Publications by authors named "Xiaolei Li"

217 Publications

HDAC inhibition potentiates anti-tumor activity of macrophages and enhances anti-PD-L1-mediated tumor suppression.

Oncogene 2021 Feb 9. Epub 2021 Feb 9.

The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, 215123, Jiangsu, China.

Despite the widespread use of the blockade of immune checkpoints, for a significant number of cancer patients, these therapies have proven ineffective, presumably due to the immunosuppressive nature of the tumor microenvironment (TME). Critical drivers of immune escape in the TME include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which not only mediate immune suppression, but also facilitate metastatic dissemination and impart resistance to immunotherapies. Thus, strategies that convert them into tumor fighters may offer great therapeutic potential. In this study, we evaluated whether pharmacologic modulation of macrophage phenotype by HDAC inhibitors (HDACi) could produce an anti-tumor effect. We demonstrated that low-dose HDACi trichostatin-A (TSA) markedly reshaped the tumor immune microenvironment by modulating the suppressive activity of infiltrating macrophages and inhibiting the recruitment of MDSCs in various tumors. These actions, in turn, augmented anti-tumor immune responses and further enhanced anti-tumor effects of immunotherapies. HDAC inhibition, however, also upregulated PD-L1, thereby limiting the beneficial therapeutic effects. Indeed, combining low-dose TSA with anti-PD-L1 in this model significantly enhanced the durability of tumor reduction and prolonged survival of tumor-bearing mice, compared with the effect of either treatment alone. These data introduce HDAC inhibition as a potential means to harness the anti-tumor potential of macrophages in cancer therapy.
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http://dx.doi.org/10.1038/s41388-020-01636-xDOI Listing
February 2021

Distributed Formation Maneuver Control of Multiagent Systems Over Directed Graphs.

IEEE Trans Cybern 2021 Feb 2;PP. Epub 2021 Feb 2.

To steer a team of multiple mobile agents to desired collective maneuvers so that the geometric pattern, translation, orientation, and scale of formation can be changed continuously, this article studies the formation maneuver control of single-integrator and double-integrator multiagent systems by a leader-follower strategy. Unlike most existing results requiring generic configurations or convex configurations, the proposed control algorithms can be applied to either nongeneric or nonconvex configurations. Distributed control algorithms are designed for the leaders and followers over directed graphs, respectively, where the formation's maneuver parameters, such as geometric pattern, translation, orientation, and scale of formation are decided by the first leader. It is worth noting that the closed-loop tracking errors converge to zero globally. Some numerical simulations are given to illustrate the theoretical results.
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http://dx.doi.org/10.1109/TCYB.2020.3044581DOI Listing
February 2021

Glabridin inhibits osteoarthritis development by protecting chondrocytes against oxidative stress, apoptosis and promoting mTOR mediated autophagy.

Life Sci 2021 Mar 5;268:118992. Epub 2021 Jan 5.

Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China. Electronic address:

Osteoarthritis (OA) is a common chronic degenerative disease that affects the elderly. Thus far, no pharmacological therapy approved by regulators has shown a convincing effect on OA. Glabridin, a small molecule, is a well-known and powerful natural antioxidant, which has a strong scavenging effect on free radicals. This study attempted to explore the role and underlying mechanisms of Glabridin on OA both in vitro and in vivo. In the in vitro study, Glabridin was found to increase the expression levels of extracellular matrix (ECM) related genes, Collagen II, Aggrecan (ACAN), SRY-box 9 (SOX9) and proteoglycan 4 (PRG4). Moreover, Glabridin was observed to significantly reduce the level of oxidative stress in OA chondrocytes while effectively reducing the apoptosis of chondrocytes. Glabridin was also found to significantly increase the autophagy of human OA chondrocytes. During the in vivo study, intraarticular injection of Glabridin was observed to alleviate OA progression and protect chondrocytes against apoptosis following anterior cruciate ligament transection (ACLT) in rats. Furthermore, the mammalian target of rapamycin (mTOR) mediated autophagy was identified as one of the potential mediators of Glabridin activity. Overall, Glabridin protects articular cartilage from damage in rats with OA by protecting chondrocytes against oxidative stress, apoptosis and promoting mTOR mediated autophagy.
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http://dx.doi.org/10.1016/j.lfs.2020.118992DOI Listing
March 2021

Adaptive Bearing-Only Formation Tracking Control for Nonholonomic Multiagent Systems.

IEEE Trans Cybern 2021 Jan 8;PP. Epub 2021 Jan 8.

In this article, we consider the formation tracking problem of nonholonomic multiagent systems only using relative bearing measurements between the agents. Such a practical and important yet challenging issue has been taken into limited consideration by existing approaches, which usually requires additional measurements such as relative positions. The contributions of this article are two-fold. First, a fully distributed reference velocity estimator is proposed. Under the proposed adaptive estimator, each agent can estimate the time-varying reference velocity asymptotically. Second, an input-to-state stable controller is designed according to the bearing rigid theory. Under the proposed controller, the formation with bearing-only constraints can be achieved. Finally, the proposed scheme is demonstrated and its effectiveness is verified by presenting some simulation and experimental tests.
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http://dx.doi.org/10.1109/TCYB.2020.3042491DOI Listing
January 2021

Wearable device for remote monitoring of transcutaneous tissue oxygenation.

Biomed Opt Express 2020 Dec 9;11(12):6989-7002. Epub 2020 Nov 9.

