian randomization study.

Rheumatology (Oxford) 2020 Nov 14. Epub 2020 Nov 14.

Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Objective: To determine causal associations between genetically predicted TNF-α, IL-12p70 and IL-17 levels and risk of PsA.

Methods: The publicly available summary-level findings from genome-wide association studies (GWAS) was used to identify loci influencing normal physiological concentrations of TNF-α, IL-12p70 and IL-17 (n = 8293) among healthy individuals as exposure and a GWAS for PsA from the UK Biobank (PsA = 900, control = 462 033) as the outcome. A two-sample Mendelian randomization (MR) analysis was performed using the inverse-variance weighted (IVW), weighted median and MR-Egger regression methods. Sensitivity analysis and MR-Egger regression analysis were performed to evaluate the heterogeneity and pleiotropic effects of each variant.

Results: Single-nucleotide polymorphisms (SNPs) at genome-wide significance from GWASs on TNF-α, IL-12p70 and IL-17 were identified as the instrumental variables. The IVW method indicated a causal association between increased IL-17 level and risk of PsA (β = -0.00186 per allele, s.e. = 0.00043, P = 0.002). Results were consistent in the weighted median method (β = -0.00145 per allele, s.e. = 0.00059, P = 0.014) although the MR-Egger method suggested a non-significant association (β = -0.00133 per allele, s.e. = 0.00087; P = 0.087). Single SNP MR results revealed that the C allele of rs117556572 was robustly associated with risk of PsA (β = 0.00210, s.e. = 0.00069, P = 0.002). However, no evidence for a causal effect was observed between TNF-α, IL-12p70, decreased IL-17 levels and risk of PsA.

Conclusion: Our findings provide preliminary evidence that genetic variants predisposing to higher physiological IL-17 level are associated with decreased risk of PsA.
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http://dx.doi.org/10.1093/rheumatology/keaa629DOI Listing
November 2020