炎症因子在糖尿病性干眼患者中的表达变化及其意义

目的研究炎症因子在糖尿病性干眼患者中的表达变化及意义。方法选择符合干眼病诊断标准的糖尿病患者(糖尿病干眼组102例102眼)及正常对照者(正常对照组84例84眼)。所有受检者均接受干眼症状询问及相关检查如:泪膜破裂时间(tear break-up time,BUT),泪液分泌试验(schirmerⅠtest,SⅠT)及角膜荧光素染色(fluoresce in staining,FLS)评分。将两组结膜上皮细胞进行印迹细胞学检查和免疫组织化学染色。采用双抗体夹心酶联免疫吸附试验法(enzyme-linked immunosorbent assay,ELISA)检测所收集的泪液中炎症因子的浓度。结果免疫组织化学染色结果显示:糖尿病组患者的结膜上皮细胞中转化生长因子β1(transforming growth factorβ1,TGF-β1)与转录因子-κB(nuclear factorκB,NF-κB)的阳性表达率均明显高于正常对照组,差异均具有统计学意义(P=0.008、0.016),Spearman相关性分析结果显示,两者之间显著正相关(r=0.654,P=0.005)。ELISA法检测结果显示,糖尿病组患者的泪液中白细胞介素-1β(interleukin 1β,IL-1β)、肿瘤坏死因子-α(tumor necrosis factorα,TNF-α)、趋化因子3(chemokine C-C ligand 3,CCL3)、CCL4、CCL5及血管内皮生长因子(vascular endothelial growth factor,VEGF)的浓度均明显高于正常对照组,差异均有统计学意义(均为P<0.05)。结论 IL-1β、CCL3、TNF-α、TGF-β1等都在糖尿病性干眼患者的结膜上皮细胞及泪液中高表达,并有临床指导意义。国家自然科学基金(编号:81460091、81560167)~

Regularity of Solutions for the Evolution p-Laplacian Equations

Consider t he Cauchy pr oblem fo r the evolutio n p-Laplacian equation In terms of the uniform estimates to the r egulized solutions of the problem above, w e prove that ？ , where the Holder exponent with r espect to this great than ？2

Development and Application of a Novel Neutralization Test for Echovirus 25

目的:建立一种新型的快速、高通量的埃可病毒25型(ECHO25)中和抗体检测方法,并初步评价其在ECHO25中和抗体筛选和血清流行病学调查中的应用价值。方法:应用免疫荧光方法筛选ECHO25高亲和性抗体并将其作为检测单抗,结合酶联免疫斑点检测技术(ELISPOT)建立ECHO25中和抗体检测方法;使用不同效价的血清评价该方法的准确性;采用所建立的中和方法对ECHO25单克隆抗体、临床血清样品进行检测。结果:建立了快速检测ECHO25中和抗体的Nt-ELISPOT方法,以ECHO25单克隆抗体5B9作为检测抗体;相比经典的中和实验方法 Nt-CPE,该方法可显著缩短检测时间(从5~7 d缩短至1 d以内),检测结果具有较好的一致性;采用所建立的Nt-ELISPOT方法首次筛选获得3株对ECHO25具有较好中和能力的单克隆抗体;临床血清样品检测结果显示厦门地区可能存在ECHO25的流行。结论:该方法可以应用于中和抗体筛选和血清学的临床辅助诊断,为ECHO25的防治研究提供支持。Objective: To establish a rapid and high-throughput neutralization test for echovirus 25(ECHO25),and evaluate its application in neutralizing antibody screening and seroepidemiological surveys. Methods: Immuno-fluorescence assay was applied to screen a high affinity antibody, which was used as the detection antibody forECHO25, and a rapid neutralization test was established based on enzyme- linked immunospot assay(Nt-ELISPOT). The accuracy of this method was evaluated by detecting serum samples with different titer. Monoclonalantibodies against ECHO25 and clinical serum samples were detected via the established neutralization test. Results: A rapid method to detect neutralizing antibody against ECHO25 was established and an anti-ECHO25 anti-body, 5B9, was used as the detection antibody. The detection period could be shortened significantly comparedwith the classical neutralization test(Nt- CPE)(from five to seven days to less than one day), and the Nt-ELISPOT had good consistency with the Nt- CPE. Meanwhile, three neutralizing antibodies for ECHO25 werescreened firstly by this method. The detection results of clinical serum samples showed that infection of ECHO25 might be popular in Xiamen. Conclusion: This method can be used in neutralizing antibody screening and seroepi-demiological surveys, and it may provide support for the control of ECHO25.国家自然科学基金(81371817,81401669