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

Wearable devices have found widespread applications in recent years as both medical devices as well as consumer electronics for sports and health tracking. A metric of health that is often overlooked in currently available technology is the direct measurement of molecular oxygen in living tissue, a key component in cellular energy production. Here, we report on the development of a wireless wearable prototype for transcutaneous oxygenation monitoring based on quantifying the oxygen-dependent phosphorescence of a metalloporphyrin embedded within a highly breathable oxygen sensing film. The device is completely self-contained, weighs under 30 grams, performs on-board signal analysis, and can communicate with computers or smartphones. The wearable measures tissue oxygenation at the skin surface by detecting the lifetime and intensity of phosphorescence, which undergoes quenching in the presence of oxygen. As well as being insensitive to motion artifacts, it offers robust and reliable measurements even in variable atmospheric conditions related to temperature and humidity. Preliminary testing in a porcine ischemia model shows that the wearable is highly sensitive to changes in tissue oxygenation in the physiological range upon inducing a decrease in limb perfusion.
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http://dx.doi.org/10.1364/BOE.408850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747925PMC
December 2020

The role of activating transcription factor 6 in hydroxycamptothecin-induced fibroblast autophagy and apoptosis.

J Orthop Surg Res 2021 Jan 4;16(1). Epub 2021 Jan 4.

Department of Orthopedics, Orthopedic Institute, Clinical Medical College of Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, People's Republic of China.

Background: The over-proliferation of fibroblasts is considered to be the main cause of scar adhesion after joint surgery. Hydroxycamptothecin (HCPT), though as a potent antineoplastic drug, shows preventive effects on scar adhesion. This study aimed to investigate the role of activating transcription factor 6 (ATF-6) in the HCPT-induced inhibition of fibroblast viability.

Methods: The cell counting kit-8 (CCK-8) assay, western blot analysis, lentivirus-mediated gene silencing, transmission electron microscopy (TEM) analysis, immunofluorescent staining for autophagy-related protein light chain 3 (LC3) were used to explore the effect of HCPT on triggering fibroblast apoptosis and inhibiting fibroblast proliferation, and the involvement of possible signaling pathways.

Results: It was found that HCPT exacerbated fibroblast apoptosis and repressed its proliferation. Subsequently, endoplasmic reticulum stress (ERS)-related proteins were determined by western blot prior to ATF6 p50 was screened out and reexamined after it was silenced. As a result, ATF6-mediated ERS played a role in HCPT-induced fibroblast apoptosis. Autophagy-related proteins and autophagosomes were detected after the HCPT administration using western blot and TEM analyses, respectively. Autophagy was activated after the HCPT treatment. With the co-treatment of autophagy inhibitor 3-methyladenine (3-MA), both the western blot analysis and the CCK-8 assay showed inhibited autophagy, which indicated that the effect of HCPT on fibroblast proliferation was partially reversed. Besides, the LC3 immunofluorescence staining revealed suppressed autophagy after silencing ATF6 p50.

Conclusion: Our results demonstrate that HCPT acts as a facilitator of fibroblast apoptosis and inhibitor of fibroblast proliferation for curbing the postoperative scar adhesion, in which the ATF6-mediated ERS pathway and autophagy are involved.
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http://dx.doi.org/10.1186/s13018-020-02056-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784342PMC
January 2021

Collagen and chondroitin sulfate functionalized bioinspired fibers for tendon tissue engineering application.

Int J Biol Macromol 2021 Feb 29;170:248-260. Epub 2020 Dec 29.

College of Chemistry, Chemical Engineering & Biotechnology, Donghua University, Shanghai 201620, China. Electronic address:

Functional tendon tissue engineering depends on harnessing the biochemical and biophysical cues of the native tendon extracellular matrix. In this study, we fabricated highly-aligned poly(L-lactic acid) (PLLA) fibers with surfaces decorated by two of the crucial tendon ECM components, type 1 collagen (COL1) and chondroitin sulfate (CS), through a coaxial stable jet electrospinning approach. Effects of the biomimetic COL1-CS (shell)/PLLA (core) fibers on the tenogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro were investigated. Higher rates of cell spreading and proliferation are observed on the aligned COL1-CS/PLLA fibers compared to that on the plain PLLA fibers. Expression of the tendon-associated genes scleraxis (SCX) and COL1 as well as protein tenomodulin (TNMD) are significantly increased. Introduction of mechanical stimulation gives rise to synergistic effect on tenogenic differentiation of hMSCs. Higher expression of TGF-β2, TGFβR-II, and Smad3 by the cells on the COL1-CS/PLLA fiber substrates are observed, which indicates that COL1-CS/PLLA ultrafine fibers dictate the hMSC tenogenic differentiation through activating the TGF-β signaling pathway. Animal study in rat Achilles tendon repair model corroborated the promoting role of COL1-CS/PLLA in regenerating a tendon-like tissue. Thus, our highly aligned biomimicking fibers may serve as an efficient scaffolding system for functional tendon regeneration.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.12.152DOI Listing
February 2021

Portable Oxygen-Sensing Device for the Improved Assessment of Compartment Syndrome and other Hypoxia-Related Conditions.

ACS Sens 2021 01 16;6(1):43-53. Epub 2020 Dec 16.

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.

