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Relying on the probabilistic nature and entanglement property of quantum state, quantum communication will support the theoretically unconditional security and computational efficiency beyond that of classical communication. In this article, we present a fidelity optimized quantum teleportation protocol for multiparty quantum network communication. Firstly, a special transmission mechanism ensures the secure establishment of the channel between the communicators. Secondly, the quantum information is encoded by Shor codes to resist channel noise. Thirdly, the Open Shortest Path First (OSPF) method is of help for establishing the channel between non-adjacent communicators. In this protocol, the special transmission mechanism guarantees the security of quantum communication. The Shor codes improve the fidelity of quantum information. The OSPF method ensures efficient transmission. The effectiveness of the protocol is verified by experiments. Experimental results show that this protocol provides effective qubit fidelity improvements within the range of noise thresholds of . Compared with existing quantum communication protocols, this protocol has better reliability and fidelity performance.

OBJECTIVE: To explore the significance of lymphocytes in systemic sclerosis (SSc), by detecting the levels of T lymphocytes, B lymphocytes and natural killer (NK) cells, and analyzing the correlation between the lymphocytes and clinical laboratory indexes. METHODS: The numbers and proportion of T, CD4(+)T, CD8(+)T, B, and NK cells were detected by flow cytometry in peripheral blood of 32 SSc patients who had taken immunosuppressive drugs and 30 healthy controls (HC). The comparison of the lymphocyte subsets in SSc with them in the HC groups, and the correlation between the lymphocytes and other clinical and laboratory indicators were analyzed by the relevant statistical analysis. RESULTS: Compared with the HC group, the numbers of T, CD4(+)T, CD8(+)T, and NK cells in peripheral blood of SSc group, who had taken immunosuppressive drugs, were significantly decreased (P < 0.05). More-over, the proportion of NK cells in peripheral blood of the SSc group was also significantly lower than that in the HC group (P=0.004). In addition, all the lymphocyte subsets were decreased in peripheral blood of more than 65% of the SSc patients who had taken immunosuppressive drugs. Compared with CD4(+)T normal group, the positivity of Raynaud's phenomenon, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) was significantly increased in CD4(+)T reduction group, respectively (P＝0.024, P < 0.001, P=0.018). ESR was higher in CD8(+)T reduction group than CD8(+)T normal group (P＝0.022). The prevalence of fingertip ulcer was significantly increased in B cell decrease group (P=0.019). Compared with NK cell normal group, the prevalence of fingertip ulcer was significantly increased in NK cell lower group (P=0.033), IgM was remarkablely decreased yet (P=0.049). The correlation analysis showed that ESR was negatively correlated with the counts of T lymphocytes (r＝－0.455, P＝0.009), CD4(+)T lymphocytes (r＝－0.416, P＝0.018), CD8(+)T lymphocytes (r＝－0.430, P=0.014), B cells (r＝－0.366, P＝0.039). CONCLUSION: The number of CD4(+)T, CD8(+)T, B, and NK cells significantly decreased in peripheral blood of SSc patients who had used immunosuppressive drugs, some lymphocyte subsets might be related with Raynaud's phenomenon and fingertip ulcer, and reflected the disease activity by negatively correlated with ESR and CRP; the numbers of lymphocyte subsets in peripheral blood should be detected regularly in SSc patients who had taken immunosuppressive drugs.

Twenty-five patients diagnosed with otogenic vertigo at the outpatient clinic of the Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital from January to June 2020 were selected. Among them, 8 cases were male and 17 cases were female, aged (48±13) years. All the patients underwent internet combined with offline follow-up vestibular rehabilitation for 12 weeks, which included vestibulo-ocular reflex exercises, proprioceptive exercises and static/dynamic balance exercises. Computerized dynamic posturography (CDP) and dizziness handicap inventory (DHI) scores were compared before and after rehabilitation. The DHI score improved significantly after 12 weeks of vestibular rehabilitation (48.3±15.9 vs 26.7±17.9,选取2020年1至6月在上海交通大学附属第六人民医院耳鼻咽喉头颈外科门诊确诊为耳源性眩晕的患者25例，其中男8例，女17例，年龄（48±13）岁。进行互联网联合线下随访前庭康复12周，包括前庭-眼反射练习、本体感觉练习、静态/动态平衡练习。比较康复前后的计算机动态姿势图（CDP）、眩晕障碍量表（DHI）评分情况。结果显示，前庭康复12周后DHI得分［（48.3±15.9）分比（26.7±17.9）分，

耳源性眩晕占所有眩晕病例的半数以上，其致病机制复杂，涉及多个感觉系统和中枢信息整合，临床诊断与疗效分析普遍缺乏客观指标。前庭相关中枢网络是形成眩晕感知的最终部位，其功能改变可能是眩晕的后果及其症状慢性持续的潜在原因。脑功能评估技术从高级中枢角度探索了耳源性眩晕的特征，证实了患者的皮层多感觉前庭皮质网络发生了活动性及功能连通性改变，为临床认识提供了新的视角。本文阐述了耳源性眩晕脑功能改变的研究进展，并着重探讨脑电图在此领域的应用现状与前景。.