Combined Use of Thoracoscopy and Laparoscopy in Total Laryngectomy for Cervical Esophageal Carcinoma

目的探讨胸、腹腔镜联合全喉切除治疗颈段食管的可行性和疗效。方法 2009年1月~2014年7月胸、腹腔镜联合全喉切除治疗33例颈段食管癌。胸腔镜下分离食管、腹腔镜下管胃成形、全喉切除、气管永久造口、胃咽吻合术。结果胸部手术时间40~66 MIn,平均53 MIn;腹部手术时间35~51 MIn,平均44 MIn;颈部手术时间128~150 MIn,平均139 MIn。术中出血量130~270 Ml,平均150 Ml。术后住院时间8~14 d,平均12 d。病理均为鳞状细胞癌,其中高分化2例,中分化19例,中-低分化7例,低分化5例。切缘病理学检查无癌组织残留。31例淋巴结转移。并发症:吻合口漏2例,喉返神经损伤3例,肺部感染6例,胃排空障碍2例,吻合口狭窄1例,无死亡病例。33例随访1个月~5年,术后1、3、5年生存率分别为87.9%、54.5%、45.5%。结论颈段食管癌应采取积极的手术治疗,胃咽吻合术是颈段食管癌切除后较为理想的修复手段。Objective To investigate clinical feasibility and efficacy of combined use of thoracoscopy and laparoscopy in total laryngectomy for cervical esophageal carcinoma.Methods Clinical data of 33 patients with cervical esophageal carcinoma undergoing surgical treatment in our department from January 2009 to July 2014 were analyzed retrospectively.The esophagus was separated under thoracoscopy.And laparoscopic gastroplasty,total laryngectomy,tracheal permanent colostomy,and gastric pharyngeal anastomosis were performed.Results The thoracoscopic operation time was 40- 66 min( mean,53 min),the laparoscopic operation time was 35- 51 min( mean,44 min),and the cervical operation time was 128- 150 min( mean,139 min).The blood loss was 130- 270 ml( mean,150 ml).The postoperative hospital stay was 8- 14 d( mean,12 d).Pathological examinations showed squamous cell carcinoma in all the cases,including 2 cases of highly differentiated carcinoma,19 cases of moderately differentiated carcinoma,7 cases of moderately or lowly differentiated carcinoma,and 5 cases of lowly differentiated carcinoma.No residual cancer was found at cutting edges pathologically.Among the 33 cases,lymph node metastasis was found in 31 cases.Complications included 2 cases of anastomotic fistula,3 cases of recurrent laryngeal nerve injury,6 cases of pulmonary infection,2cases of delayed gastric emptying,and 1 case of anastomotic stenosis.There was no death.All the patients were followed up for 1months to 5 years.The survival rates at 1,3,and 5 postoperative year were 87.9%,54.5%,and 45.5%,respectively.Conclusions Cervical esophageal carcinoma should be surgically treated actively.Gastric pharyngeal anastomosis is an ideal option for the repair of cervical esophageal cancer resection