Measurement of intramuscular oxygen could play a key role in the early diagnosis of acute compartment syndrome, a common condition occurring after severe trauma leading to ischemia and long-term consequences including rhabdomyolysis, limb loss, and death. However, to date, there is no existing oxygen sensor approved for such a purpose. To address the need to improve the assessment of compartment syndrome, a portable fiber-optic device for intramuscular oxygen measurements was developed. The device is based on phosphorescence quenching, where the tip of an optical fiber was coated with a poly(propyl methacrylate) (PPMA) matrix containing a brightly emitting Pt(II)-core porphyrin. The optoelectronic circuit is highly portable and is based on a microspectrometer and a microcontroller readout with a smartphone. Results from an tourniquet porcine model show that the sensor is sensitive across the physiological oxygen partial pressure range of 0-80 mmHg and exhibits an appropriate and reproducible response to changes in intramuscular oxygen. A commercial laboratory oxygen sensor based on a lifetime measurement did not respond as expected.
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http://dx.doi.org/10.1021/acssensors.0c01686DOI Listing
January 2021

Bmi1 drives the formation and development of intrahepatic cholangiocarcinoma independent of Ink4A/Arf repression.

Pharmacol Res 2021 Feb 8;164:105365. Epub 2020 Dec 8.

School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address:

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. Compared with HCC, for which several drugs have been approved, ICC is associated with shorter survival, and no drug has been approved for this type. Previously, we reported that Bmi1 drives HCC and is required for HCC development and growth. However, whether Bmi1 plays a critical role in ICC is not clear, although it reportedly is highly expressed in ICC. Therefore, we investigated its role in ICC. Here, we report that Bmi1 promotes ICC initiation and progression independent of the Ink4A/Arf pathway, a canonical downstream pathway of Bmi1. We found that Bmi1 is overexpressed in human ICC. Co-expression of Bmi1 and NRas induced ICC formation in mice. Knockdown or inactivation of Bmi1 inhibited ICC growth in vitro. Liver-specific knockout or inactivation of Bmi1 remarkably suppressed ICC tumor formation and development in vivo. Mechanistically, no correlation between Bmi1 and Ink4A/Arf levels was found in mouse and human ICC tissues. Together, our data indicate that Bmi1 functions as an oncogene independent of repression of the Ink4A/Arf locus in ICC and that it can serve as a target for ICC treatment.
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http://dx.doi.org/10.1016/j.phrs.2020.105365DOI Listing
February 2021

Topical application with conjugated linoleic acid ameliorates 2, 4-dinitrofluorobenzene-induced atopic dermatitis-like lesions in BALB/c mice.

Exp Dermatol 2021 Feb 6;30(2):237-248. Epub 2021 Jan 6.

School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.

Atopic dermatitis (AD) is a multifactorial chronic inflammatory skin disease characterized by skin barrier dysfunction, eczematous lesions, pruritus, and abnormal immune responses. In this study, we assessed the therapeutic effect of topical applied conjugated linoleic acid (CLA) on a murine AD model that was developed by repetitive applications of 2, 4-dinitrofluorobenzene (DNFB). 2% or 5% CLA could markedly ameliorate AD-like skin lesions, scratching behaviour and skin inflammation as evidenced by the reduced inflammatory blood cells, IgE and Th2-related cytokine levels, and the infiltration of mast cells and inflammatory cells to the dermal tissues. Moreover, topical application with CLA modulated skin barrier repair including maintaining a balanced skin pH and increasing skin hydration, partially mediated by upregulating skin barrier-related protein, filaggrin (FLG). In addition, topical CLA significantly dose-dependently inhibited pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, tumour necrosis factor (TNF)-α and pro-inflammatory enzyme expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in inflamed mice skin. Its anti-inflammatory effect was associated with the inhibition of DNFB-stimulated IκBα and NF-κB p65 phosphorylation in mouse skin. Taken together, our results suggest that locally applied CLA exerts potentially protective effects against AD lesional skin at least in part, due to regulation of skin barrier function and inflammatory response.
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http://dx.doi.org/10.1111/exd.14242DOI Listing
February 2021

RAD-Deficient Human Cardiomyocytes Develop Hypertrophic Cardiomyopathy Phenotypes Due to Calcium Dysregulation.

Front Cell Dev Biol 2020 22;8:585879. Epub 2020 Oct 22.

Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China.

Ras associated with diabetes (RAD) is a membrane protein that acts as a calcium channel regulator by interacting with cardiac L-type Ca channels (LTCC). RAD defects can disrupt intracellular calcium dynamics and lead to cardiac hypertrophy. However, due to the lack of reliable human disease models, the pathological mechanism of RAD deficiency leading to cardiac hypertrophy is not well understood. In this study, we created a H9 cell line using CRISPR/Cas9 technology. RAD disruption did not affect the ability and efficiency of cardiomyocytes differentiation. However, RAD deficient hESC-CMs recapitulate hypertrophic phenotype . Further studies have shown that elevated intracellular calcium level and abnormal calcium regulation are the core mechanisms by which RAD deficiency leads to cardiac hypertrophy. More importantly, management of calcium dysregulation has been found to be an effective way to prevent the development of cardiac hypertrophy .
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http://dx.doi.org/10.3389/fcell.2020.585879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642210PMC
October 2020

A Multilayer Ceramic Electrolyte for All-Solid-State Li Batteries.

Angew Chem Int Ed Engl 2021 Feb 16;60(7):3781-3790. Epub 2020 Dec 16.

Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, 100029, China.

