Publications by authors named "Tian Yu Zhang"

115 Publications

Effect of aging and sex on cardiovascular structure and function in wildtype mice assessed with echocardiography.

Sci Rep 2021 Nov 23;11(1):22800. Epub 2021 Nov 23.

Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

This study employed traditional and advanced echocardiographic techniques to assess comprehensively age- and sex-related changes in cardiovascular structure and function in wildtype (WT) mice. Forty-five normal adult wildtype mice were apportioned to groups based on age and sex: 2-month (young) male or female, and 24-month (old) male or female (n = 13, 13, 13, and 6, respectively). Each underwent 2-dimensional (2D) imaging echocardiography, Doppler, tissue Doppler imaging echocardiography, and speckle-tracking echocardiography (STE) for comparison of cardiovascular structure and function parameters. Compared to the young mice, the old had significantly higher body weight (BW), and lower diastolic and mean arterial pressure. The left ventricular (LV) end-diastolic and end-systolic volumes, and left ventricular mass, were significantly higher in the old mice. Within each sex, the cardiac diastolic and systolic function parameters were comparable between the young and old. Isovolumetric relaxation time (IVRT)/diastolic time interval (DT) and the maximum drop rate of pressure in LV (- dP/dtmax) were significantly lower in the old mice, while the LV relaxation time constant (Tau) was significantly higher. Spearman's rank correlation showed a positive association between IVRT/DT and - dp/dtmax (male r = 0.663; female r = 0.639). Among the males, the maximum rise rate of pressure in LV (+ dp/dtmax), and systolic global longitudinal strains and rates (S-GLS, S-GLSR) were significantly different between the young and old. Spearman's rank correlation showed positive association between S-GLS, S-GLSR and + dp/dtmax (r = 0.709 and r = 0.499). Regarding vascular structure, the ascending aorta systolic and diastolic diameters were significantly higher in the old mice compared with the young. The male mice had progressive, age-related aortic stiffness. Ageing in mice leads to changes in cardiovascular structure and cardiac diastolic function, but systolic function is relatively well preserved in females. Changes in cardiac function and arterial stiffness were more significant in males than females. Traditional ECG is better than STE for evaluating LV diastolic function; STE is better for LV systolic function.
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http://dx.doi.org/10.1038/s41598-021-02196-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611093PMC
November 2021

Superiority of Adipose-derived CD34 + Cells over Adipose-derived Stem Cells in Promoting Ischemic Tissue Survival.

Stem Cell Rev Rep 2021 Nov 17. Epub 2021 Nov 17.

Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizhaoju Road, Shanghai, People's Republic of China, 200011.

Background: Tissue ischemia usually leads to necrosis and is a threatening condition associated with reconstructive surgery. Promoting the survival of ischemic tissue is critical for improving clinical outcomes. Although various solutions based on stem cells have been reported, there are still limitations to clinical translation. The aim of this study was to develop an effective method to promote the survival of ischemic tissue.

Methods: Adipose-derived CD34 + and CD34- cells were obtained by magnetic bead sorting from the stromal vascular faction (SVF). Adipose-derived stem cells (ADSCs) were collected by subculture. The angiogenic capacities of CD34 + cells, CD34- cells and ADSCs were evaluated in vitro by comparing mRNA and protein expression. Random axial flaps in nude mice were used to evaluate the efficacy of these cells in protecting tissue from necrosis. The effect of these cells in preventing inflammation was also evaluated.

Results: Our data suggest that CD34 + cells expressed higher levels of angiogenetic factors and lower levels of inflammatory factors than the other cell types. More vessel branches were formed when human umbilical vein endothelial cells (HUVECs) were treated with conditioned medium from CD34 + cells than conditioned medium from the other cell types. Compared to ADSCs, CD34 + cells showed significantly higher efficacy in promoting tissue survival. More CD31 + cells and higher levels of angiogenic factors were observed in tissues from the CD34 + group than in those from the other groups. Lower levels of the proinflammatory factors TNF-α and IL-1b and higher levels of anti-inflammatory factors were found in the CD34 + group than in the other groups.

Conclusion: Adipose-derived CD34 + cells showed better efficacy in improving ischemic tissue survival than ADSCs by reducing tissue inflammation and promoting angiogenesis. CD34 + cells can be obtained easily and may be suitable for clinical applications.
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http://dx.doi.org/10.1007/s12015-021-10276-xDOI Listing
November 2021

Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening.

Acta Pharmacol Sin 2021 Oct 19. Epub 2021 Oct 19.

Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.

Decaprenylphosphoryl-β-D-ribose oxidase (DprE1) plays important roles in the biosynthesis of mycobacterium cell wall. DprE1 inhibitors have shown great potentials in the development of new regimens for tuberculosis (TB) treatment. In this study, an integrated molecular modeling strategy, which combined computational bioactivity fingerprints and structure-based virtual screening, was employed to identify potential DprE1 inhibitors. Two lead compounds (B2 and H3) that could inhibit DprE1 and thus kill Mycobacterium smegmatis in vitro were identified. Moreover, compound H3 showed potent inhibitory activity against Mycobacterium tuberculosis in vitro (MIC = 1.25 μM) and low cytotoxicity against mouse embryo fibroblast NIH-3T3 cells. Our research provided an effective strategy to discover novel anti-TB lead compounds.
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http://dx.doi.org/10.1038/s41401-021-00779-1DOI Listing
October 2021

Runjing extract promotes spermatogenesis in rats with ornidazole-induced oligoasthenoteratozoospermia through extracellular signal-regulated kinase signalling, and regulating vimentin expression.

J Tradit Chin Med 2021 Aug;41(4):581-587

Department of Andrology,The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.

Objective: To investigate the efficacy of Runjing (RJ) extract on oligoasthenoteratozoospermia (OAT) induced by ornidazole (ORN) in rats, and to study the underlying mechanism.