BackgroundBone homeostasis is maintained by the balance between bone formation and resorption. In inflammatory arthritis, such as rheumatoid arthritis (RA), the pro-inflammatory environment promotes osteoclast differentiation and skews this balance towards bone resorption, leading to destructive bone erosion and bone loss. O-GlcNAcylation is one of the most common post-translational modifications, which attaches a single N-acetylglucosamine (GlcNAc) molecular to the serine or threonine of the target protein. O-GlcNAcylation is controlled by the activities of a single pair of enzymes: OGT, which facilitates the transfer of GlcNAc onto proteins; OGA, which removes GlcNAc from proteins. The activity of O-GlcNAcylation has been reported to be involved in several cellular events, such as transcription, translation, intracellular trafficking, and differentiation. We previously showed that the dynamics of O-GlcNAcylation are essential for osteoclast differentiation. TNF-α, a key pro-inflammatory factor in RA, intensified the O-GlcNAcylation dynamics. Inhibition of OGT arrests osteoclast precursors at early stages, whereas OGA inhibition blocks osteoclast maturation. However, the molecular mechanism of these regulations remains unclear.ObjectivesWe aimed to identify the O-GlcNAcylation targets in osteoclast precursors in a pro-inflammatory milieu and to decipher the molecular mechanism of O-GlcNAcylation mediated regulation of osteoclastogenesis.MethodsWe first identify the O-GlcNAc-dependent molecular pathways in osteoclast precursors with pharmacological OGT and OGA inhibition by RNA sequencing. Then, we identified the O-GlcNAcylated proteins by mass spectrometry-based proteomics analysis and confirmed by immunoprecipitation. We found the potential molecular mechanism by combining the data from transcriptomics and proteomics. The proposed mechanism was further validated through siRNA-mediated knockdown and high-content screening analysis.ResultsOur transcriptomics data showed that OGT inhibition arrested osteoclast differentiation at early stages through interfering the cytokine signaling and metabolic adaption. The upstream analysis proposed MYC as the most potent regulator for the transcriptomic profile under OGT inhibition. Recent studies proposed MYC as a master regulator for metabolic reprograming during osteoclast differentiation. However, O-GlcNAcylation of MYC was not detected by mass spectrometry, suggesting indirect effects of O-GlcNAcylation on MYC signaling in osteoclast precursors. We detected upregulated levels of O-GlcNAc on NUP153, MTDH, RBM27, IFI207 upon RANKL+TNFα stimulation. An integrated analysis of transcriptomic and proteomic data by Ingenuity Pathway Analysis indicated that NUP153 might regulate the most DEGs among all the identified targets and indicated potential of NUP153 to regulate nuclear shuttling of MYC. Subcellular fractionation and confocal microscopy showed enhanced MYC nuclear translocation upon RANKL+TNFα stimulation, which could be blocked by NUP153 knockdown or OGT inhibition. Functionally, knockdown of NUP153 arrested cells at similar stages to OGT inhibition and reduced bone resorption ability. Together, these results suggest a model, in which O-GlcNAcylation regulates the shuttling activity of the nuclear pore component NUP153 to control the access of MYC to the nucleus during osteoclast differentiation.ConclusionOur results indicated that OGT inhibition arrests osteoclastogenesis at early stages through hampering MYC-dependent metabolic adaption. NUP153 was proposed as the most potent O-GlcNAcylation target by multi-omics data integration. NUP153-mediated MYC nuclear trafficking is required for osteoclast differentiation. These findings reveal the molecular mechanism of O-GlcNAcylation-dependent osteoclastogenesis and provide therapeutic insights on targeting O-GlcNAcylation in pathologic bone resorption.Disclosure of InterestsYi-Nan Li: None declared, Chih-Wei Chen: None declared, Thuong Trinh-Minh: None declared, ZHU Honglin: None declared, Philipp Hubel: None declared, Jens Pfannstiel: None declared, Georg Schett: None declared, Jörg H.W. Distler Shareholder of: 4D Science, Speakers bureau: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Employee of: FibroCure

To elucidate the role of TUG1 in the onset of type 2 diabetes mellitus (T2DM) and the potential mechanism.Relative levels of TUG1 and SP1 in high-fat diet animal model and high-glucose cell model were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), and their correlation was analyzed. Potential binding sites in the promoter sequences of TUG1 and SP1 were predicted using the JASPAR. Their interaction was further confirmed by chromatin immunoprecipitation (ChIP) and Dual-Luciferase reporter assay. The influences of TUG1 on proliferative and apoptotic potentials in Min6 cells were examined by Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry, respectively. Subsequently, the interaction in the TUG1/miR-188-3p /FGF5 axis was similarly explored by Dual-Luciferase reporter assay.SP1 and TUG1 were downregulated in high-fat and high-glucose models, and they displayed a positive correlation. TUG1 bound E2 region in SP1 promoters. Knockdown of TUG1 inhibited proliferative rate and induced apoptosis in high-glucose-treated Min6 cells. Furthermore, the TUG1 / miR-188-3p /FGF5 axis was identified to be responsible for regulating Min6 cell functions.SP1 induces TUG1 downregulation in T2DM cell models, which further regulates proliferative and apoptotic potentials in islet cells by activating the miR-188-3p/FGF5 axis.

OBJECTIVE: To detect the serum level of a novel autoantibody, anti-tubulin-α-1C, in patients with systemic sclerosis (SSc) and to investigate its clinical significance. METHODS: Anti-tubulin-α-1C antibody levels were determined by enzyme-linked immunosorbent assay (ELISA) in 62 patients with SSc, 38 systemic lupus erythematosus (SLE), 24 primary Sjögren's syndrome (pSS) patients, and 30 healthy controls (HCs). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin A(IgA), immunoglobulin M (IgM), immunoglobulin G (IgG), C3, C4, rheumatoid factor (RF), antinuclear antibody(ANA), anti-centromere antibodies(ACA), anticardiolipin (aCL), anti-dsDNA antibody, anti-Sm antibody, anti-RNP antibody, anti-Scl-70 antibody, anti-Ro52 antibody, anti-SSA antibody, anti-SSB antibody, centromere protein A(CENP-A), centromere protein B (CENP-B) were measured by standard laboratory techniques. Raynaud's phenomenon and modified Rodnan skin score(MRSS) were recorded to evaluate the disease status of SSc. Independent sample t test, Chi square test, Mann-Whitney U test, Spearman rank correlation were used for statistical analyses. RESULTS: The serum anti-tubulin-α-1C antibody concentration in SSc group was 81.24±34.38, the serum anti-tubulin-α-1C antibody concentration in SLE group was 87.84±38.52, the serum anti-tubulin-α-1C antibody concentration in pSS group was 59.79±25.24, and the serum anti-tubulin-α-1C antibody concentration in healthy group was 39.37±18.7. Multivariate analysis revealed that anti-tubulin-α-1C antibody levels were significantly increased in the SSc and SLE patients. The expression level of anti-tubulin-α-1C antibody in SSc was higher compared with the pSS group and the health control group (P < 0.01). Further analysis demonstrated that the elevated anti-tubulin-α-1C antibody were correlated with the SSc inflammation and disease activity markers ESR(r=0.313, P=0.019), The levels of anti-tubulin-α-1C antibody were also significantly correlated with MRSS(r=0.636, P < 0.01). The best cut-off value for the diagnose of SSc was 76.77 as mean+2SD value. The proportion of Raynaud's phenomenon was higher in the group of anti-tubulin-α-1C autoantibody-postive SSc patients than that in anti-tubulin-α-1C autoantibody negative group(71.4% vs. 37.5%, P=0.039). The proportions of anti-Scl-70 antibody, anti-CENP antibody and anti-cardiolipin antibody were higher in the group of anti-tubulin-α-1C autoantibody-postive SSc patients than in the anti-tubulin-α-1C autoantibody negative group (37.9% vs. 15.2%, 34.5% vs. 12.1%, 13.8 vs. 0, respectively, all P < 0.05). CONCLUSION: Based on this explorative stu-dy, the level of anti-tubulin-α-1C antibody increased in the serum of the patients with SSc. There were correlations between anti-tubulin-α-1C autoantibody and clinical and laboratory indicators of the SSc patients. It may become a novel biomarker indicative of active SSc and could be applied in future clinical practice.