Despite of the good stability with Li-metal, Li La Zr Ta O (LLZTO) suffers from large interfacial resistance and severe Li-metal penetration. Herein, a dual layer ceramic electrolyte of Ti-doped LLZTO(Ti-LLZTO)/LLZTO was developed, with the reducible Ti-LLZTO layer contacting Li-metal and the LLZTO layer contacting cathode. The identical crystal structures of Ti-LLZTO and LLZTO enables a seamless contact and a barrierless Li transport between them. The densities of Ti-LLZTO pellets are higher than that of LLZTO. With an in situ reduction of Ti-LLZTO by Li-metal, the interfacial wettability was improved and a mixed ion-electron conducting layer was created. Both features help to reduce defects/pores on interface and homogenize the interfacial ionic/electronic flux, facilitating the reduction of interfacial resistance and suppression of dendrites. With the help of Ti-LLZTO layer, long-term stable lithium plating/stripping was reached in an areal capacity of 3.0 mAh cm .
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http://dx.doi.org/10.1002/anie.202014265DOI Listing
February 2021

Multi-resolution estimation of the interference spectrum per pair of modes in the frequency domain.

J Acoust Soc Am 2020 Oct;148(4):EL340

Department of Marine Technology, Ocean University of China, Qingdao 266100,

A multi-resolution estimation method for interference spectrum separation from a one-dimensional broadband acoustic intensity is presented in this letter. The key of the proposed method is the recursion reconstruction and singular value decomposition of a 2×L Hankel matrix, which is constructed by a broadband intensity data sequence of length L + 1. Numerical simulation results show that this method can be used to achieve the zero-phase-shift estimation of each interference spectrum without any prior environmental information.
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http://dx.doi.org/10.1121/10.0002136DOI Listing
October 2020

Spermidine endows macrophages anti-inflammatory properties by inducing mitochondrial superoxide-dependent AMPK activation, Hif-1α upregulation and autophagy.

Free Radic Biol Med 2020 Dec 24;161:339-350. Epub 2020 Oct 24.

The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, Jiangsu, 215123, China. Electronic address:

Distinct metabolic programs, either energy-consuming anabolism or energy-generating catabolism, were required for different biological functions. Macrophages can adopt different immune phenotypes in response to various cues and exhibit anti- or pro-inflammatory properties relying on catabolic pathways associated with oxidative phosphorylation (OXPHOS) or glycolysis. Spermidine, a natural polyamine, has been reported to regulate inflammation through inducing anti-inflammatory (M2) macrophages. However, the underlying mechanisms remain elusive. We show here that the M2-polarization induced by spermidine is mediated by mitochondrial reactive oxygen species (mtROS). The levels of mitochondrial superoxide and HO were markedly elevated by spermidine. Mechanistically, mtROS were found to activate AMP-activated protein kinase (AMPK), which in turn enhanced mitochondrial function. Furthermore, hypoxia-inducible factor-1α (Hif-1α) was upregulated by the AMPK activation and mtROS and was required for the expression of anti-inflammatory genes and induction of autophagy. Consistent with previous report that autophagy is required for the M2 polarization, we found that the M2 polarization induced by spermidine was also mediated by increased autophagy. The macrophages treated with spermidine in vitro were found to ameliorate Dextran Sulfate Sodium (DSS)-induced inflammatory bowel disease (IBD) in mice. Thus, spermidine can elicit an anti-inflammatory program driven by mtROS-dependent AMPK activation, Hif-1α stabilization and autophagy induction in macrophages. Our studies revealed a critical role of mtROS in shaping macrophages into M2-like phenotype and provided novel information for management of inflammatory disease by spermidine.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.10.029DOI Listing
December 2020

Optimisation of double-enzymatic extraction of arabinoxylan from fresh corn fibre.

J Food Sci Technol 2020 Dec 13;57(12):4649-4659. Epub 2020 May 13.

Key Laboratory of Agroproducts Processing Technology at Jilin Provincial Universities, Education Department of Jilin Provincial Government, College of Food Science and Engineering, Changchun University, Changchun, 130022 Jilin People's Republic of China.

Enzymatic extraction of arabinoxylans (AXs) is an attractive and environmentally friendly extraction option, in which technical considerations (yield and purity) have been coupled with environmental concerns. Amano HC 90 and Cellulase were combined to evaluate their interactive effects on AX extraction from destarched, deproteinised bran (DSDPB). A response surface methodology was used to obtain the optimal extraction conditions. The experimental data fit well with the predicted values and the model adequately represented the actual relationship among the measured parameters. The extraction yield and AX content in the extract under optimal conditions (double-enzyme dose of 920 U/g, pH of 3.0, extraction temperature of 35.0 °C; extraction time of 6 h; and DSDPB to liquid ratio of 1:30) were 40.73 ± 0.09% and 75.88 ± 0.11%, respectively. The double-enzymatic extraction method of AX from fresh corn fibre was more efficient than the chemical method.
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http://dx.doi.org/10.1007/s13197-020-04502-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550493PMC
December 2020

Immune characteristics distinguish patients with severe disease associated with SARS-CoV-2.

Immunol Res 2020 12 28;68(6):398-404. Epub 2020 Sep 28.

Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.