Methods: Twenty-four adult male Sprague-Dawley rats were treated with normal saline (control), ORN (OAT model), ORN + 4.725 g·kg-1·d-1 RJ extract (low-dose) and ORN+ 18.9 g·kg-1·d-1 RJ extract (high-dose) for 4 weeks. The rats were then euthanized and sperm and testis samples were collected for analysis. Sperm count, motility and morphology were calculated by sperm suspension from cauda epididymis. Testicular histopathological changes were analyzed by hematoxylin and eosin staining and TdT mediated dUTP nick end labelling. Moreover, the expression of vimentin and extracellular signal-regulated kinase (ERK) were examined through Western blot, and the distribution of vimentin was detected via immunohistochemistry.

Results: ORN successfully induces seminiferous epithelium injury, cellular apoptosis, and finally OAT (P < 0.05). However, both low-dose and highdose RJ extract partially rescues the phenotypes (P < 0.05). Moreover, the expressions of vimentin and ERK were significantly altered in ORN testes (all P < 0.001), while RJ extract partially reversed these effects (P < 0.01 or P < 0.001).

Conclusion: RJ extract can help maintain spermatogenesis through ERK signalling, and regulating vimentin expression.
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http://dx.doi.org/10.19852/j.cnki.jtcm.2021.03.010DOI Listing
August 2021

Integrated ionomic and transcriptomic dissection reveals the core transporter genes responsive to varying cadmium abundances in allotetraploid rapeseed.

BMC Plant Biol 2021 Aug 13;21(1):372. Epub 2021 Aug 13.

School of Agricultural Sciences, Zhengzhou University, Zhengzhou, 450001, China.

Background: Oilseed rape (B. napus L.) has great potential for phytoremediation of cadmium (Cd)-polluted soils due to its large plant biomass production and strong metal accumulation. Soil properties and the presence of other soluble compounds or ions, cause a heterogeneous distribution of Cd.

Results: The aim of our study was to reveal the differential responses of B. napus to different Cd abundances. Herein, we found that high Cd (50 μM) severely inhibited the growth of B. napus, which was not repressed by low Cd (0.50 μM) under hydroponic culture system. ICP-MS assays showed that the Cd concentrations in both shoots and roots under 50 μM Cd were over 10 times higher than those under 0.50 μM Cd. Under low Cd, the concentrations of only shoot Ca/Mn and root Mn were obviously changed (both reduced); under high Cd, the concentrations of most cations assayed were significantly altered in both shoots and roots except root Ca and Mg. High-throughput transcriptomic profiling revealed a total of 18,021 and 1408 differentially expressed genes under high Cd and low Cd conditions, respectively. The biological categories related to the biosynthesis of plant cell wall components and response to external stimulus were over-accumulated under low Cd, whereas the terms involving photosynthesis, nitrogen transport and response, and cellular metal ion homeostasis were highly enriched under high Cd. Differential expression of the transporters responsible for Cd uptake (NRAMPs), transport (IRTs and ZIPs), sequestration (HMAs, ABCs, and CAXs), and detoxification (MTPs, PCR, MTs, and PCSs), and some other essential nutrient transporters were investigated, and gene co-expression network analysis revealed the core members of these Cd transporters. Some Cd transporter genes, especially NRAMPs and IRTs, showed opposite responsive patterns between high Cd and low Cd conditions.

Conclusions: Our findings would enrich our understanding of the interaction between essential nutrients and Cd, and might also provide suitable gene resources and important implications for the genetic improvement of plant Cd accumulation and resistance through molecular engineering of these core genes under varying Cd abundances in soils.
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http://dx.doi.org/10.1186/s12870-021-03136-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362225PMC
August 2021

BDNF modulated KCC2 ubiquitylation in spinal cord dorsal horn of mice.

Eur J Pharmacol 2021 Sep 25;906:174205. Epub 2021 May 25.

Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China. Electronic address:

The K-Cl co-transporter 2 (KCC2) is a neuron-specific Cl extruder in the dorsal horn of spinal cord. The low intracellular Cl concentration established by KCC2 is critical for GABAergic and glycinergic systems to generate synaptic inhibition. Peripheral nerve lesions have been shown to cause KCC2 dysfunction in adult spinal cord through brain-derived neurotrophic factor (BDNF) signaling, which switches the hyperpolarizing inhibitory transmission to be depolarizing and excitatory. However, the mechanisms by which BDNF impairs KCC2 function remain to be elucidated. Here we found that BDNF treatment enhanced KCC2 ubiquitination in the dorsal horn of adult mice, a post-translational modification that leads to KCC2 degradation. Our data showed that spinal BDNF application promoted KCC2 interaction with Casitas B-lineage lymphoma b (Cbl-b), one of the E3 ubiquitin ligases that are involved in the spinal processing of nociceptive information. Knockdown of Cbl-b expression decreased KCC2 ubiquitination level and attenuated the pain hypersensitivity induced by BDNF. Spared nerve injury significantly increased KCC2 ubiquitination, which could be reversed by inhibition of TrkB receptor. Our data implicated that KCC2 was one of the important pain-related substrates of Cbl-b and that ubiquitin modification contributed to BDNF-induced KCC2 hypofunction in the spinal cord.
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http://dx.doi.org/10.1016/j.ejphar.2021.174205DOI Listing
September 2021

Multiomics reveal pivotal roles of sodium translocation and compartmentation in regulating salinity resistance in allotetraploid rapeseed.

J Exp Bot 2021 07;72(15):5687-5708

School of Agricultural Sciences, Zhengzhou University, Zhengzhou, China.

