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作者：尤婷婷南方医科大学

学位级别：博士

目的:前期实验证明,敲低或抑制磷酸二酯酶-4(phosphodiesterase-4,PDE4)能抑制脑内炎症反应,但是机制尚未完全清楚。最近几年有报道cAMP能诱导自噬,另一方面,研究发现自噬活动调控炎症反应,而抑制自噬能使炎症反应失控。新型PDE4抑制剂... 详细信息

目的:前期实验证明,敲低或抑制磷酸二酯酶-4(phosphodiesterase-4,PDE4)能抑制脑内炎症反应,但是机制尚未完全清楚。最近几年有报道cAMP能诱导自噬,另一方面,研究发现自噬活动调控炎症反应,而抑制自噬能使炎症反应失控。新型PDE4抑制剂罗氟普兰(Roflupram,ROf)能提高cAMP水平和抑制炎症,但是ROf能否能通过提高cAMP水平诱导小胶质细胞自噬并通过诱导自噬发挥抗炎作用仍待探讨。方法:(1)使用MTT法检测不同浓度ROf对正常及活化的BV-2小胶质细胞生存率的影响;(2)Western blot检测自噬相关蛋白、NLRP3炎性小体通路相关蛋白、凋亡相关蛋白、突触相关蛋白水平的变化;(3)AO、LYT染色标记细胞内酸性囊泡;(4)LC3免疫荧光检测自噬水平变化;(5)使用药理学自噬抑制剂3-MA及基因组学siRNA ATG7转染抑制自噬;(6)采用CQ检测自噬潮;(7)ELISA检测细胞因子;(8)Hoechst染色和相差显微镜检测凋亡N2a细胞及存活细胞突触变化;(9)条件培养基共培养系统评价BV-2小胶质细胞介导的炎性微环境对N2a的损害及PDE4抑制剂ROf的保护作用。结果:(1)MTT的结果显示,ROf在0.625-20μM的浓度范围内不对正常BV-2细胞的活力产生影响,ROf(10 μM)与LPS+ATP及Aβ25-35刺激的BV-2细胞有良好相容性。(2)Western blot结果显示,与溶剂对照组相比,ROf增加BV-2小胶质细胞内的LC3-Ⅱ蛋白水平且呈剂量依赖性(2.5-10 μM)和时间依赖性(2-8h),p62的改变与LC3-μ的改变呈负相关;自噬潮检测显示,与溶剂对照组相比,CQ(20M)处理后,BV-2细胞LC3-Ⅱ蛋白水平升高,而ROf(5μM)与CQ(20 μM)联用后,LC3-Ⅱ蛋白水平显著升高,比单独CQ组的LC3-Ⅱ水平更高。另外,ROf在AO及LYT染色中都使BV-2细胞酸性囊泡荧光增加;自噬抑制剂3-MA(1 mM)能逆转ROf的作用。这些结果显示ROf诱导了 BV-2细胞自噬;雷帕霉素、咯利普兰和毛喉素在AO和LYT染色中的显示的变化与ROf相似,提示cAMP信号通路可能参与其自噬的诱导。(3)相差显微镜结果显示,与对照组相比,LPS(1μg/ml)+ATP(1 mM)或Aβ25-35(5 μM)在刺激6 h后明显激活BV-2小胶质细胞,另一方面,Western blot结果显示,被激活BV-2小胶质细胞在功能上发生相应的改变,包括自噬诱导和NLRP3炎性小体通路活化,表现为自噬标记物LC3-Ⅱ增加和NLRP3炎性小体通路活化相关蛋白IL-1β p17、Caspase-1 p10和NLRP3水平的增加。(4)ELISA结果显示,与溶剂对照组相比,ROf对细胞释放IL-1β无明显影响,但在联合LPS+ATP或Aβ25-35处理BV-2细胞后,剂量依赖性减少NLRP3炎性小体通路的细胞因子产物IL-1β的释放,而且Western blot结果显示,与LPS+ATP或Aβ25-35组相比,ROf增加活化BV-2细胞LC3-Ⅱ,同时减少其IL-1βp17和Caspase-1 p10,该作用能被自噬抑制剂3-MA逆转,表明ROf诱导活化的BV-2细胞自噬,同时抑制LPS+ATP和Aβ25-35对活化BV-2细胞NLRP3炎性小体通路的激活,该作用与其自噬诱导作用有关;另外,与LPS+ATP和Aβ25-35组相比,ROf与LPS+ATP或Aβ25-35组共培养使BV-2细胞内的pro-IL-1β和NLRP3减少,提示ROf的自噬介导的抗炎作用与自噬性降解pro-IL-1β和NLRP3有关。(5)在进一步研究小胶质细胞介导的炎症对神经元的毒性作用实验中,收集不同方法处理的BV-2小胶质细胞条件培养基,用于培养N2a神经元细胞24h。Hoechst结合相差显微镜结果显示,LPS+ATP和Aβ25-35处理BV-2细胞的条件培养基增加N2a细胞凋亡和神经损伤,ROf在一定程度上能间接改善该损伤,而该作用能被3-MA逆转;Western blot检测进一步验证了形态学结果,表现为LPS+ATP和Aβ25-35处理BV-2细胞的条件培养基升高N2a细胞凋亡相关蛋白Caspase-3和突触相关蛋白PSD95水平,ROf在一定程度上抑制其升高,而该作用能被siRNA ATG7逆转,提示ROf自噬介导的抗炎作用能在一定程度上减轻BV-2小胶质细胞介导的神经炎症反应对N2a细胞的毒性。结论:(1)PDE4抑制剂ROf能诱导正常及活化的BV-2小胶质细胞自噬,该作用可能与cAMP信号通路有关。(2)NLRP3炎性小体特异性激活剂LPS+ATP和Aβ25-35能激活BV-2细胞及其NL