This single-center, retrospective study aimed to explore the immune characteristics of COVID-19 and biomarkers to predict the severity of this disease. Patients infected with SARS-CoV-2 (n = 215) treated at the First Affiliated Hospital of Nanchang University from January 24 to March 12, 2020, were included in the study and classified into severe and non-severe groups. Peripheral immunocyte count and cytokine statuses were compared. The correlation between immune status, cytokine levels, and disease severity was analyzed. Leukocyte numbers were normal in both groups; however, they were relatively high (7.19 × 10/L) in patients of the severe group. Leukocyte distributions differed between the two groups; the severe group had a higher percentage of neutrophils and lower percentage of lymphocytes compared with the non-severe group, and absolute lymphocyte numbers were below normal in both groups, and particularly deficient in patients in the severe group. Lymphocyte counts have negative correlation with duration of hospital period whereas neutrophil count has no significant correlation with it. Of tested cytokines, IL-6 levels were significantly higher in the severe group (P = 0.0418). Low level of lymphocyte predicts severity of COVID-19. IL-6 levels were significantly higher in the severe group, especially in some extremely severe patients. But we did not detect the significant correlation between severity of COVID-19 with IL-6 level which may be due to limited case numbers. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of COVID-19.
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http://dx.doi.org/10.1007/s12026-020-09156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521864PMC
December 2020

Everolimus reduces postoperative arthrofibrosis in rabbits by inducing autophagy-mediated fibroblast apoptosis by PI3K/Akt/mTOR signaling pathway.

Biochem Biophys Res Commun 2020 Nov 9;533(1):1-8. Epub 2020 Sep 9.

Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, 210008, China. Electronic address:

Objective: To investigate the effects of everolimus (EVE) on postoperative fibrosis in the knee joint and the potentially relevant signaling pathways.

Methods: CCK-8 and flow cytometry assays were used to detect the effect of EVE on human fibroblast viability and apoptosis induction. IF and TEM were used to assess fibroblast autophagy. 3-methyladenine (3-MA) was applied to inhibit autophagy to clarify the relationship between autophagy and apoptosis. WB was used to measure the expression of proteins related to apoptosis, autophagy and the mTOR signaling pathway. A rabbit model of knee joint fibrosis was established and topically treated with various concentrations of EVE. IF-P was applied to identify that the main components cells of the fibrotic tissue and histomorphological staining was used to detect the degree of fibrosis and the content of collagen.

Results: Histomorphological staining demonstrated that EVE could reduce the degree of postoperative fibrosis and collagen deposition in the knee joint. The results of IF, TEM, flow cytometry assays and WB detection showed that EVE could activate autophagy and induce fibroblasts apoptosis. Meanwhile, the expression levels of p-PI3K, p-Akt, p-mTOR were downregulated with EVE treatment. After the inhibition of autophagy by 3-MA treatment, the increased fibroblasts apoptosis by EVE treatment was partially decreased.

Conclusion: Everolimus can reduce surgery-induced knee fibrosis by inducing autophagy-mediated fibroblast apoptosis, which may be involved with the regulation of the PI3K/Akt/mTOR signaling pathway.
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http://dx.doi.org/10.1016/j.bbrc.2020.08.039DOI Listing
November 2020

Incorporated Guanidinium Expands the CHNHPbI Lattice and Enhances Photovoltaic Performance.

ACS Appl Mater Interfaces 2020 Sep 15;12(39):43885-43891. Epub 2020 Sep 15.

Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.

Guanidinium (GA) has been widely used as an additive in solar cells for enhanced performance. However, the size of the guanidinium cation is too large to be incorporated in the cage of the perovskite structure. Instead, GA forms a variety of structures with lead iodide, where its role in the perovskite crystal as well as solar cell devices is unclear. In this study, we demonstrate that GA can be incorporated into the structure of MAPbI as (GA)(MA)PbI. From single-crystal X-ray crystallographic refinement, we observe lattice expansion and Pb-I bond elongation with GA incorporation similar to exerting "negative pressure", which weakens orbital overlap and widens the band gap from 1.49 to 1.53 eV. We find that the highest percentage of GA that can be incorporated into the 3D MAPbI structure is 5.26%, as confirmed by nuclear magnetic resonance. The alloyed (GA)(MA)PbI exhibits increased PL lifetimes from 154.4 to 266.3 ns after GA incorporation while the of (GA)(MA)PbI devices enlarges from 1.05 to 1.11 V. High efficiencies in solar cell devices up to 20.38% with a of 23.55 mA cm, of 1.11 V, and FF of 0.78 have been achieved, with stable photovoltaic performance for 900 h in air.
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http://dx.doi.org/10.1021/acsami.0c14925DOI Listing
September 2020

Adipose-derived mesenchymal stromal cells promote corneal wound healing by accelerating the clearance of neutrophils in cornea.

Cell Death Dis 2020 08 26;11(8):707. Epub 2020 Aug 26.

The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, Jiangsu, 215123, China.

The dome-shaped cornea is a transparent, non-vascularized, and epithelialized highly organized tissue. Physical and chemical injuries may trigger corneal wound healing (CWH) response and result in neovascularization that impairs the visual function. CWH involves not only migration, proliferation, and differentiation of the cells in different layers of cornea, but also the mobilization of immune cells. We demonstrated here that human adipose-derived mesenchymal stromal cells (ADSCs) could effectively inhibit neovascularization during ethanol-induced injury in mouse cornea. Importantly, we found that while neutrophils are essential for CWH, excessive and prolonged neutrophil retention during the granulation stage contributes to neovascularization. ADSCs were found to promote the clearance of neutrophils in the cornea during the granulation stage, likely via increasing the reverse transendothelial cell migration of CXCR4 neutrophils from cornea to the lung. Our results demonstrate that ADSCs are effective in treating CWH-induced neovascularization and modulation of neutrophil clearance could be novel strategies for better vision recovery after injury.
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http://dx.doi.org/10.1038/s41419-020-02914-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450061PMC
August 2020

DNA Dosimeter Measurement of Relative Biological Effectiveness for 160 kVp and 6 MV X Rays.