The large size and complexity of the allotetraploid rapeseed (Brassica napus) genome present huge challenges for understanding salinity resistance in this important crop. In this study, we identified two rapeseed genotypes with significantly different degrees of salinity resistance and examined the underlying mechanisms using an integrated analysis of phenomics, ionomics, genomics, and transcriptomics. Under salinity, a higher accumulation of osmoregulation substances and better root-system architecture was observed in the resistant genotype, H159, than in the sensitive one, L339. A lower shoot Na+ concentration and a higher root vacuolar Na+ concentration indicated lower root-to-shoot translocation and higher compartmentation in H159 than in L339. Whole-genome re-sequencing (WGRS) and transcriptome sequencing identified numerous DNA variants and differentially expressed genes involved in abiotic stress responses and ion transport. Combining ionomics with transcriptomics identified plasma membrane-localized BnaC2.HKT1;1 and tonoplast-localized BnaC5.NHX2 as the central factors regulating differential root xylem unloading and vacuolar sequestration of Na+ between the two genotypes. Identification of polymorphisms by WGRS and PCR revealed two polymorphic MYB-binding sites in the promoter regions that might determine the differential gene expression of BnaC2.HKT1;1 and BnaC5.NHX2. Our multiomics approach thus identified core transporters involved in Na+ translocation and compartmentation that regulate salinity resistance in rapeseed. Our results may provide elite gene resources for the improvement of salinity resistance in this crop, and our multiomics approach can be applied to other similar studies.
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http://dx.doi.org/10.1093/jxb/erab215DOI Listing
July 2021

Finite element simulation of cochlear traveling wave under air and bone conduction hearing.

Biomech Model Mechanobiol 2021 Aug 30;20(4):1251-1265. Epub 2021 Mar 30.

ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai, China.

Besides the normal hearing pathway known as air conduction (AC), sound can also transmit to the cochlea through the skull, known as bone conduction (BC). During BC stimulation, the cochlear walls demonstrate rigid body motion (RBM) and compressional motion (CPM), both inducing the basilar membrane traveling wave (TW). Despite numerous measuring and modeling efforts for the TW phenomenon, the mechanism remains unclear, especially in the case of BC. This paper proposes a 3D finite element cochlea model mimicking the TW under BC. The model uses a traditional "box model" form, but in a spiral shape, with two fluid chambers separated by the long and flexible BM. The cochlear fluid was enclosed by bony walls, the oval and round window membranes. Contingent boundary conditions and stimulations are introduced according to the physical basis of AC and BC. Particularly for BC, both RBM and CPM of the cochlea walls are simulated. Harmonic numerical solutions are obtained at multiple frequencies among the hearing range. The BM vibration amplitude ([Formula: see text]) and its relation with volume displacement difference between the oval and round windows [Formula: see text], as well as the pressure difference at the base of the cochlea ([Formula: see text]), are analyzed. The simulated BM response at 12 mm from the base is peaked at about 3 k Hz, which is consistent with published experimental data. The TW properties under AC and BC are the same and have a common mechanism. (1) [Formula: see text] is proportional to [Formula: see text] at low frequencies. (2) [Formula: see text] is also proportional to [Formula: see text], within 5 dB error at high frequencies such as 16 k Hz. This study partly reveals the common quantitative relations between the TW and related factors under AC and BC hearing.
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http://dx.doi.org/10.1007/s10237-021-01443-7DOI Listing
August 2021

Instant auditory benefit of an adhesive BCHD on children with bilateral congenital microtia.

Clin Otolaryngol 2021 09 21;46(5):1089-1094. Epub 2021 Apr 21.

ENT institute, Eye & ENT Hospital, Fudan University, Shanghai, China.

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http://dx.doi.org/10.1111/coa.13770DOI Listing
September 2021

Functional expression of glycine receptors in DRG neurons of mice.

Eur J Pharmacol 2021 May 13;899:174034. Epub 2021 Mar 13.

Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China. Electronic address:

Glycine receptor is one of the chloride-permeable ion channels composed of combinations of four α subunits and one β subunit. In adult spinal cord, the glycine receptor α1 subunit is crucial for the generation of inhibitory neurotransmission. The reduced glycinergic inhibition is regarded as one of the key spinal mechanisms underlying pathological pain symptoms. However, the expression and function of glycine receptors in the peripheral system are largely unknown as yet. Here we found that glycine receptor α1 subunit was prevalent in the dorsal root ganglia (DRG) neurons as well as in the sciatic nerves of adult mice. Intraganglionar or intraplantar injection of glycine receptor antagonist strychnine caused the hypersensitivity to mechanical, thermal and cold stimuli, suggesting the functional importance of peripheral glycine receptors in the control of nociceptive signal transmission. Our data showed that peripheral inflammation induced by formalin decreased the expression of glycine receptor α1 subunit on the plasma membrane of DRG neurons, which was attributed to the activation of protein kinase C signaling. Intraplantar application of glycine receptor agonist glycine or positive modulator divalent zinc ion alleviated the first-phase painful behaviors induced by formalin. These data suggested that peripheral glycine receptor might serve as an effective target for pain therapy.
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http://dx.doi.org/10.1016/j.ejphar.2021.174034DOI Listing
May 2021

Completely Event-Triggered Consensus for Multiagent Systems With Directed Switching Topologies.

IEEE Trans Cybern 2021 Feb 18;PP. Epub 2021 Feb 18.

This article studies the leader-following consensus of multiagent systems (MASs) with completely event-triggered mechanisms (CETMs) and directed switching topologies. When most event-triggered schemes in MASs only reduce each agent's data transmissions to neighbor agents, CETMs further reduce data transmissions to actuators with one triggered function in each agent. To guarantee the switching links utilized by CETMs contain a directed spanning tree at any time, triggered decisions are improved to include the instants at which each agent's output links or leader link change. Furthermore, a less conservative method based on matrix inequalities is combined to minimize the allowable average dwell time (ADT) of switching topologies under the design conditions of CETMs. Based on multiple Lyapunov functions (MLFs), the sufficient conditions for controller gains that guarantee the leader-following consensus of MASs are proposed when the ADT of switching topologies is larger than the allowable value. Finally, an example of autonomous underwater vehicles (AUVs) is given to illustrate the effectiveness of CETMs.
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http://dx.doi.org/10.1109/TCYB.2021.3052988DOI Listing
February 2021

Prevalence of Lumbar Spondylolisthesis in Middle-Aged People in Beijing Community.

Orthop Surg 2021 Feb 12;13(1):202-206. Epub 2021 Jan 12.

Fourth Clinical Medical College of Peking University, Beijing Jishuitan Hospital, Beijing, China.