Background:Bone remodeling is a constant process maintained by the balance between osteoclast-triggered bone resorption and osteoblast-mediated bone formation. In inflammatory arthritis, such as rheumatoid arthritis (RA), the pro-inflammatory environment favors osteoclast differentiation and skews the balance towards resorption, leading to progressive bone erosion and bone loss. O-GlcNAcylation is a post-translational modification, which transfers a single N-acetylglucosamine molecule to the serine or threonine of the target protein. The modification is accomplished by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Unlike other glycosylation, O-GlcNAcylation occurs in multiple cellular compartments, including the nucleus. Although O-GlcNAcylation is one of the most common modifications, its role in bone homeostasis is still poorly understood.Objectives:We aimed to investigate the role of O-GlcNAcylation in osteoclastogenesis under pro-inflammatory milieus. We also focused on dissecting the signaling pathways affected by O-GlcNAcylation during osteoclast differentiation.Methods:We examined the levels of O-GlcNAc during in vitro osteoclastogenesis by western blotting. The levels of O-GlcNAc in tissue from RA patients and experimental arthritis were detected by immunofluorescence. Pharmacological inhibition and genetic knockout were used to manipulate O-GlcNAcylaiton during osteoclastogenesis. RNA sequencing was performed to study O-GlcNAc-mediated pathways.Results:We demonstrate the dynamic changes in O-GlcNAcylation during osteoclastogenesis. The elevated O-GlcNAcylation was found in the early differentiation stages, whereas its downregulation was detected in the maturation process. TNFα elaborates the dynamic changes in O-GlcNAcylation, which further intensifies osteoclast differentiation.Targeting OGT by selective inhibitor and genetic knockout restrain O-GlcNAcylation and hinder the expression of the early differentiation marker Nfatc1. Inhibition of OGA, which forces high levels of O-GlcNAcylation throughout the differentiation, reduces the formation of multinucleated mature osteoclasts. Consistent with our in vitro data, suppressing OGT and OGA both ameliorate bone loss in experimental arthritis. We detected a reduced number of TRAP-expressing precursors and mature osteoclasts in the mice subjected to OGT inhibition. While inhibiting OGA only lowers the number of TRAP+F4/80– mature osteoclasts without affecting the number of TRAP+F4/80+ precursors.Transcriptome profiling reveals that O-GlcNAcylation regulates several biological processes. Increased O-GlcNAcylation promotes cytokine signaling and oxidative phosphorylation. The downregulation of O-GlcNAcylation is essential for cytoskeleton organization and cell fusion.Conclusion:We demonstrate that the dynamic changes of O-GlcNAcylation are essential for osteoclast differentiation. These findings reveal the therapeutic potential of targeting O-GlcNAcylation in pathologic bone resorption.Disclosure of Interests:Chih-Wei Chen: None declared, Yi-Nan Li: None declared, Thuong Trinh-Minh: None declared, ZHU Honglin: None declared, Alexandru-Emil Matei: None declared, Xiao Ding: None declared, Cuong Tran Manh: None declared, Xiaohan Xu: None declared, Christoph Liebel: None declared, Ruifang Liang: None declared, Min-Chuan Huang: None declared, Neng-Yu Lin: None declared, Andreas Ramming Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Grant/research support from: Pfizer, Novartis, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Jörg H.W. Distler Shareholder of: 4D Science, Speakers bureau: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Employee of: FibroCure

In the information age, teaching methods are undergoing tremendous changes, and the traditional teaching methods are difficult to draw students' attention. As the core course of stomatology, oral histopathology is an important foundation for oral students. Along with the rapid development of medical science, it is imperative to deepen the reform of teaching. This article discussed the diversified teaching methods conducted in oral histopathology course in Zhejiang University School of Stomatology in the past 10 years with the core teaching theory of "learning before teaching" including the exploration design course, case based learning, journal club, etc. Diversified teaching methods activated students' subjective initiative, which laid a foundation for the next stage of clinical study, and provided a guiding framework for the future teaching reforms.信息化时代下教学方法迎来巨大变革，传统单一的教学模式难以集中学生注意力。作为口腔核心基础和临床桥梁学科，口腔组织病理学教学对于口腔医学生的培养至关重要。随着医学科学的进步，现代口腔组织病理学高速发展，深化课堂教学改革势在必行。本文以浙江大学口腔医学院口腔组织病理学课堂近10年教学改革的探索为例，贯彻“先学后教”的教学理念，开展以免疫组织化学和原位杂交为基础的病理探索性课程，结合临床病理讨论会等多种教学方法，多元化教学模式与考核内容相辅相成，充分发挥学生的主观能动性，调动其学习积极性，为下一步的临床学习奠定基础，为深化课堂教学实践提供指导性框架。.

Extra-cellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway participates in cell proliferation, cycle and apoptosis. MAPK kinase 1 (MAP2K1) activates the ERK/MAPK pathway. The down-regulation of miR-195 is correlated with the onset and drug resistance of prostate cancer. Bioinformatics analysis identified complementary binding sites between miR-195 and MAP2K1. This study aimed to investigate the effect of miR-195 on the proliferation, apoptosis and adriamycin (ADM) resistance of prostate cancer cells.Dual-Luciferase reporter gene assay confirmed targeted regulation between miR-195 and MAP2K1. ADM resistant cell line DU145/ADM and PC-3/ADM were generated for comparing the miR-195 and MAP2K1 expression. Apoptosis was measured by flow cytometry and caspase-3 activity was quantified. Cultured cells were treated with miR-195 mimic, followed by quantitative real-time PCR (qRT-PCR) was used for MAP2K1 expression. Western blot measured MAP2K1, ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) expression, and flow cytometry quantified cell apoptosis, followed by EdU staining for cell proliferation.Targeted regulation existed between miR-195 and MAP2K1 mRNA. Drug-resistant cells had lower miR-195 than parental cells, whilst MAP2K1 expression was higher. Under ADM treatment with IC50 concentration, drug resistant cells showed lower apoptosis. The transfection of miR-195 decreased MAP2K1 expression and p-ERK1/2, elevated cell apoptosis and suppressed EdU positive rate or cell proliferation.The down-regulation of miR-195 is correlated with ADM resistance of prostate cancer cells. The over-expression of miR-195 weakens cancer cell proliferation, facilitates cell apoptosis and decreases ADM resistance via targeted inhibition on MAP2K1 expression and ERK/MAPK signal pathway.

朗格汉斯细胞组织细胞增生症（Langerhans cell histiocytosis，LCH）是一种罕见的以朗格汉斯细胞增生为特征的单克隆性疾病。该文报道1例发生于胃的LCH。患者男，59岁。镜下观察肿瘤细胞呈片状及巢状排列，细胞呈圆形及椭圆形，仅部分有核沟，嗜酸性小核仁可见，背景缺乏淋巴细胞、嗜酸性粒细胞，见大量泡沫样组织细胞，核分裂象约2个/HPF。免疫组织化学表达Langerin、S-100蛋白和CD1α，BRAF V600E为阴性，PCR-免疫荧光法BRAF V600E基因发生突变。胃孤立性LCH是一种肿瘤性病变，确诊依赖于病理学诊断，极易漏诊且需要与黑色素瘤、组织细胞肉瘤等恶性肿瘤相鉴别，临床多给予局部切除的治疗方法。.