Radiat Res 2020 08;194(2):173-179

Departments of a Radiation Oncology.

In this work, we developed a DNA dosimeter, consisting of 4-kb DNA strands attached to magnetic streptavidin beads and labeled with fluorescein, to detect double-strand breaks (DSBs). The purpose here was to evaluate whether the DNA dosimeter readings reflect the relative biological effects of 160 kVp and 6 MV X rays. AVarian 600 C/D linac (6 MV) and a Faxitron cabinet X-ray system (160 kVp), both calibrated using traceable methods, were used to deliver high- and low-energy photons, respectively, to DNA dosimeters and multiple cell lines (mNs-5, HT-22 and Daoy). The responses were fit versus dose, and were used to quantify the dose of low-energy photons that produced the same response as that of the high-energy photons, at doses of 3, 6 and 9 Gy. The equivalent doses were utilized to calculate the relative biological effectiveness (RBEDSB and RBEcell survival). Additionally, a neutral comet assay was performed to measure the amount of intracellular DNA DSB, and ultimately the RBEcomet assay. The results of this work showed 160-kVp photon RBE values and 95% confidence intervals of 1.12 ± 0.04 (mNS-5), 1.16 ± 0.06 (HT-22), 1.25 ± 0.09 (Daoy) and 1.21 ± 0.24 (DNA dosimeter) at 9 Gy and 1.32 ± 0.16 (comet assay) at 3 Gy. Within the current error, the DNA dosimeter measured RBEDSB values in agreement with the RBEcell survival and assay from the cell survival and comet assay RBEcomet measurements. These results suggest that the DNA dosimeter can measure the changes in the radiobiological effects from different energy photons.
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http://dx.doi.org/10.1667/RR15500.1DOI Listing
August 2020

A novel fluorescent probe for the localization of nucleoli developed via a chain reaction of endogenous cysteine in cells.

J Mater Chem B 2020 09 11;8(34):7652-7658. Epub 2020 Aug 11.

College of Chemistry, Jilin University, Qianjin Street 2699, Changchun 130012, China.

Nucleolus imaging is important for the understanding of gene expression, proliferation, and growth of cells. Traditional nucleoli localization mainly relies on the use of RNA fluorescent probes which are required in large amounts. These probes also have low selectivity, thus causing the generated images to have high background noise and the localization of nucleoli to become vague. In the present paper, a novel probe for nucleoli localization, BEB-A, which can specifically bind to RNA via the chain reaction of endogenous cysteine (Cys), was designed and developed. In addition to its mitochondria-targeting ability, the BEB-A probe could be used in the imaging of Cys in the cytoplasm, and its product, BEB-OH, could quickly penetrate into the cell nucleus to combine with nucleolar RNA to generate strong red fluorescence signals. The luminescence property and RNA-binding capability of the probe were also investigated via theoretical calculations and molecular docking simulations. This work presents a tool that can be applied to analyze the variation of Cys in mitochondria and RNA in cells.
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http://dx.doi.org/10.1039/d0tb01366hDOI Listing
September 2020

Adaptive T cell immunotherapy in cancer.

Sci China Life Sci 2020 Jul 23. Epub 2020 Jul 23.

Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.

Impaired tumor-specific effector T cells contribute to tumor progression and unfavorable clinical outcomes. As a compensatory T cell-dependent cancer immunoediting strategy, adoptive T cell therapy (ACT) has achieved encouraging therapeutic results, and this strategy is now on the center stage of cancer treatment and research. ACT involves the ex vivo stimulation and expansion of tumor-infiltrating lymphocytes (TILs) with inherent tumor reactivity or T cells that have been genetically modified to express the cognate chimeric antigen receptor or T cell receptor (CAR/TCR), followed by the passive transfer of these cells into a lymphodepleted host. Primed T cells must provide highly efficient and long-lasting immune defense against transformed cells during ACT. Anin-depth understanding of the basic mechanisms of these living drugs can help us improve upon current strategies and design better next-generation T cell-based immunotherapies. From this perspective, we provide an overview of current developments in different ACT strategies, with a focus on frontier clinical trials that offer a proof of principle. Meanwhile, insights into the determinants of ACT are discussed, which will lead to more rational, potent and widespread applications in the future.
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http://dx.doi.org/10.1007/s11427-020-1713-9DOI Listing
July 2020

Macrophages inhibit adipogenic differentiation of adipose tissue derived mesenchymal stem/stromal cells by producing pro-inflammatory cytokines.

Cell Biosci 2020 20;10:88. Epub 2020 Jul 20.

The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Suzhou, 215123 Jiangsu China.

Background: Mesenchymal stem/stromal cells (MSCs) and macrophages are critical components in many tissue microenvironments, including that in adipose tissue. The close interaction between MSCs and macrophages modulates various adipose-related disease development. However, the effects of macrophages on the fate of MSCs remain largely elusive. We here studied the effect of macrophages on the adipogenic differentiation of MSCs.