Objective: Lumbar spondylolisthesis (LS) is a common lumbar disease, and the prevalence of LS in different countries or regions was not consistent in the past. This study intends to make statistics on the prevalence of lumbar spondylolisthesis in middle-aged people in Beijing community.

Methods: This is an epidemiological study. 4548 people in Beijing community aged 50 to 64 years were recruited from the local communities by advertisements placed in housing estates and community centres for people to take part in a prospective cohort study from August from September 2013 to March 2014. There is no intervention on the subjects. RadiAnt DICOM Viewer is adopted to read the lateral CT positioning images of all the studied objects, adjust the image as bone window, observe and evaluate the slide of L1 to L5 vertebra in the lateral CT positioning image.

Results: Among the 4,548 subjects included in the study, 2,490 (54.75%) were male and 2,058 (45.25%) were female. A total of 785 subjects had lumbar spondylolisthesis, with a total incidence of 17.26%. There was no significant difference between prevalence of males and females in the subgroup 50-54 years old (13.55% males / 12.53% females) and 55-59 years old (14.77% males / 14.93% females). But the prevalence of LS in 60-64 years old females (28.57%) increased significantly, compared with 55-59 years old females (14.93%) and 60-64 years old males (18.76%). There were 847 levels that had slipped, L5S1 > L4/5 > L3/4 > L2/3 > L1/2. The retrolisthesis was the most, accounting for 61.51% (521/847), and the anterolisthesis was 38.49% (326/847), including anterolisthesis gradeI for 95.71% (312/326), anterolisthesis gradeII for 4.29% (14/326). Neither of anterolisthesis and retrolisthesis presented more than grade III. Among all the subjects, 318 had anterolisthesis, with a total incidence of 6.99%, and 467 subjects only had retrolisthesis.

Conclusion: The total prevalence of LS in the middle-aged people in Beijing community was 17.26%, 15.98% in males and 18.80% in females, and women are more likely to suffer from LS after 60 years old.
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http://dx.doi.org/10.1111/os.12871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862163PMC
February 2021

Risk factors for cement leakage and nomogram for predicting the intradiscal cement leakage after the vertebra augmented surgery.

BMC Musculoskelet Disord 2020 Nov 30;21(1):792. Epub 2020 Nov 30.

Department of Traumatic Orthopaedics, Peking University People's Hospital, No.11 South Avenue, Xi Zhi Men, Xicheng District, Beijing, 100044, China.

Background: Vertebral augmentation is the first-line treatment for the osteoporosis vertebral compression fractures. Bone cement leakage is the most common complication of this surgery. This study aims to assess the risk factors for different types of cement leakage and provides a nomogram for predicting the cement intradiscal leakage.

Methods: We retrospectively reviewed 268 patients who underwent vertebral augmentation procedure between January 2015 and March 2019. The cement leakage risk factors were evaluated by univariate analysis. Different types of cement leakage risk factors were identified by the stepwise logistic analysis. We provided a nomogram for predicting the cement intradiscal leakage and used the concordance index to assess the prediction ability.

Results: A total of 295 levels of vertebrae were included, with a leakage rate of 32.5%. Univariate analysis showed delayed surgery and lower vertebral compression ratio were the independent risk factors of cement leakage. The stepwise logistic analysis revealed percutaneous vertebroplasty was a risk factor in vein cement leakage; delayed surgery, preoperative compression ratio, and upper endplate disruption were in intradiscal cement leakage; age, preoperative fracture severity, and intravertebral vacuum cleft were in perivertebral soft tissue cement leakage; no factor was in spinal canal cement leakage. The nomogram for intradiscal cement leakage had a precise prediction ability with an original concordance index of 0.75.

Conclusions: Delayed surgery and more vertebral compression increase the risk of cement leakage. Different types of cement leakage have different risk factors. We provided a nomogram for precise predicting the intradiscal cement leakage.
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http://dx.doi.org/10.1186/s12891-020-03810-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702672PMC
November 2020

The combination of trehalose and glycerol: an effective and non-toxic recipe for cryopreservation of human adipose-derived stem cells.

Stem Cell Res Ther 2020 10 31;11(1):460. Epub 2020 Oct 31.

Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizhaoju Road, Shanghai, 200011, People's Republic of China.

Background: Adipose-derived stem cells (ADSCs) promote tissue regeneration and repair. Cryoprotective agents (CPAs) protect cells from cryodamage during cryopreservation. Safe and efficient cryopreservation of ADSCs is critical for cell-based therapy in clinical applications. However, most CPAs are used at toxic concentrations, limiting their clinical application.

Objective: The aim of this study is to develop a non-toxic xeno-free novel CPA aiming at achieving high-efficiency and low-risk ADSC cryopreservation.

Methods: We explored different concentrations of trehalose (0.3 M, 0.6 M, 1.0 M, and 1.25 M) and glycerol (10%, 20%, and 30% v/v) for optimization and evaluated and compared the outcomes of ADSCs cryopreservation between a combination of trehalose and glycerol and the commonly used CPA DMSO (10%) + FBS (90%). All samples were slowly frozen and stored in liquid nitrogen for 30 days. The effectiveness was evaluated by the viability, proliferation, migration, and multi-potential differentiation of the ADSCs after thawing.

Results: Compared with the groups treated with individual reagents, the 1.0 M trehalose (Tre) + 20% glycerol (Gly) group showed significantly higher efficiency in preserving ADSC activities after thawing, with better outcomes in both cell viability and proliferation capacity. Compared with the 10% DMSO + 90% FBS treatment, the ADSCs preserved in 1.0 M Tre + 20% Gly showed similar cell viability, surface markers, and multi-potential differentiation but a significantly higher migration capability. The results indicated that cell function preservation can be improved by 1.0 M Tre + 20% Gly.