Prostate cancer is one of the most ordinary malignant tumors. Recently, the role of long non-coding RNAs (lncRNAs) in tumor progression has caught the attention of numerous researchers. In this work, lncRNA SNHG14 was studied to identify how it functioned in the progression of prostate cancer.First, Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to measure SNHG14 expression in prostate cancer tissues and cell lines. Furthermore, to identify the function of SNHG14 in prostate cancer, functional experiments were conducted in vitro and in vivo. In addition, by performing Luciferase assays and RNA immunoprecipitation assay (RIP), the underlying mechanism was explored.In this work, SNHG14 expression was remarkably higher in prostate cancer samples when compared with that in the corresponding ones. Moreover, cell proliferation was inhibited after SNHG14 was silenced in prostate cancer cells and the expression of miR-613 was upregulated after SNHG14 was silenced. Further mechanism assays showed that miR-613 was a direct target of SNHG14 in prostate cancer. In addition, tumor formation was inhibited after SNHG14 was knocked-down in vivo.Our study discovers a potential oncogene in prostate cancer and identifies that SNHG14 enhances cell proliferation via sponging miR-613.

OBJECTIVE: Antibodies against carbamylated protein (anti-CarP) were found to be a promising marker to evaluate joint damage and disease activity in patients with rheumatoid arthritis (RA). However, whether anti-CarP antibodies were present in systemic lupus erythematosus (SLE) remained ambiguity. We have therefore undertaken this study to assess the levels of serum anti-CarP antibodies and to evaluate their clinical value in SLE. METHODS: Serum levels of antibodies against carbamylated-fibrinogen (anti-CarP) were measured by enzyme-linked immunosorbent assay (ELISA) in 105 SLE patients and 73 healthy controls. Other clinical and laboratory measurements of the SLE patients were collected from medical records. Data analyses between anti-CarP antibodies and other laboratory measurements were performed using SPSS software for Windows 24.0. RESULTS: The levels of serum anti-CarP antibodies in the patients with SLE were significantly higher than those in the healthy controls (P

ObjectivesFibrosis is a complex pathophysiological process involving interplay between multiple cell types. Experimental modelling of fibrosis is essential for the understanding of its pathogenesis and for testing of putative antifibrotic drugs. However, most current models employ either phylogenetically distant species or rely on human cells cultured in an artificial environment. Here we evaluated the potential of vascularised in vitro human skin equivalents as a novel model of skin fibrosis and a platform for the evaluation of antifibrotic drugs.MethodsSkin equivalents were assembled on a three-dimensional extracellular matrix by sequential seeding of endothelial cells, fibroblasts and keratinocytes. Fibrotic transformation on exposure to transforming growth factor-β (TGFβ) and response to treatment with nintedanib as an established antifibrotic agent were evaluated by quantitative polymerase chain reaction (qPCR), capillary Western immunoassay, immunostaining and histology.ResultsSkin equivalents perfused at a physiological pressure formed a mature, polarised epidermis, a stratified dermis and a functional vessel system. Exposure of these models to TGFβ recapitulated key features of SSc skin with activation of TGFβ pathways, fibroblast to myofibroblast transition, increased release of collagen and excessive deposition of extracellular matrix. Treatment with the antifibrotic agent nintedanib ameliorated this fibrotic transformation.ConclusionOur data provide evidence that vascularised skin equivalents can replicate key features of fibrotic skin and may serve as a platform for evaluation of antifibrotic drugs in a pathophysiologically relevant human setting.

In China, the thermal environment of family showers in old communities is quite different from that of other living spaces, especially when the thermal environment changes drastically during showering, which can easily cause health problems. The human thermal physiological model is an effective tool to predict and evaluate the non-uniform and unstable shower thermal environment and human health risks. In this research, the showering experiment was carried out in a typical bathroom in an old community in China, during which environmental parameters such as air temperature, wall temperature and water temperature of the bathroom during the showering were recorded, and physiological parameters such as skin temperature, core temperature and blood pressure during the whole showering process were detected. Based on the multi-node numerical human body model of Stowljik and a cardiovascular control model with human body temperature as the driving force, a temperature-blood pressure coupling prediction model was established. The validity of the proposed model was examined for blood circulation. This predictive model can accurately reflect changes in physiological parameters and is verified as suitable for the health assessment of showering environment in residential buildings.

Background:The aldehyde dehydrogenase (ALDH) superfamily composes a group of 20 enzymes that catalyze aldehyde oxidation. Within this enzyme family, ALDH3A2 stands out for its central role in the oxidation of long-chain aldehydes. Of particular interest, the substrates of ALDH3A2 include also profibrotic lipid mediators such as sphingosine 1-phosphate or leukotrienes, which have been reported to be deregulated in the context of SSc.Objectives:We aimed to investigate the role of ALDH3A2 in fibrotic tissue remodeling in SSc.Methods:Fibroblast-to-myofibroblast transition was analyzed by quantification of ACTA2/αSMA, by assessment of stress fiber formation and mRNA and protein levels of type I collagens. ALDH3A2/Aldh3a2 siRNAs were employed to specifically knockdown ALDH3A2 in dermal fibroblasts both in vitro and in vivo. Overexpression of ALDH3A2 was achieved by ALDH3A2-pcDNA transfection. The role of ALDH3A2 was investigated in three different mouse models: Bleomycin- and cGvHD-induced dermal fibrosis as well as fibrosis induced by overexpression of a constitutively active TGFβ receptor I (TBRICA). Target genes of ALDH3A2 in fibroblasts were identified by RNA sequencing.Results:The expression of ALDH3A2 was modestly reduced in dermal fibroblasts of SSc skin as compared to matched healthy controls. This reduction in ALDH3A2 expression was phenocopied by activation of TGFβ signaling, whereas selective inhibition of TGFβ signaling prevented the downregulation of ALDH3A2 in experimental fibrosis. ALDH3A2 overexpression promoted fibroblast-to-myofibroblast transition with increased levels of αSMA, enhanced formation of stress fibers and reduced collagen release. In contrast, knockdown of ALDH3A2 in dermal fibroblasts inhibited fibroblast activation and collagen release. Moreover, in vivo knockdown of ALDH3A2 in the skin of mice ameliorated dermal thickening, myofibroblast differentiation and collagen deposition in three different murine models of skin fibrosis: Bleomycin-induced skin fibrosis and sclerodermatous GvHD-as models of inflammatory stages of SSc and TBRICA-induced fibrosis as an inflammation-independent model of SSc. RNA sequencing of ALDH3A2-knockdown fibroblasts demonstrated that ALDH3A2 regulates the activity of a network of profibrotic developmental pathways including TGFβ, Wnt, Notch, and Hedgehog signaling.Conclusion:We demonstrate that ALDH3A2 regulates a network of profibrotic pathways to control fibroblast activation and tissue fibrosis. ALDH3A2 is modestly downregulated in SSc fibroblasts as result of an endogenous, TGFβ-driven feedback loop. Although this modest downregulation is not sufficient to counterbalance the aberrant fibroblast activation in SSc, augmentation of this endogenous regulation by knockdown of ALDH3A2 demonstrates potent antifibrotic potential in experimental dermal fibrosis, thereby providing first evidence for ALDH3A2 as a target for antifibrotic therapies.Disclosure of Interests:Xiaohan Xu: None declared, Yi-Nan Li: None declared, Chih-Wei Chen: None declared, Thuong Trinh-Minh: None declared, Georg Schett: None declared, Jörg H.W. Distler Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB

Background:Autophagy is catabolic process allowing cells to degrade unnecessary or dysfunctional cellular organelles. Failure of appropriate regulation of autophagy, however, can severely perturb tissue homeostasis. Recent studies demonstrate that autophagy is activated in several fibrotic diseases such as liver fibrosis, renal interstitial fibrosis, cardiac fibrosis.Objectives:The objective of this work was to characterize the activation of autophagy in systemic sclerosis (SSc) and to decipher its role in the pathogenesis of SSc.Methods:Activation of autophagy in skin samples of patients and murine models of SSc was assessed by co-staining of LC3B and P62 with the lysosomal marker LAMP2. The role of the autophagy was investigated in the model of bleomycin-induced dermal fibrosis. Beclin1 was overexpressed using adenovirus encoding for Beclin1. To knockdown Atg7 in vivo was achieved by subcutaneous injections of Atg7 siRNA or non-targeting siRNA. In vivo, 3-methyladenine (3-MA) was administered i.p. in a concentration of 15 mg/kg ones daily. Protein expression was measured by Western blot. Target genes were analyzed by qPCR. To monitor the autophagic flux, we generated adenoviral vectors encoding for tandem fluorescent-tagged LC3 (mRFP-EGFP-LC3).Results:In the present study, we demonstrate that autophagy is activated in fibroblasts in SSc skin and also in experimental fibrosis models as compared to respective non-fibrotic control tissue with enhanced activity in in vivo and in vitro autophagy reporter studies. The aberrant activation of autophagy had profound stimulatory effects on fibroblasts. Activation of autophagy by forced expression of BECLIN1 promoted fibroblast-to-myofibroblast transition and stimulated the collagen release by cultured human fibroblasts and induced fibrosis in murine model. Nevertheless, inhibition of autophagy can deactivate myofibroblasts and induce regression of tissue fibrosis. Knockdown of ATG7 or BECLIN1 in human fibroblasts reduced the expression of αSMA and the number of stress fibers in myofibroblasts, indicating re-differentiation of myofibroblasts into resting fibroblasts upon inhibition of autophagy. Similar results were obtained with the autophagy inhibitors CQ and 3-MA. In vivo, siRNA mediated knockdown of Atg7 effectively prevented progression of fibrosis in a model of established bleomycin-induced skin fibrosis. Inactivation of autophagy decreased dermal thickness, myofibroblast counts and hydroxyproline content to below pretreatment levels, indicating regression of bleomycin-induced skin fibrosis. In addition, treatment of mice with the autophagy inhibitor 3-MA ameliorated bleomycin-induced skin fibrosis.Conclusion:We demonstrate that autophagy activity is enhanced in fibroblasts of SSc patients and in murine models of SSc. The increased activation of autophagy induces fibroblast-to-myofibroblast transition and promotes fibrotic tissue remodeling. However, inhibition of autophagy can deactivate myofibroblasts and induce regression of tissue fibrosis.References:[1]Wynn, T. Cellular and molecular mechanisms of fibrosis. J Pathol 214, 199-210 (2008).[2]Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151-175 (2008).[3]Wang, CW & Klionsky, DJ. The molecular mechanism of autophagy. Mol Med 9, 65-76 (2003).[4]Hernández-Gea V, Ghiassi-Nejad Z, Rozenfeld R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938-946 (2012).Disclosure of Interests:Ariella Zehender: None declared, Yi-Nan Li: None declared, Neng-Yu Lin: None declared, Andrea-Hermina Györfi: None declared, Alina Soare: None declared, Christina Bergmann: None declared, Andreas Ramming: None declared, Georg Schett: None declared, Jörg H.W. Distler Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB., Grant/research support from: Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingel-heim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB., Employee of: stock owner of 4D Science and Scientific head of FibroCure

CeO2 films were prepared by chemical solution deposition on Ni–5 at% W substrates with special surface morphologies. The special morphologies of the NiW substrates including pores and grooves could be obtained by an electrochemical etching process. The influence of substrate surface morphologies on the nucleation and growth behaviors of cerium oxide films was investigated. The micropores had a strong influence on the random nucleation of the CeO2 films. With increasing pore size on the surface of the NiW substrates, the epitaxial nucleation mode became the dominant mode. The amount of c-axis-oriented grains increased and the in-plane FWHM values decreased. On the other hand, the grooves had a weak effect on the crystallization of the CeO2 films. Pure (00l)-oriented grains and sharp texture of the CeO2 films could be acquired on the substrate with large grooves. This reveals that the substrate surface morphology plays a vital role in the crystallization behaviors of CeO2 films.

Finding new luminescent materials is always a meaningful goal in the field of photoelectricity studies. Herein, a new diphosphate compound Ba2LiGa(P2O7)2 (BLGP) was prepared using a high-temperature flux method. It displays an anionic chain structure of [LiGa(P2O7)2]∞, constructed from P2O7, LiO5 and GaO6 polyhedra. The Ba2+ ions are distributed in the voids between the [LiGa(P2O7)2]∞ chains, bonding them and maintaining charge balance. To test its potential as a luminescent host, Eu3+ doped phosphors BLGP:xEu3+ (x = 0.05, 0.10, 0.15, 0.20, 0.25 and 0.30) were synthesized and studied in detail. Upon 394 nm light irradiation, BLGP:xEu3+ showed bright orange emission with a dominant peak at 595 nm due to the 5D0 → 7F1 transition of Eu3+. The optimal doping amount of Eu3+ is 0.20, and the internal quantum efficiency of the phosphor B1.8LGP:0.2Eu3+ was determined to be 67%. The temperature quenching behavior of B1.8LGP:0.2Eu3+ was studied, suggesting that the photoluminescence (PL) intensity decreased to about 50% at 450 K due to thermal quenching. All these features show that this compound is a good luminescent host material for Eu3+ activators.

This study detected the expressions of microRNA-26a (miR-26a), miR-146a and miR-31 in lung tissues and BALF (bronchoalveolar lavage fluid) of asthma mice and children. Besides, cytokine levels of interleukin-5 (IL-5), IL-8, IL-12 and tumor necrosis factor-α (TNF-α) were detected as well. We aim to provide an experimental basis for clinical treatment of asthma.Forty female BALB/c mice were randomly assigned into control group and asthma group, respectively. Mice in asthma group (n=20) were immunized by intraperitoneal injection of OVA (ovalbumin) and provoked by atomization inhalation of OVA from the 15th day for 10 days. Mice in control group (n=20) were immunized and provoked with isodose saline during the same period. At the 26th day, mice were sacrificed for collecting lung tissues and BALF. Besides, we enrolled 17 cases of asthma children and 13 cases of children with airway foreign body as controls. BALF of each subject was collected. Total cellular score and differential counting in BALF were recorded. Expression levels of miR-26a, miR-146a, and miR-31 were detected by reverse transcription-polymerase chain reaction (RT-PCR). Levels of IL-5, IL-8, IL-12, and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA).The total cellular score in BALF of asthma mice and asthma children was higher than that of controls (p0.05). Percentages of eosinophils, neutrophils, and lymphocytes in BALF of asthma mice and asthma children were higher than those of controls, whereas the percentage of macrophages was lower (p0.05). Levels of IL-5, IL-8, IL-12, and TNF-α in lung tissues of asthma mice were markedly elevated compared with those of controls (p0.05). Similarly, levels of IL-5, IL-8, IL-12, and TNF-α were higher in BALF of asthma children than controls (p0.05). RT-PCR data showed higher mRNA levels of miR-26a, miR-146a, and miR-31 in lung tissues of asthma mice than controls (p0.05). The mRNA levels of miR-26a, miR-146a, and miR-31 in BALF of asthma children were highly expressed compared with those of controls as well (p0.05).MiR-26a, miR-146a, and miR-31 are involved in asthma progression mainly through regulating inflammatory factors and cells.