Video-assisted Thoracoscopic 3D Mode Operation for Solitary Pulmonary Nodules

目的探讨三维胸腔镜手术(3d VIdEO-ASSISTEd THOrACIC SurgEry,3d-VATS治疗孤立性肺结节(SOlITAry PulMOnAry nOdulE,SPn)的效果。方法回顾性分析2013年3月~2014年3月50例SPn的资料,采用3d-VATS手术模式楔形切除结节,根据快速病理结果决定是否行肺叶切除加淋巴结清扫术。统计手术时间(去除快速冰冻时间)、术后24 H引流量、总引流量、引流管拔除时间、淋巴结清扫数及术后并发症等。结果 3d-VATS模式下,50例均行肺结节楔形切除,其中23例病理为恶性,继续行肺癌根治术,手术顺利。肺癌根治术手术时间(62±12)MIn,术中出血量(35±5)Ml,清扫淋巴结(19±3)个,术后24 H引流量(120±20)Ml,术后胸管引流时间(4±1)d,术后住院时间(7±2)d。并发症3例,其中术后肺炎2例,阵发性心房纤颤1例,均治愈。无围手术期死亡。随访2~12个月,平均6.3月。1例术后3个月脑转移,1例术后5个月肺癌复发。结论胸腔镜3d模式下治疗SPn是一种新的选择方式,安全可行,值得推广应用。Objective To evaluate the effects of surgical treatment for solitary pulmonary nodules under thoracoscopic 3D mode(3D-VATS).Methods A total of 50 cases of solitary pulmonary nodules from March 2013 to March 2014 were retrospectively analyzed.Intraoperative wedge pulmonary resection with 3D-VATS was utilized.According to intraoperative pathological findings,lobectomy plus lymph node dissection was given or not.Intraoperative time( minus fast freezing time),drainage volume for 24 h,total drainage volume,drainage tube removal time,number of lymph node dissected,and postoperative complications were recorded.Results Under 3D-VATS mode,50 cases of solitary pulmonary nodules were treated with wedge resection,including 23 cases of malignant pathology receiving radical resection, which was smoothly.The radical resection time( lung lobectomy plus lymphadenectomy) was(62 ± 12) min,the bleeding volume was(35 ± 5) ml,the lymphadenectomy number was 19 ± 3,the drainage volume for 24 h was(120 ± 20) ml,the postoperative chest tube removal time was(4 ± 1) days,and the postoperative hospital stay was(7 ± 2) days.Postoperative complications occurred in 3 cases,including 2 cases of pneumonia and 1 case of paroxysmal atrial fibrillation.No perioperative deaths were observed.All the cases were followed up for 2- 12 months,with an average of 6.3 months.Brain metastases was found in 1 case at the third postoperative month and recurrence of lung cancer was noted in 1 case at the fifth postoperative month.Conclusion Thoracoscopic 3D mode treatment for solitary pulmonary nodules is a new,safe,and feasible alternative and should be widely applied

Y型聚乙二醇干扰素琢-2b注射液治疗HCV基因2/3型慢性丙型肝炎患者疗效和安全性的多中心随机对照试验研究

目的以标准剂量的聚乙二醇干扰素(Peg IFN)α-2a联合利巴韦林作为阳性对照,评价新型试验药物Y型Peg IFNα-2b注射液联合利巴韦林治疗2型/3型慢性丙型肝炎(CHC)患者的疗效和安全性。方法采用多中心、随机开放、阳性药对照的Ⅲ期临床试验,筛选符合要求的2型/3型CHC患者,按照2:1的比例随机分配到Y型Peg IFNα-2b组和Peg IFNα-2a组,同时口服利巴韦林,疗程24 w,停药随访24 w。采用Abbott Real Time HCV Genotype II检测HCV基因型,采用Cobas Taq Man实时定量PCR法检测血清HCV RNA水平。详细记录不良事件。主要疗效指标为持续病毒学应答(SVR),并进行非劣效检验。结果本试验实际入组2型/3型CHC患者255例,实际治疗241例。全分析集(FAS)数据显示,158例试验组和83例对照组患者SVR分别为85.4%(95%CI 79.94%~90.94%)和79.5%(95%CI 70.84%~88.20%,P=0.2402);对符合方案分析集(PPS)人群分析显示,试验组和对照组患者SVR分别为87.9%(95%CI 82.45%~93.27%)和85.9%(95%CI 77.82%~94.01%,P=0.7060),率差的95%可置信区间均符合非劣效标准;对PPS人群分析显示,85.8%受试者获得了早期病毒学应答(RVR),RVR的阳性预测值为90.1%;试验组和对照组不良事件发生率相似,分别为95.6%和95.2%,严重不良事件发生率分别为3.8%和3.6%。结论应用Peg IFNα联合利巴韦林治疗2型/3型CHC患者,新型试验药物Y型Peg IFNα-2b具有与对照药物Peg IFNα-2a相似的疗效和安全性。国家科技部“十二五”重大专项(编号:2012ZX10002-003)；“重大新药创制”十二五科技重大专项(编号:2012ZX09303019)