Conclusions: The 1.0 M Tre + 20% Gly treatment preserved ADSCs with a higher migration capability than 10% DMSO + 90% FBS and with viability higher than that with trehalose or glycerol alone but similar to that with 10% DMSO + 90% FBS and fresh cells. Moreover, the new CPA achieves stemness and multi-potential differentiation similar to those in fresh cells. Our results demonstrate that 1.0 M Tre + 20% Gly can more efficiently cryopreserve ADSCs and is a non-toxic CPA that may be suitable for clinical applications.
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http://dx.doi.org/10.1186/s13287-020-01969-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602354PMC
October 2020

Scutellarein alleviates the dysfunction of inner blood-retinal-barrier initiated by hyperglycemia-stimulated microglia cells.

Int J Ophthalmol 2020 18;13(10):1538-1545. Epub 2020 Oct 18.

The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Aim: To investigate the alleviation of scutellarein (SN) against inner blood-retinal-barrier (iBRB) dysfunction in microglia cells stimulated by hyperglycemia and to elucidate the engaged mechanism.

Methods: Microglia BV2 cells were stimulated by using 25 mmol/L D-glucose. The same concentration of mannitol (25 mmol/L) was applied as an isotonic contrast. Real-time PCR, Western-blot assay and immunofluorescence staining assay was performed. The dysfunction of iBRB was detected by using transendothelial electrical resistance (TEER) assay. Additionally, the leakage of fluorescein isothiocyanate (FITC)-conjugated dextran (70 kDa) was detected.

Results: SN abrogated microglia BV2 cells activation and reduced the phosphorylated activation of extracellular signal-regulated protein kinase (ERK)1/2. SN also decreased the transcriptional activation of nuclear factor κB (NFκB) and the elevated expression of tumor necrosis factor α (TNFα), interleukin (IL)-6 and IL-1β in BV2 cells treated with D-glucose (25 mmol/L). SN attenuated iBRB dysfunction in human retinal endothelial cells (HRECs) or choroid-retinal endothelial RF/6A cells when those cells were treated with TNFα, IL-1β or IL-6, or co-cultured with microglia cells stimulated by D-glucose. Moreover, SN restored the decreased protein expression of tight junctions (TJs) in TNFα-treated HRECs and RF/6A cells.

Conclusion: SN not only alleviate iBRB dysfunction directly inhibiting retinal endothelial injury caused by TNFα, IL-1β or IL-6, but also reduce the release of TNFα, IL-1β and IL-6 from microglia cells by abrogating hyperglycemia-mediated the activation of microglia cells.
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http://dx.doi.org/10.18240/ijo.2020.10.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511377PMC
October 2020

Ultrasonographic evaluation of costal cartilage for microtia reconstruction surgery.

Int J Pediatr Otorhinolaryngol 2020 Oct 10;137:110234. Epub 2020 Jul 10.

Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai, China; ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, 200031, China. Electronic address:

Purpose: Autogenous costal cartilage grafts have gained the golden standard method in microtia reconstruction. Right now, there was no useful method to assess the quality of costal cartilage before microtia reconstruction surgery. The purpose of this study was to evaluate the role of ultrasonography in assessing costal cartilage in patients who were ready to do microtia reconstruction surgery.

Methods: A prospective controlled study was conducted to collect 65 patients who underwent microtia reconstruction and underwent ultrasonography of costal cartilage before operation. The results of costal cartilage calcification and honeycombed phenomenon measured by ultrasonography were compared with those during operation. The age-specific patterns in calcification and honeycombed phenomenon were explored.

Results: According to the results of ultrasonography, the positive rate of calcification was 10.9% in patients under 18 years old, while 80% in patients over 18 years old. The positive rate of honeycombed phenomenon was 2.8% in patients under 12 years old, 42.9% in patients between 12 and 18 years old, and 25% in patients over 18 years old. Compared with intraoperative results, the accuracy rate of ultrasonography for calcification was 100%. The accuracy rate for honeycombed phenomenon was 83.3%.

Conclusion: Ultrasonography has high accuracy rate in assessing the calcification and honeycombed phenomenon of the costal cartilage, which was of vital importance for microtia reconstruction. The quality of costal cartilage changed with the age.
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http://dx.doi.org/10.1016/j.ijporl.2020.110234DOI Listing
October 2020

Measurement method for external auditory canal and clinical application in congenital aural stenosis.

Int J Pediatr Otorhinolaryngol 2020 Oct 10;137:110233. Epub 2020 Jul 10.

ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai, China; Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, China. Electronic address:

Objective: To describe a measurement method for external auditory canal (EAC), especially in congenital aural stenosis (CAS).

Methods: High-resolution CT (HRCT) datasets of CAS were imported into the MIMICS 15.0 software for image processing. We used two methods to evaluate the degree of CAS. One is sagittal reconstruction measurement method, the minor axis of the bony ear canal was measured in each layer using sagittal reconstruction. The other is Matlab procedure calculation, we calculated the midpoint axis values of the EAC in each Frankfurt plane. Finally, we compared the minimum value of each method, and verified the sagittal reconstruction measurement method retrospectively in the CAS cases without cholesteatoma who had undergone meatoplasty.

Results: Twenty CAS cases were selected using the sagittal reconstruction measurement method and Matlab procedure calculation to evaluate the degree of CAS. The mean age was 9.55 ± 2.85 years old (range: 6-15). The mean degree of CAS was 2.09 ± 0.50 mm by sagittal reconstruction measurement method and 2.03 ± 0.58 mm by Matlab procedure calculation. There were no significant differences in the two groups (t = -1.371, p = 0.186). A total of 94 HRCT datasets were imported into MIMICS for verification. The mean age was 11.66 ± 6.56 years old (range: 6-39). Mean stenosis of EAC at surgery was 2.88 ± 0.93 mm (range: 1-4) by using sagittal reconstruction measurement method.

Conclusions: Matlab procedure calculation is precise but relatively complicated and is only for scientific research. The sagittal reconstruction measurement method to calculate the most stenotic part of the bony ear canal is relatively simple and accurate to evaluate the degree of CAS. In cases of CAS without cholesteatoma, the precise measurement was critical for the next consultation.
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http://dx.doi.org/10.1016/j.ijporl.2020.110233DOI Listing
October 2020

Tumor cell-derived autophagosomes (DRibbles)-activated B cells induce specific naïve CD8 T cell response and exhibit antitumor effect.