MicroRNAs (miRNAs) have critical roles in the progression of prostate cancer (PCa) and have the potential to be used as prognosis biomarkers. In this study, we aimed to investigate the role of miR-425-5p in the progression of PCa.miR-425-5p expression in PCa tumor tissues and cell lines was measured by Quantitative Real-time PCR (RT-qPCR). Effects of miR-425-5p expression on PCa cell proliferation, colony formation, cell migration, and cell invasion were measured.We found miR-425-5p expression was elevated in both PCa tissues and cell lines. Importantly, we found overexpression of miR-425-5p promoted proliferation, colony formation, migration and invasion of PCa cell lines in vitro. Forkhead box J3 (FOXJ3) was validated as a downstream target of miR-425-5p. Finally, we found the stimulation effects of miR-425-5p on PCa cell behaviors were fulfilled through directly regulating the expression of FOXJ3, which validated FOXJ3 as a functional target of miR-425-5p in PCa.Taken together, our results demonstrated miR-425-5p may contribute the malignancy progression of PCa in a mechanism involving FOXJ3, implicating miR-425-5p may be developed as therapeutic target for PCa in the future.

To study the effects of disintegrin and metalloproteinase (ADAM) 9, 15 and 17 on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs).BMMSCs of ADAM9, ADAM15, ADAM17 conditional knockout mice and wild type mice (WT) were induced and cultured. Alkaline phosphatase (ALP) activity was measured by colorimetry, early osteogenic transcription factors Runx and Osterix were detected by Real-time PCR, and mineral formation was analyzed by alizarin red staining.ALP activity was lower in ADAM9 group (8.08±0.34), ADAM15 group (6.46±3.40), ADAM17 group (9.30±2.30) than that in WT group (9.44±2.50), but there was no significant difference (P0.05). Stimulated with bone morphogenetic protein 2(BMP2),there was significant difference (P0.05) between ADAM9 group (14.22±3.25), ADAM15 group (10.14±2.40) and WT group (20.89±3.40), and ADAM 17 group (23.56±2.50) was higher than WT group (20.89±3.40), but no significant difference (P0.05). Similarly, cultured by osteogenic induction medium (OST), compared with WT group (12.97±1.30), ADAM9 group (9.63±1.00) and ADAM15 group (7.75±1.30) were lower, ADAM17 group (20.09±1.68) was higher, and the difference was statistically significant (P0.05). Using stimulated culture by BMP2 and OST combined, ADAM9 group (15.75±1.30), ADAM 15 group (12.43±1.30) were less than WT group (26.15 ±1.50), while ADAM17 group (29.55±2.10) was higher than WT group were statistically significant (P0.05). The expression of Runx2 in ADAM9 group (2.02±0.24), ADAM15 group (3.09±0.19), ADAM17 group (3.89±0.91) had no significant difference compared with WT (2.02±0.21) group (P0.05). ADAM9 group stimulated by BMP2 (7.00±0.23), ADAM15 group (6.04±0.23) were lower than WT group (12.6±0.23), ADAM17 group (18.52±1.39) was higher than WT group (12.6±0.23), and the difference was statistically significant (P0.05). In non-stimulating culture, there was no significant difference in Osterix expression between ADAM9 group (9.60±3.87), ADAM17 group (12.40±3.00) and WT group (10.9±1.10, P0.05), but in ADAM15 group (6.50±1.51) it was slightly lower than that in WT group (P0.05). After BMP2 stimulation, ADAM9 group (39.20±3.23) and ADAM15 group (20.50±4.80) were less than WT group (60.30±5.93), while ADAM17 group (80.20±3.30) was higher than WT group (P0.05). Alizarin red staining showed no obvious orange-red mass in the non-induction group. Local calcified nodules could be seen in the BMP2, OST, OST + BMP2 induction culture conditions in all the experimental groups, but there was no significant difference in quantitative analysis (P0.05).ADAM9, 15, 17 took part in the osteogenic differentiation of BMMSCs, and provided new targets for its regulation.

It is known that childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood. Previous studies have demonstrated that gender, ADHD symptoms, functional impairment severity, medication treatment, IQ, comorbid with oppositional defiant disorder, conduct disorder and follow-up periods were associated with ADHD persistence in longitudinal samples of western population. In this study, we attempted to widely investigate the predictors particularly in a Chinese Han ADHD cohort. 399 children who met DSM-IV ADHD criteria were followed up into early adulthood. Ordinal logistic regression combined with survival analysis were conducted to examine the association of retrospectively reported childhood factors with adult ADHD persistence based on both categorical indicators and quantitative traits. 46.37% of the participants still met ADHD criteria in adulthood. Logistic models and survival analyses indicated that ADHD combined type appeared as a significant risk factor for ADHD persistence while superior IQ played a protective role even after controlling for the other potential confounders. When quantitative traits were applied, a number of hyperactivity/impulsivity symptoms and IQ still made significant contributions. In conclusion, our results indicated the syndromic continuity of ADHD. Further, a number of hyperactivity/impulsivity symptoms were a risk factor while higher IQ was protective for ADHD persistence.