Room-temperature quantum interference in single perovskite quantum dot junctions

钙钛矿材料由于其高量子产率、载流子迁移率和独特的光致发光特性而在光电材料领域存在诸多潜在的重要应用。研究钙钛矿材料在纳米尺度下电荷输运的独特尺寸效应对钙钛矿光电器件的设计和开发具有重要的指导意义。洪文晶教授课题组基于机械可控裂结技术自主研发了具有皮米级位移调控灵敏度和飞安级电学测量精度的精密科学仪器，对南开大学李跃龙副教授团队合成的钙钛矿量子点进行了深入表征，研究工作成功将量子干涉的研究体系拓展至在光电领域具有重要应用的钙钛矿材料领域，为未来制备基于量子干涉效应的新型钙钛矿器件提供了一种全新的思路。 这一跨学科国际合作研究工作是在化学化工学院洪文晶教授、英国Lancaster 大学物理系Colin J. Lambert教授以及南开大学电子信息与光电工程学院李跃龙副教授的共同指导下完成的。化工系硕士研究生郑海宁、Lancaster University大学Songjun Hou博士、南开大学硕士研究生辛晨光为论文第一作者。博士后林禄春，博士研究生谭志冰、郑珏婷，硕士研究生蒋枫、张珑漪，本科生何文翔、李庆民等参与了论文的研究工作。刘俊扬特任副研究员、师佳副教授和萨本栋微纳米研究院杨扬副教授也参与了部分指导工作。The studies of quantum interference effects through bulk perovskite materials at the Ångstrom scale still remain as a major challenge. Herein, we provide the observation of roomtemperature quantum interference effects in metal halide perovskite quantum dots (QDs) using the mechanically controllable break junction technique. Single-QD conductance measurements reveal that there are multiple conductance peaks for the CH3NH3PbBr3 and CH3NH3PbBr2.15Cl0.85 QDs, whose displacement distributions match the lattice constant of QDs, suggesting that the gold electrodes slide through different lattice sites of the QD via Auhalogen coupling. We also observe a distinct conductance ‘jump’ at the end of the sliding process, which is further evidence that quantum interference effects dominate charge transport in these single-QD junctions. This conductance ‘jump’ is also confirmed by our theoretical calculations utilizing density functional theory combined with quantum transport theory. Our measurements and theory create a pathway to exploit quantum interference effects in quantum-controlled perovskite materials.This work was supported by the National Key R&D Program of China (2017YFA0204902, 2014DFE60170, 2018YFB1500105), the National Natural Science Foundation of China (Nos. 21673195, 21503179, 21490573, 61674084, 61874167), the Open Fund of the Key Laboratory of Optical Information Science & Technology (Nankai University) of China, the Fundamental Research Funds for the Central Universities of China (63181321, 63191414, 96173224), and the 111 Project (B16027), the Tianjin Natural Science Foundation (17JCYBJC41400), FET Open project 767187—QuIET, the EU project BAC-TO-FUEL and the UK EPSRC projects EP/N017188/1, EP/M014452/1. 该工作得到国家重点研发计划课题（2017YFA0204902）、国家自然科学基金（21673195、21503179、21490573）、厦门大学“人工智能分析引擎”双一流重大专项等项目的资助，也得到了固体表面物理化学国家重点实验室、能源材料化学协同创新中心的支持

胰岛素降低海马谷氨酸及-Ｄ-丝氨酸含量改善糖尿病大鼠空间学习记忆能力

目的　观察胰岛素对糖尿病大鼠空间学习记忆及海马组织中谷氨酸、Ｄ-丝氨酸含量的影响。方法　采用尾静脉注射链脲佐菌素（ＳＴＺ）制备大鼠糖尿病（ＤＭ）模型。注射ＳＴＺ第３天模型成功后，每天 １次 ｓｃ给予胰岛素 ２Ｕ·ｋｇ－１，持续 ８２ｄ。定期检测各组动物体重及空腹血糖。造模 １１周后进行 Ｍｏｒｒｉｓ水迷宫实验，检测大鼠学习记忆能力；实验结束后取海马组织，观察形态变化，并测定谷氨酸及 Ｄ-丝氨酸含量。结果　与正常对照组比较，ＤＭ模型组大鼠体重明显减轻（Ｐ＜０．０１），血糖明显升高（Ｐ＜０．０１），逃避潜伏期明显延长及原平台象限游泳时间显著减少（Ｐ＜０．０１），海马组织中谷氨酸及Ｄ-丝氨酸的含量均显著升高（Ｐ＜０．０１）。胰岛素治疗组体重增加、血糖含量恢复到正常水平。与 ＤＭ模型组相比，胰岛素治疗组大鼠逃避潜伏期显著缩短（Ｐ＜０．０１），原平台象限游泳时间占总时间百分比显著增加（Ｐ＜０．０１）；海马组织中谷氨酸及Ｄ-丝氨酸的含量也分别由 ＤＭ模型组的（１．５５０±０．０５４）和（０．０８４±０．０５）ｍｇ·ｇ－１下降为胰岛素治疗组的（１．１３７±０．０２３）和（０．０６８±０．００４）ｍｇ·ｇ－１。结论　胰岛素可以改善糖尿病大鼠空间学习记忆能力，这可能与其降低海马组织中谷氨酸及Ｄ-丝氨酸的含量有关