Cancer Immunol Immunother 2021 Feb 18;70(2):463-474. Epub 2020 Aug 18.

Department of Microbiology and Immunology, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China.

Dendritic cell (DC) vaccine has been proved to be an effective way in cancer immunotherapy in both preclinical and clinical studies. However, limitations in DC isolation and culture have hampered its practice and promoted the development of other antigen-presenting cells (APCs) sources to fulfill that role. Our previous studies have shown that B cells loaded by tumor cell-derived autophagosomes, which we named as DRibbles (defective ribosomal products-containing blebs), could reactivate DC-induced effector T cell response. In this study, the roles of DRibble-loaded B cells in priming naïve CD8 T cell responses and controlling tumors were investigated. We found that high-mobility group box 1 protein (HMGB1) on DRibbles was involved in DRibble-induced B cell activation, and the DRibble-triggered B cell phagocytosis via the caveolae-mediated endocytosis pathway. By using OT-I mouse-derived T cells, we demonstrated that DRibble-loaded B cells could activate specific naïve CD8 T cells in vitro and ex vivo. In a tumor-bearing mouse model, DRibble-loaded B cells elicited systemic antitumor immunity and significantly suppressed the tumor growth. Moreover, the antitumor efficacy of DRibble-loaded B cells was enhanced when they were combined with CpG and anti-CD40 stimulation. These results suggest that DRibble-loaded B cells represent a viable and practical therapeutic vaccination strategy that might have important clinical implications for tumor immunotherapy.
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http://dx.doi.org/10.1007/s00262-020-02695-5DOI Listing
February 2021

Unravelling the Enigma of Nonoxidative Conversion of Methane on Iron Single-Atom Catalysts.

Angew Chem Int Ed Engl 2020 Oct 20;59(42):18586-18590. Epub 2020 Aug 20.

Department of chemistry and Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education, Tsinghua University, Beijing, 100084, China.

The direct, nonoxidative conversion of methane on a silica-confined single-atom iron catalyst is a landmark discovery in catalysis, but the proposed gas-phase reaction mechanism is still open to discussion. Here, we report a surface reaction mechanism by computational modeling and simulations. The activation of methane occurs at the single iron site, whereas the dissociated methyl disfavors desorption into gas phase under the reactive conditions. In contrast, the dissociated methyl prefers transferring to adjacent carbon sites of the active center (Fe ©SiC ), followed by C-C coupling and hydrogen transfer to produce the main product (ethylene) via a key -CH-CH intermediate. We find a quasi Mars-van Krevelen (quasi-MvK) surface reaction mechanism involving extracting and refilling the surface carbon atoms for the nonoxidative conversion of methane on Fe ©SiO and this surface process is identified to be more plausible than the alternative gas-phase reaction mechanism.
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http://dx.doi.org/10.1002/anie.202003908DOI Listing
October 2020

Ubiquitination and functional modification of GluN2B subunit-containing NMDA receptors by Cbl-b in the spinal cord dorsal horn.

Sci Signal 2020 06 30;13(638). Epub 2020 Jun 30.

Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou 730000, Gansu, P.R. China.

-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) containing GluN2B subunits are prevalent early after birth in most brain regions in rodents. Upon synapse maturation, GluN2B is progressively removed from synapses, which affects NMDAR function and synaptic plasticity. Aberrant recruitment of GluN2B into mature synapses has been implicated in several neuropathologies that afflict adults. We found that the E3 ubiquitin ligase Cbl-b was enriched in the spinal cord dorsal horn neurons of mice and rats and suppressed GluN2B abundance during development and inflammatory pain. Cbl-b abundance increased from postnatal day 1 (P1) to P14, a critical time period for synapse maturation. Through its N-terminal tyrosine kinase binding domain, Cbl-b interacted with GluN2B. Ubiquitination of GluN2B by Cbl-b decreased the synaptic transmission mediated by GluN2B-containing NMDARs. Knocking down Cbl-b in vivo during P1 to P14 led to sustained retention of GluN2B at dorsal horn synapses, suggesting that Cbl-b limits the synaptic abundance of GluN2B in adult mice. However, peripheral inflammation induced by intraplantar injection of complete Freund's adjuvant resulted in the dephosphorylation of Cbl-b at Tyr, which impaired its binding to and ubiquitylation of GluN2B, enabling the reappearance of GluN2B-containing NMDARs at synapses. Expression of a phosphomimic Cbl-b mutant in the dorsal horn suppressed both GluN2B-mediated synaptic currents and manifestations of pain induced by inflammation. The findings indicate a ubiquitin-mediated developmental switch in NMDAR subunit composition that is dysregulated by inflammation, which can enhance nociception.
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http://dx.doi.org/10.1126/scisignal.aaw1519DOI Listing
June 2020

Analgesic action of adenosine A1 receptor involves the dephosphorylation of glycine receptor α1 subunit in spinal dorsal horn of mice.

Neuropharmacology 2020 10 21;176:108219. Epub 2020 Jun 21.

Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, 730000, PR China. Electronic address:

Glycine receptor α1 subunit is located at inhibitory synapses in the superficial dorsal horn of adult spinal cord and is engaged in the glycinergic inhibition of nociceptive neuronal excitability and transmission. The α1 phosphorylation at Ser380 by extracellular signal-regulated kinase (ERK) has been shown to decrease glycinergic synaptic currents and contribute to spinal disinhibition. Here we found that peripheral inflammation induced by Complete Freund's Adjuvant increased Ser380 phosphorylation in spinal cord dorsal horn of mice, which was repressed by specific activation of adenosine A1 receptor (A1R). Protein phosphatase-1 (PP1), a ubiquitously-distributed serine/threonine phosphatase, was required for A1R to reduce Ser380 phosphorylation. Our data showed that Gβγ dimer, when released after activation of Gi protein-coupled A1R, interacted with PP1 and directed this phosphatase to α1, allowing for the full dephosphorylation of Ser380 residue. Sequestration of Gβγ dimer by viral expression of the C-terminal tail of β-adrenergic receptor kinase (βARKct) dissociated PP1 from α1 complex, leading to robust Ser380 phosphorylation. Meanwhile, Gβγ inhibition compromised the ability of A1R to alleviate inflammatory pain. The inhibitory effect of A1R on Ser380 phosphorylation was also attributed to the inactivation of ERK in CFA mice. Our data thus identified glycine receptor α1 subunit as an important target for adenosinergic suppression of inflammatory pain.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108219DOI Listing
October 2020

Effects of Ochratoxin A exposure on DNA damage in porcine granulosa cells in vitro.