Background:Autophagy is catabolic process allowing cells to degrade unnecessary or dysfunctional cellular organelles. Failure of appropriate regulation of autophagy, however, can severely perturb tissue homeostasis. Several stimuli present in fibrosis such as pro-fibrotic cytokines are known to activate autophagy.Objectives:The objective of this work was to characterize the regulation of autophagy in systemic sclerosis (SSc) and to decipher its role in the pathogenesis of SSc.Methods:Activation of autophagy in SSc skin and matched tissue samples from healthy individuals was assessed by immunofluorescence staining for ATG7, BECLIN1 and P62. We generatedAtg7fl/flxCol1a2;CreER mice to selectively disable autophagy in fibroblasts. The role of the autophagy was investigated in the model of bleomycin- and TβRIact-induced dermal and pulmonary fibrosis. Overexpression of Myst1 was achieved by adenovirus encoding forMyst1. Collagen release and protein expression were measure by Western blot. Target genes were analyzed by RT-PCR. Co-immunoprecipitation and reporter assay were performed to study physical and functional interactions between MYST1 and SMAD3. To monitor the autophagic fluxin vitroandin vivowe generated adenoviral vectors encoding for tandem fluorescent-tagged LC3 (mRFP-EGFP-LC3).Results:Transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy, deregulated epigenetics in fibrotic diseases and may open new avenues for therapeutic intervention in fibrotic diseases.Conclusion:We demonstrate that the epigenetic control of autophagy is disturbed by a TGFβ-dependent downregulation of the H4K16 histone acetyltransferase MYST1. The increased activation of autophagy induces fibroblast-to-myofibroblast transition and promotes fibrotic tissue remodeling. Re-expression of MYST1 prevents aberrant autophagy, limits the profibrotic effects of TGFβ and ameliorates experimental fibrosis. Restoration of the epigenetic control of autophagy might thus be a novel approach to ameliorate fibrotic tissue remodeling.References:[1]Wynn, T.A. Cellular and molecular mechanisms of fibrosis. J Pathol 214, 199-210 (2008).[2]Distler, J.H., et al. Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis. Arthritis & rheumatology (Hoboken, N.J.) 69, 257-267 (2017).[3]Gyorfi, A.H., Matei, A.E. & Distler, J.H.W. Targeting TGF-beta signaling for the treatment of fibrosis. Matrix biology: journal of the International Society for Matrix Biology 68-69, 8-27 (2018).[4]Wang, C.W. & Klionsky, D.J. The molecular mechanism of autophagy. Mol Med 9, 65-76 (2003).[5]Hernandez-Gea, V., et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938-946 (2012).Disclosure of Interests:Ariella Zehender: None declared, Neng Yu Lin: None declared, Yi-Nan Li: None declared, Andrea-Hermina Györfi: None declared, Christina Bergmann: None declared, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim

Background:Fibroblast growth factor receptor 3 (FGFR3) is a member of the family of different fibroblast growth factor receptors with several ligands called fibroblast growth factors (FGFs) in humans. Each FGFR has different isoforms resulting from natural alternative splice variants. Upon binding FGF ligands, fibroblast growth factor receptors (FGFRs) trigger various intracellular signaling pathways to regulate important biological processes. Systematic evaluation of FGF/FGFR signaling in the context of SSc has not been performed so far.Objectives:The aim of this study was to characterize FGFR3/FGF9 signaling in the context of fibroblast activation and to evaluate FGFR3 as a potential molecular target for antifibrotic treatment in SSc.Methods:Differential expression profiling of dermal cells from SSc patients and healthy volunteers were performed employing GEArray cDNA microarray. Real-time PCR, Western Blot, immunohistochemistry and immunofluorescence were done in skin tissues and fibroblasts from SSc patients. Selective inhibitors in conjunction with genetic knockdown and knockout strategies were used to target FGFR3 signalingin vitroand in mouse models of SSc: skin fibrosis induced by bleomycin and by overexpression of a constitutively active transforming growth factor receptor 1 (TBR) and tight skin-1 (TSK) mice. Affymetrix gene arrays in dermal fibroblasts from mice with constitutive FGFR3 signaling and mice lacking FGFR3.Results:Expression of FGFR3, specifically the isoform FGFR3IIIb and its ligand FGF9, was significantly upregulated in the dermis and dermal fibroblasts of SSc patients as compared to healthy volunteers. Furthermore, an increase of FGFR3 IIIb/FGF9 expression comparable to that in SSc fibroblasts could also be obtained by stimulating normal healthy dermal fibroblasts with transforming growth factor (TGFβ)in vitroand in mice constitutively overexpressing active TGFβ receptor type I.Transcriptome profiling,in silicoanalysis and functional experiments revealed that FGFR3 synergistigically induces multiple profibrotic pathways including Endothelin-, Interleukin-4- and CTGF-signaling in a CREB-dependent manner. FGFR3 exerts profibrotic effects by modulating phosphorylation of CREB by ERK-, AKT-, CAMK2- and p38-kinases. Activation of FGFR3 in healthy or SSc dermal fibroblasts by stimulation with recombinant FGF9 was sufficient to induce resting fibroblast-to-myofibroblast differentiation along with increased collagen secretion and alpha-SMA production.Genetic knockout of Fgfr3 abrogates myofibroblast differentiationin vitroand ameliorates skin fibrosis in TSK and TBR mice and in bleomycin-induced fibrosis. Further confirming the translational potential of these findings in the preclinical models of SSc, we demonstrate that pharmacological inactivation of FGFR3 by PD173074 could induce the regression of experimental fibrosis invitroand in bleomycin-challenged, TSK and TBR mice.Conclusion:Our findings characterize FGFR3 as an upstream regulator of a network of profibrotic mediators in SSc and thus, we could demonstrate successfully that the targeted inhibition of FGFR3 could inhibit multiple signaling pathwaysin vitroand ameliorated fibrosis in different preclinical models of SSc. These findings may have direct translational implications as FGFR3 inhibitors are currently in development.Disclosure of Interests:Debomita Chakraborty: None declared, Honglin Zhu: None declared, Astrid Juengel: None declared, Lena Summa: None declared, Yi-Nan Li: None declared, Christina Bergmann: None declared, Alexandru-Emil Matei: None declared, Thuong Trinh-Minh: None declared, Chih-Wei Chen: None declared, Clara Dees: None declared, Andreas Ramming: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim

Background:The complex pathophysiological processes that result in fibrotic tissue remodeling in systemic sclerosis involve interplay between multiple cell types (1). Experimental models of fibrosis are essential to provide a conceptual understanding of the pathogenesis of these diseases and to test antifibrotic drugs. Current models of fibrosis have important limitations: thein vivomodels rely on species that are phylogenetically distant, whereas thein vitromodels are oversimplified cultures of a single cell type in an artificial two-dimensional environment of excessive stiffness, which imposes an unphysiological cell polarization (2).Objectives:Here we evaluated the potential use of vascularized, three-dimensionalin vitrohuman skin equivalents as a novel model of skin fibrosis and a platform for the evaluation of antifibrotic drugs.Methods:Skin equivalents were generated by seeding human endothelial cells, fibroblasts and keratinocytes on a decellularized porcine extracellular matrix with perfusable vascular structure. The skin models were cultured for one month in a system that ensured perfusion of the vascular network at physiological pressure. Fibrotic transformation induced by TGFβ and response to nintedanib as an established antifibrotic drug was evaluated by capillary Western immunoassays, qPCR, histology and immunostaining.Results:The vascularized human skin equivalents formed the major skin structures relevant for the pathogenesis of fibrosis: a polarized, fully matured epidermis, a stratified dermis and a perfused vessel system with small capillaries. Exposure to TGFβ led to the fibrotic transformation of the skin equivalents, with activated TGFβ downstream pathways, increased fibroblast-to-myofibroblast transition and excessive deposition of extracellular matrix. Treatment of models exposed to TGFβ with nintedanib (a drug with proven antifibrotic effects) ameliorated the fibrotic transformation of skin equivalents with reduced TGFβ signaling, fibroblast-to-myofibroblast transition and decreased extracellular matrix deposition.Conclusion:Here we describe a novelin vitromodel of skin fibrosis. Our data show that vascularized skin equivalents can reproduce all skin layers affected by fibrosis, that, upon exposure to TGFβ, these models recapitulate key features of fibrotic skin and that these skin models can be used as a platform for evaluation of antifibrotic drugs in a setting with high relevance for human disease.References:[1]Distler JHW, Gyorfi AH, Ramanujam M, Whitfield ML, Konigshoff M, Lafyatis R. Shared and distinct mechanisms of fibrosis. Nature reviews Rheumatology. 2019;15(12):705-30.[2]Garrett SM, Baker Frost D, Feghali-Bostwick C. The mighty fibroblast and its utility in scleroderma research. Journal of scleroderma and related disorders. 2017;2(2):69-134.Disclosure of Interests:Alexandru-Emil Matei: None declared, Chih-Wei Chen: None declared, Lisa Kiesewetter: None declared, Andrea-Hermina Györfi: None declared, Yi-Nan Li: None declared, Thuong Trinh-Minh: None declared, Toin van Kuppevelt: None declared, Jan Hansmann: None declared, Astrid Juengel: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Florian Groeber-Becker: None declared, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim

Synopsis We investigate the polarization characteristics of terahertz (THz) emission from gaseous plasma induced by the two-color incommensurate femtosecond laser fields, which contains a circularly polarized laser field and a linear pulse. Our simulations show that strong linearly, elliptically, and circularly polarized THz radiation can be generated, by choosing appropriate wavelength, carrier-envelope phase and intensity for linear pump pulse.

Sinus floor elevation was needed in 11 patients having 15 implant sites with the residual bone height (RBH) was less than 10 mm in the posterior maxillary region from Feb to May 2017. The RBH ranged from 3.10 to 8.34 mm [averaged (6.18±1.60) mm]. RBH6 mm was observed in 40% implant sites (6 implant sites) and RBH≥6 mm was observed in 60% implant sites (9 implant sites). The thickness of the sinus floor membrane correspond to the implant site measured by cone beam CT (CBCT) ranged from 0.50 to 4.24 mm [averaged (1.21±0.92) mm]. Sequential drills with stops were used to perforate the cortical bone of the sinus floor firstly, then the transcrestal around detached sinus floor elevation technique (TADSFET) was carried with osteotomes. Anorganic bovine bone was used as the augmentation material.Fifteen implants were placed in 15 implant sites. CBCT pictures showed that there was a smooth and continuous tent-shaped apophysis on each lifted site and no air fluid level was observed in the sinus immediately after operation. The mean elevated height of the 15 implant sites was (7.83±1.57) mm (ranged from 5.94 to 11.01 mm). The mean follow-up time was 7.91 months (7-10 months). The survival rate was 100% during the follow up period.纳入2017年2月至5月于清华大学附属垂杨柳医院口腔科就诊的11例上颌后牙缺失患者（15个种植位点），术前锥形束CT测量剩余骨高度（residual bone height，RBH）10 mm，需行上颌窦底提升术。术前RBH为（6.18±1.60）mm [（3.10~8.34）mm]，其中6个位点RBH6 mm，9个位点RBH≥6 mm。种植位点对应上颌窦底黏膜厚度（1.21±0.92）mm [（0.50~4.24）mm]。15个种植位点均应用带止动环序列钻逐级备洞磨穿上颌窦底骨皮质后用新型骨凿行穿牙槽嵴顶四周剥离上颌窦底提升术，术中植入无机牛骨基质及种植体15枚。术后即刻拍摄锥形束CT显示所有上颌窦底提升种植位点区域均形成一外形连续界限清晰的"帐篷状"隆起，上颌窦内均未见异常液平面。上颌窦底提升高度（7.83±1.57）mm [（5.94~11.01）mm]。随访7~10个月，随访期间所有种植体均存留无松动脱落。.

In this study, we aimed at investigating whether MEG3 may be involved in the pathogenesis of glaucoma by regulating the autophagy of retinal ganglion cells (RGCs).We used qRT-PCR to detect the expression of MEG3 in RGC-5s cell line under high hydrostatic pressure. RGC-5s were transfected with a lentiviral vector to achieve MEG3 overexpression or knockdown. The influence of overexpression or inhibition of MEG3 on cell proliferation and apoptosis was observed using CCK-8 test and flow cytometry. After overexpression of MEG3 and/or knockdown of MEG3 or Beclin-1, detection of the expressions of autophagy-related and apoptosis-related proteins was performed using Western blot.MEG3 expression level increased in RGC-5 cells under high hydrostatic pressure, while exogenously decreased MEG3 expression can reverse the impact of the high pressure on RGC-5 cells. Additionally, overexpression of MEG3 can improve Atg3 expression, promote cell apoptosis, inhibit cell proliferation, and enhance autophagy levels. Meanwhile, knockdown of Beclin-1 up-regulated Bcl-2 level.Upregulation of MEG3 is involved in the pathogenesis of glaucoma through promoting apoptosis of retinal ganglion cells, the mechanism of which may be related to the enhanced autophagy levels.

The differentiation between autoimmune hepatitis (AIH) and drug-induced liver injury (DILI) is a difficult task in clinical practice. Some AIH patients had a medication history before disease onset, and some DILI patients may have positive serum antibody. In addition, these two groups of patients have similar clinical symptoms, serological examination results, and liver histopathology, which lead to the difficulties in differentiation. However, correct differential diagnosis is of great significance in making clinical treatment decisions and preventing liver cirrhosis. Therefore, it is necessary to investigate the association between immunological and drug-induced liver injury from the perspectives of pathogenesis, similarities and differences in clinical features, serological examination results, and histological changes, prospects of new biomarkers in differentiation, and the significance of hormone therapy and clinical follow-up in differential diagnosis and treatment, in order to provide a reference for clinical decision-making and research in future.自身免疫性肝炎（AIH）和药物性肝损伤（DILI）的鉴别是临床工作的难点。部分AIH患者发病前有用药史，一些DILI患者可以出现血清抗体阳性，除此之外二者的临床症状、血清学检查结果和肝组织病理学改变也非常相似，这些特点导致了二者鉴别的困难，但正确的鉴别诊断对临床治疗决策、预防肝硬化的发生具有重要意义。因此，有必要探讨AIH和DILI在发病机制方面的关系，在临床特点、血清学检查结果和组织学改变方面的异同，以及新型标志物在二者鉴别方面的作用，以及激素治疗和临床随诊在鉴别诊断和治疗中的意义，以便为今后的临床决策和研究提供参考。.

To evaluate the application of 43-plex SNP typing system in forensic science.The typing of 43 SNP loci in 123 unrelated Han individuals from East China was detected by MALDI-TOF-MS. The application value of 43-plex SNP typing system was assessed according to the forensic parameters of population genetics.All the 43 SNP loci of 123 individuals showed no significant departure from Hardy-Weinberg equilibrium （The 43-plex SNP typing system in present study shows a high polymorphism, which can be an effective supplement and verification for traditional STR genetic markers. It also can be used with other commercial kits for the forensic paternity testing and individual identification.