Methods: Macrophages were obtained from THP-1 cells treated with phorbol-12-myristate-13-acetate (PMA). The induced matured macrophages were then induced to undergo classically activated macrophage (M1) or alternatively activated macrophage (M2) polarization with Iipopolysaccharide (LPS)/interferon (IFN)-γ and interleukin (IL)-4/IL-13, respectively. The supernatants derived from macrophages under different conditions were applied to cultured human adipose tissue-derived mesenchymal stem/stromal cells (hADSCs) undergoing adipogenic differentiation. Adipogenic differentiation was evaluated by examining Oil Red O staining of lipid droplets and the expression of adipogenesis-related genes with real-time quantitative polymerase chain reaction (Q-PCR) and western blot analysis.

Results: The adipogenic differentiation of hADSCs was impaired when treated with macrophage-derived supernatants, especially that from the M1-polarized macrophage (M1-sup). The inhibitory effect was found to be mediated by the inflammatory cytokines, mainly tumor necrosis factor-α (TNF-α) and IL-1β. Blocking TNF-α and IL-1β with neutralizing antibodies partially alleviated the inhibitory effect of M1-sup.

Conclusion: Macrophage-derived supernatants inhibited the adipogenic differentiation of hADSCs in vitro, irrespective of the polarization status (M0, M1 or M2 macrophages). M1-sup was more potent because of the higher expression of pro-inflammatory cytokines. Our findings shed new light on the interaction between hADSCs and macrophages and have implications in our understanding of disrupted adipose tissue homeostasis under inflammation.
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http://dx.doi.org/10.1186/s13578-020-00450-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372775PMC
July 2020

Erratum: "DNA double-strand breaks as a method of radiation measurements for therapeutic beams" [Med. Phys. Vol 45(7), 3460-3465 (2018)].

Med Phys 2020 06 21;47(6):2576. Epub 2020 Apr 21.

Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.

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http://dx.doi.org/10.1002/mp.14105DOI Listing
June 2020

Implication of a High Risk for Type 2 Vaccine-Derived Poliovirus Emergence and Transmission After the Switch From Trivalent to Bivalent Oral Poliovirus Vaccine.

J Infect Dis 2021 Jan;223(1):113-118

World Health Organization Western Pacific Regional Office Regional Reference Poliomyelitis Laboratory and NHC Key Laboratory of Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Background: China implemented the globally synchronized switch from trivalent oral poliovirus vaccine (tOPV) to bivalent OPV (bOPV) and introduced 1 dose of inactivated poliovirus vaccine on 1 May 2016. We assessed the impact of the switch on the immunity level against poliovirus, especially type 2.

Methods: Children born between 2014 and 2017, who were brought to the hospitals in Urumqi city, Xinjiang Province in 2017, were enrolled and blood samples were collected to test for antibody titers against poliovirus. A comparison of seroprevalence between the children born before (preswitch group) and after the switch (postswitch group) was performed to assess the impact of the switch on the immunity level against polio.

Results: A total of 172 subjects were enrolled. The overall seroprevalences were 98.8%, 79.1%, and 98.3% for types 1, 2, and 3, respectively. Seroprevalence for type 2 significantly decreased from 91.6% in the preswitch group to 67.4% in the postswitch group, but no statistically significant change was observed for both types 1 and 3.

Conclusions: The switch from tOPV to bOPV can provide high-level immunity against types 1 and 3 but not against type 2, indicating a high risk of type 2 vaccine-derived poliovirus emergence and transmission.
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http://dx.doi.org/10.1093/infdis/jiaa386DOI Listing
January 2021

Fluorometric detection of dopamine based on 3-aminophenylboronic acid-functionalized AgInZnS QDs and cells imaging.

Talanta 2020 Sep 25;217:121081. Epub 2020 Apr 25.

College of Chemistry, Jilin University, Qianjin Street 2699, Changchun, 130012, China. Electronic address:

Herein, cysteine capped AgInZnS QDs (Cys-AIZS QDs) with a large stoke shift and excellent biocompatibility were synthesized by a one-step aqueous method, followed by modified with 3-aminophenylboronic acid (APBA). Dopamine (DA) as an important neurotransmitter in brain can lead to significantly decrease in the fluorescence intensity of 3-aminophenylboronic acid-functionalized Cys-AIZS QDs (APBA-AIZS QDs) in a large concentration range of 1.5-900 μM. Good linearity can be obtained in the range of 15-120 μM, with a limit of detection (LOD) of 0.65 μM. Moreover, Cys-AIZS QDs and APBA-AIZS QDs were applied to living cells imaging, and Cys-AIZS QDs were applied to the co-localization with lysosomes, indicative of the feasibility of intracellular detection.
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http://dx.doi.org/10.1016/j.talanta.2020.121081DOI Listing
September 2020

Overexpression of laminin α4 facilitates proliferation and migration of fibroblasts in knee arthrofibrosis by targeting canonical Shh/Gli1 signaling.

Connect Tissue Res 2020 Jun 10:1-11. Epub 2020 Jun 10.

Department of Orthopedics, Orthopedic Institute, Northern Jiangsu People's Hospital Affiliated to Yangzhou University , Yangzhou, Jiangsu, China.