Toxicol Lett 2020 May 23;330:167-175. Epub 2020 May 23.

College of Life Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China. Electronic address:

Ochratoxin A (OTA), a feed mycotoxin, tends to impair the reproductive performance of animals. Our previous studies have demonstrated that OTA exposure inhibits porcine ovarian granulosa cell (GC) proliferation and induces their apoptosis, but the underlying toxic mechanism is still uncertain. In this study, we explored the OTA exposure on porcine GCs in vitro and found that OTA exposure inhibited the proliferation of porcine GCs and arrested cell cycle of GCs in the G2/M phase. The results based on RNA-Seq revealed that 20 μM and 40 μM OTA exposure increase DNA damage of porcine GCs in vitro. The differentially expressed genes (DEGs) of 40 μM OTA exposure were enriched in the pathways of mismatch repair, nucleotide excision repair and homologous recombination in DNA replication compared with control group and 20 μM OTA exposure group. Meanwhile, OTA exposure increased the expression levels of DNA double-strand breaks (DSBs) gene γ-H2AX, and DNA repair related genes, such as BRCA1, XRCC1, PARP1, and RAD51. Above all, our research revealed that OTA might exert deleterious effects on porcine ovarian GCs, influencing DNA repair-related biological processes and causing DNA damage response.
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http://dx.doi.org/10.1016/j.toxlet.2020.05.011DOI Listing
May 2020

Simultaneous evaluation of bioactivity and settleability of activated sludge using fractal dimension as an intermediate variable.

Water Res 2020 Jul 18;178:115834. Epub 2020 Apr 18.

CAS Key Laboratory of Urban Pollutant Conversion, Department of Applied Chemistry, University of Science & Technology of China, Hefei, 230026, China. Electronic address:

Bioactivity and settleability of activated sludge are essential for the operation of activated sludge systems in wastewater treatment. In this work, the fractal dimension of sludge image is proposed as a tool to evaluate these two factors. The specific endogenous respiration rate (SOUR) and the specific quasi-endogenous respiration rate (SOUR) are found to be more dependent on the 3D structure of sludge than the specific total respiration rate (SOUR). The relationship between the fractal structure and bioactivity suggests that the bioactivity governs the acceptable upper bound of the fractal dimension (D), as at its theoretical maximum of 2.0, the non-porous compact flocs are predominant. The settleability or the biomass concentration determines the acceptable lower bound of D, as at its theoretical minimum of 1.0, the free-swimming microbes are predominant. Our data reveal that the activated sludge has an acceptable fractal dimension D in a range of 1.07-1.68. In practice, the fractal dimension should be controlled at a reasonable value as there is a trade-off between the bioactivity and physical structure to achieve better performance. A decrease or increase in the fractal dimension can serve as a signal for the change of the operational status, and this is further elucidated from the perspective of settling tanks using state point analysis. Compared with respirogram measurement, measuring fractal dimension is a complex process and its online implementation is challenging. Also, the measured value varies with the methods used. In addition, the difference in their theoretical values depends on the homogeneity of the sludge structure. Since the fractal dimension D reflects both bioactivity and settleability of the sludge but is difficult to measure, in this work a relationship between D and the easily measurable respirogram is established, and a method using the respirogram as a proxy of D is proposed to control the bioactivity and settleability simultaneously. This respiration-based method is able to simultaneously control aeration and settling tanks, and could serve as an efficient tool for the management of wastewater treatment plants.
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http://dx.doi.org/10.1016/j.watres.2020.115834DOI Listing
July 2020

Functional ear reconstruction strategies for microtia with congenital aural stenosis in seventy-six patients.

Clin Otolaryngol 2020 07 26;45(4):611-615. Epub 2020 Apr 26.

ENT institute, Eye & ENT Hospital, Fudan University, Shanghai, China.

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http://dx.doi.org/10.1111/coa.13537DOI Listing
July 2020

Distributed Secure Control Against Denial-of-Service Attacks in Cyber-Physical Systems Based on K-Connected Communication Topology.

IEEE Trans Cybern 2020 Jul 27;50(7):3094-3103. Epub 2020 Feb 27.

In this article, the security problem in cyber-physical systems (CPSs) against denial-of-service (DoS) attacks is studied from the perspectives of the designs of communication topology and distributed controller. To resist the DoS attacks, a new construction algorithm of the k -connected communication topology is developed based on the proposed necessary and sufficient criteria of the k -connected graph. Furthermore, combined with the k -connected topology, a distributed event-triggered controller is designed to guarantee the consensus of CPSs under mode-switching DoS (MSDoS) attacks. Different from the existing distributed control schemes, a new technology, that is, the extended Laplacian matrix method, is combined to design the distributed controller independent on the knowledge and the dwell time of DoS attack modes. Finally, the simulation example illustrates the superiority and effectiveness of the proposed construction algorithm and a distributed control scheme.
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http://dx.doi.org/10.1109/TCYB.2020.2973303DOI Listing
July 2020

Interfacial self-assembly of amphiphilic conjugated block copolymer into 2D nanotapes.

Soft Matter 2019 Nov 9;15(43):8790-8799. Epub 2019 Oct 9.

MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science & Engineering, Zhejiang University, Hangzhou 310027, China.