A multimechanistic antibody targeting receptor-binding sites potently cross-protects against influenza B viruses

流感病毒HA是研制流感药物和流感疫苗的重要靶标，但HA具有高度变异性，如何在高变异HA中找到不变之处，即高度保守表位，是研制流感特效药物和广谱疫苗的关键。近年来国外报道的流感HA广谱中和单抗的识别位点均在较为保守的HA茎部区，而针对流感病毒与细胞受体结合部位的HA头部区尤其是RBS区，一直未能发现广谱中和抗体。夏宁邵教授团队通过探索多种免疫策略和筛选策略，成功筛选出一株广谱中和单抗12G6，识别一个位于HA头部RBS上的全新保守性表位。体外实验显示12G6人源化改造的C12G6抗体能高效中和1940-2016年间世界各地历年流行的代表三个遗传变异亚系的18个乙型流感病毒代表株对细胞的感染，并能保护小鼠致死性感染，治疗效果显著优于已报道的代表性抗体以及抗流感药物；C12G6与“达菲”联合用药具有明显的协同效果。此外，雪貂感染模型的预防和治疗效果进一步证实了C12G6作为抗体药物的治疗潜能。研究还显示该表位是病毒感染复制的关键表位，该位点的突变会造成病毒毒力显著下降。最后，研究揭示了C12G6通过五种不同的抗病毒作用机制发挥作用，提示其高效的抗病毒活性得益于多机制协同效应，这也是目前国内外第一次发现一个流感抗体能通过如此全面的抗病毒机制发挥作用。 该发现为研制能抵抗各种变异株的乙型流感特效治疗药物和通用疫苗带来新希望。 该研究工作依托分子疫苗学和分子诊断学国家重点实验室（厦门大学）、国家传染病诊断试剂与疫苗工程技术研究中心、厦门大学养生堂生物药物联合实验室完成。陈毅歆副教授、夏宁邵教授为该研究论文的共同通讯作者。在读博士研究生沈晨光、陈俊煜、李睿、王国松和硕士研究生张梦娅等为共同第一作者。【Abstract】Influenza B virus causes considerable disease burden worldwide annually, highlighting the limitations of current influenza vaccines and antiviral drugs. In recent years, broadly neutralizing antibodies (bnAbs) against hemagglutinin (HA) have emerged as a new approach for combating influenza. We describe the generation and characterization of a chimeric monoclonal antibody, C12G6, that cross-neutralizes representative viruses spanning the 76 years of influenza B antigenic evolution since 1940, including viruses belonging to the Yamagata, Victoria, and earlier lineages. Notably, C12G6 exhibits broad cross-lineage hemagglutination inhibition activity against influenza B viruses and has higher potency and breadth of neutralization when compared to four previously reported influenza B bnAbs. In vivo, C12G6 confers stronger cross-protection against Yamagata and Victoria lineages of influenza B viruses in mice and ferrets than other bnAbs or the anti-influenza drug oseltamivir and has an additive antiviral effect when administered in combination with oseltamivir. Epitope mapping indicated that C12G6 targets a conserved epitope that overlaps with the receptor binding site in the HA region of influenza B virus, indicating why it neutralizes virus so potently. Mechanistic analyses revealed that C12G6 inhibits influenza B viruses via multiple mechanisms, including preventing viral entry, egress, and HA-mediated membrane fusion and triggering antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity responses. C12G6 is therefore a promising candidate for the development of prophylactics or therapeutics against influenza B infection and may inform the design of a truly universal influenza vaccine.This research was supported by grants from the National Natural Science Foundation of China (31670934 and 81371817), the Ministry of Science and Technology of the People’s Republic of China (2011ZX09102-009-12 and 2012DFH30020), the Research Grants Council of the Hong Kong Special Administrative Region (7629/13M, 17103214, and 17154516), and a sponsored research agreement from Sanofi Pasteur. 研究工作得到了香港大学新发传染病国家重点实验室和赛诺菲巴斯德公司的技术支持和帮助，获得国家自然科学基金、新药创制国家科技重大专项、科技部对港科技合作项目等课题资助