Aim: Pathologic hyperplasia of fibroblast is responsible for the progression of intraarticular fibrosis. Laminin α4 (LAMA4), a subunit of laminin macromolecule family, was found to be overexpressed in various fibrotic tissues. However, the role of LAMA4 in knee arthrofibrosis remains elusive. Therefore, the aim of this study was to investigate the effect and mechanism of LAMA4 on fibroblast proliferation and migration.

Materials And Methods: Following knee surgery, LAMA4 expression was detected in intraarticular fibrous tissues in rabbits at week 2 and week 4, respectively. In lentivirus-mediated LAMA4-overexpressed fibroblasts, cellular proliferation was assessed by EdU labeling and cell cycle analysis, cellular migration was evaluated using Transwell assay, and the expressions of key components in Shh/Gli1 signaling were detected by qRT-PCR, western blot and immunofluorescence analysis. Additionally, canonical Shh cascade was further blocked in LAMA4-overexpressed fibroblasts by cyclopamine, and the changes in cellular proliferation and migration were investigated.

Results: LAMA4 expression was positively correlated with the severity of knee arthrofibrosis. Functional studies demonstrated that LAMA4 overexpression facilitated proliferation, cell cycle progression and migration in fibroblasts. Mechanically, LAMA4 activated the canonical Shh/Gli1 signaling and promoted the nuclear translocation of Gli1 to upregulate expression of genes associated with cellular proliferation and migration. Intriguingly, blockage of Shh/Gli1 signaling with cyclopamine reversed the promoting effects of LAMA4 on proliferation and migration of fibroblasts.

Conclusions: LAMA4 positively regulated cellular proliferation and migration in fibroblasts via activating the Shh/Gli1 signaling. LAMA4/Shh/Gli1 signaling axis might be a potential therapeutic target for the prevention of surgery-induced intraarticular fibrosis.
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http://dx.doi.org/10.1080/03008207.2020.1773451DOI Listing
June 2020

Resilient Cooperative Control for Networked Lagrangian Systems Against DoS Attacks.

IEEE Trans Cybern 2020 May 14;PP. Epub 2020 May 14.

In this article, we study the distributed resilient cooperative control problem for directed networked Lagrangian systems under denial-of-service (DoS) attacks. The DoS attacks will block the communication channels between the agents. Compared with the existing methods for the linear networked systems, the considered nonlinear networked Lagrangian systems with asymmetric channels under DoS attacks are more challenging and still not well explored. In order to solve this problem, a novel resilient cooperative control scheme is proposed by using the sampling control approach. Sufficient conditions are first derived in the absence of DoS attacks according to a multidimensional small-gain scheme. Then, in the presence of DoS attacks, the proposed resilient scheme works in a switching manner. Inspired by multidimensional small-gain techniques, the Lyapunov approach is used to analyze the closed-loop system, which enables us to establish sufficient stability conditions for the control gains in terms of the duration and frequency of the DoS attacks.
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http://dx.doi.org/10.1109/TCYB.2020.2988883DOI Listing
May 2020

Training a U-Net based on a random mode-coupling matrix model to recover acoustic interference striations.

J Acoust Soc Am 2020 Apr;147(4):EL363

Department of Marine Technology, Ocean University of China, Qingdao, 266100, China.

A U-Net is trained to recover acoustic interference striations (AISs) from distorted ones. A random mode-coupling matrix model is introduced to generate a large number of training data quickly, which are used to train the U-Net. The performance of AIS recovery of the U-Net is tested in range-dependent waveguides with nonlinear internal waves (NLIWs). Although the random mode-coupling matrix model is not an accurate physical model, the test results show that the U-Net successfully recovers AISs under different signal-to-noise ratios and different amplitudes and widths of NLIWs for different shapes.
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http://dx.doi.org/10.1121/10.0001125DOI Listing
April 2020

A cold-active 1,4-α-glucan branching enzyme from Bifidobacterium longum reduces the retrogradation and enhances the slow digestibility of wheat starch.

Food Chem 2020 Sep 20;324:126855. Epub 2020 Apr 20.

Key Laboratory of Agro-products Processing Technology, Jilin Provincial Department of Education, Changchun University, 6543 Weixing Road, Changchun 130022, People's Republic of China; Key Laboratory of Human Health Status Identification and Function Enhancement, Jilin Provincial Department of Science and Technology, Changchun University, 6543 Weixing Road, Changchun 130022, People's Republic of China. Electronic address:

To develop a 1,4-α-glucan branching enzyme (BE) without homology to known allergens, the glgB gene from Bifidobacterium longum was overexpressed under the control of BLMA promoter in Escherichia coli. B. longum BE (BlBE) had a molecular weight of 86.1 kDa and a specific activity of more than 18.5U/mg protein at 25-35 °C and pH 5.5-7.0, and exhibited 30% of the maximum activity at 10 °C. The cold-active BlBE preferred to transfer maltohexaose and introduced DP 4-36 branches into amylose. BlBE also increased the proportion of DP 2-10 branches in amylopectin and decreased its Mw from 1.39 × 10 to 1.16 × 10 g/mol. As the BlBE concentration increased from 0.0 to 0.5U/mg substrate, the retrogradation enthalpy of BlBE-modified wheat starch decreased from 4.50 to 1.83 J/g (p < 0.05) at day 14 and the slowly digestible starch content increased from 2.10% to 17.39% (p < 0.05).
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http://dx.doi.org/10.1016/j.foodchem.2020.126855DOI Listing
September 2020