In the present work, the evaporation-induced interfacial self-assembly behavior of an amphiphilic conjugated polymer, poly(3-hexylthiophene)-b-poly(acrylic acid) (P3HT-b-PAA), at the oil-water interface is explored. Novel 2D nanotapes of P3HT-b-PAA are prepared via the interfacial self-assembly. It is inferred that P3HT segments adopt a special conformation at the oil-water interface, which facilitates the packing of alkyl side chains and π-π interaction. The UV-vis spectrum further confirms that the ordering degree of P3HT segments is increased while transmission IR and Raman spectroscopic studies suggest that the P3HT chains adopt a more planar conformation at the oil-water interface. It is proposed that the formation of the nanotapes is driven by the ordered packing of the P3HT chains at the oil-water interface. Finally, the packing model of the P3HT chains inside the nanotapes is roughly proposed.
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http://dx.doi.org/10.1039/c9sm01503eDOI Listing
November 2019

Transformation of Viral Light Particles into Near-Infrared Fluorescence Quantum Dot-Labeled Active Tumor-Targeting Nanovectors for Drug Delivery.

Nano Lett 2019 10 11;19(10):7035-7042. Epub 2019 Sep 11.

Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology , Wuhan University , Wuhan 430072 , People's Republic of China.

Nanosized oncolytic viral light particles (L-particles), separated from progeny virions, are composed of envelopes and several tegument proteins of viruses, free of nucleocapsids. The noninfectious L-particles experience the same internalization process as mature oncolytic virions, which exhibits great potential to act as targeted therapeutic platforms. However, the clinical applications of L-particle-based theranostic platforms are rare due to the lack of effective methods to transform L-particles into nanovectors. Herein, a convenient and mild strategy has been developed to transform L-particles into near-infrared (NIR) fluorescence AgSe quantum dot (QD)-labeled active tumor-targeting nanovectors for real-time imaging and drug delivery. Utilizing the electroporation technique, L-particles can be labeled with ultrasmall water-dispersible NIR fluorescence AgSe QDs with a labeling efficiency of . 85% and loaded with antitumor drug with a loading efficiency of . 87%. Meanwhile, by harnessing the infection mechanism of viruses, viral L-particles are able to recognize and enter tumor cells without further modification. In sum, a trackable and actively tumor-targeted theranostics nanovector can be obtained efficiently and simultaneously. Such multifunctional nanovectors transformed from viral L-particles have exhibited excellent properties of active tumor-targeting, tumor imaging, and antitumor efficacy, which opens a new window for the development of natural therapeutic nanoplatforms.
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http://dx.doi.org/10.1021/acs.nanolett.9b02483DOI Listing
October 2019

Ortho-phenylphenol exposure impairs porcine sperm motility through AMPK/AKT signaling pathway.

Environ Mol Mutagen 2019 12 9;60(9):830-836. Epub 2019 Sep 9.

College of Life Sciences, Institute of Reproductive Science, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, Qingdao Agricultural University, Qingdao, China.

Ortho-phenylphenol (OPP), as an active ingredient of disinfectants, has been worldwide utilized as fungicides and antibacterial agents in hospital, agriculture, wood preservation, and veterinary products. However, little is known about the toxic effects of OPP on male reproduction, especially sperm motility, and the underlying mechanisms. In this study, we chose porcine sperms as in vitro model to investigate the effects and mechanisms of OPP exposure on sperm motility. Our results indicated that porcine sperm motility decreases significantly in a dose-dependent manner after exposed to OPP. Additionally, ATP synthesis deficiency was revealed by downregulation of ATP synthase subunit beta and adenosine 5'-monophosphate-activated protein kinase expression. Furthermore, OPP disturbed the expression of TP53 and PTEN, which contributed to AKT pathway deactivation. OPP exposure also disrupted platelet-derived growth factor receptor A expression, which further inhibited 3-phosphoinositide-dependent protein kinase 1 activation, resulting in protein kinase B and pyruvate dehydrogenase phosphatase catalytic subunit 1 deactivation. In conclusion, these observations suggest that OPP exposure decreases porcine sperm motility by disturbing the AMPK/AKT signaling pathway. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/em.22324DOI Listing
December 2019

International Consensus Recommendations on Microtia, Aural Atresia and Functional Ear Reconstruction.

J Int Adv Otol 2019 Aug;15(2):204-208

Department of Otolaryngology, La Timone Children's Hospital, Aix-Marseille University, Marseille, France.

The aim of this report is to provide international recommendations for functional ear reconstruction in patients with microtia and aural atresia. All patients with microtia and external auditory atresia should be seen in the setting of a multidisciplinary team and agreed treatment outcomes should be measured, so that techniques, approaches, and results can be compared. The methods are expert opinion from the members of the International Microtia and Atresia Workgroup (IMAW). The consensus recommendations reported herein take into account the variability in practice patterns present among experts in the field; the degree of consensus was quantified by presenting the percentage of above authors who agree or partially agree with each statement. Recommendations include the definition and classification of microtia/atresia, treatment of microtia, treatment of congenital aural atresia, flowchart of functional ear reconstruction, and future research directions. Patients with microtia and aural atresia can be guided by the consensus recommendations provided herein.
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http://dx.doi.org/10.5152/iao.2019.7383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750779PMC
August 2019

Tumor-released autophagosomes induces CD4 T cell-mediated immunosuppression via a TLR2-IL-6 cascade.

J Immunother Cancer 2019 07 12;7(1):178. Epub 2019 Jul 12.

Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China.

Background: CD4 T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4 T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4 T cells in the tumor microenvironment.

Methods: TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4 T cells to examine the function and mechanism of TRAPs in CD4 T cell differentiation and function. TRAPs-elicited CD4 T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model.

Results: Heat shock protein 90α (HSP90α) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4 T cell production of IL-6 via a TLR2-MyD88-NF-κB signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4 T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4 T cells inhibited CD4 and CD8 effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4 T cells markedly retarded tumor growth. Furthermore, B cell or CD4 T cell depletion impeded tumor growth by increasing effector T cell function.

Conclusions: HSP90α on the surface of TRAPs programs the immunosuppressive functions of CD4 T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90α represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.
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http://dx.doi.org/10.1186/s40425-019-0646-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625067PMC
July 2019
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