关键词： RO f P D E 4抑制剂神经炎症自噬 BV-2小胶质细胞 NLRP3炎性小体

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Differences in clinical features of Crohn's disease and intestinal tuberculosis

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World Journal of Gastroenterology 2015年第12期21卷 3650-3656页

作者： Xin Huang Wang-Di Liao Chen Yu Yi Tu Xiao-Lin Pan You-Xiang Chen Nong-Hua Lv Xuan Zhu Department of Gastroenterology First Affiliated Hospital of Nanchang University Department of Radiology First Affiliated Hospital of Nanchang University Department of Pathology First Affiliated Hospital of Nanchang University

AIM: To investigate the clinical features of Crohn's disease(CD) and intestinal tuberculosis(ITB) with a scoring system that we have ***: A total of 25 CD and 40 ITB patients were prospectively enrolled from August 2011 to July *** characteristics and clinical features were recorded. Laboratory, endoscopic, histologic and radiographic features were determined. The features with a high specificity were selected to establish a scoring system. The features supporting CD scored +1, and those supporting ITB scored-1; each patient received a final total score. A receiver operating characteristic(ROC) curve was used to determine the best cut-off value for distinguishing CD from ***: Based on a high specificity of differentiating between CD and ITB, 12 features, including longitudinal ulcers, nodular hyperplasia, cobblestone-like mucosa, intestinal diseases, intestinal fistula, the target sign, the comb sign, night sweats, the purified protein derivative test, the interferon-γ release assay(***), ring ulcers and ulcer scars, were selected for the scoring system. The results showed that the average total score of the CD group was 3.12 ± 1.740, the average total score of the ITB group was-2.58 ± 0.984, the best cutoff value for the ROC curve was-0.5, and the diagnostic area under the curve was 0.997, which was statistically significant(P < 0.001). The patients whose total scores were higher than-0.5 were diagnosed with CD; otherwise, patients were diagnosed with ITB. Overall, the diagnostic accuracy rate and misdiagnosis rate of this scoring system were 97% and 3%, respectively. CONCLUSION: Some clinical features are valuable for CD and ITB diagnosis. The described scoring system is key to differentiating between CD and ITB.

关键词： Crohn’s disease Intestinal tuberculosis Clinical f

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Influence of blood flow occlusion on the development of peripheral and central fatigue during small muscle mass handgrip exercise

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JOURNAL Of PHYSIOLOGY-LONDON 2015年第17期593卷 4043-4054页

作者： Broxterman, R. M. Craig, J. C. Smith, J. R. Wilcox, S. L. Jia, C. Warren, S. Barstow, T. J. Kansas State Univ Dept Kinesiol Manhattan KS 66506 USA Kansas State Univ Dept Anat & Physiol Manhattan KS 66506 USA Kansas State Univ Dept Elect & Comp Engn Manhattan KS 66506 USA

The influence of the muscle metabolic milieu on peripheral and central fatigue is currently unclear. Moreover, the relationships between peripheral and central fatigue and the curvature constant (W) have not been investigated. Six men (age: 25 +/- 4 years, body mass: 82 +/- 10kg, height: 179 +/- 4cm) completed four constant power handgrip tests to exhaustion under conditions of control exercise (Con), blood flow occlusion exercise (Occ), Con with 5min post-exercise blood flow occlusion (Con+Occ), and Occ with 5min post-exercise blood flow occlusion (Occ+Occ). Neuromuscular fatigue measurements and W were obtained for each subject. Each trial resulted in significant peripheral and central fatigue. Significantly greater peripheral (79.7 +/- 5.1%vs. 22.7 +/- 6.0%) and central (42.6 +/- 3.9%vs. 4.9 +/- 2.0%) fatigue occurred for Occ than for Con. In addition, significantly greater peripheral (83.0 +/- 4.2%vs. 69.0 +/- 6.2%) and central (65.5 +/- 14.6%vs. 18.6 +/- 4.1%) fatigue occurred for Occ+Occ than for Con+Occ. W was significantly related to the magnitude of global (r=0.91) and peripheral (r=0.83) fatigue. The current findings demonstrate that blood flow occlusion exacerbated the development of both peripheral and central fatigue and that post-exercise blood flow occlusion prevented the recovery of both peripheral and central fatigue. Moreover, the current findings suggest that W may be determined by the magnitude of fatigue accrued during exercise.

关键词： Con control exercise Con+Occ control exercise with 5min post-exercise blood flow occlusion CP critical power deoxy-[Hb+Mb] deoxygenated-[haemoglobin+myoglobin] d displacement EMG electromyography f contraction frequency iEMG intergrated electromyography LED light-emitting diodes MedPf median power frequency MVC maximal voluntary contraction NIRS near infrared spectroscopy Occ blood flow occlusion exercise Occ+Occ blood flow occlusion exercise with 5min post-exercise blood flow occlusion oxy-[Hb+Mb] oxygenated-[haemoglobin+myoglobin] P power PCr phosphocreatine Pi inorganic phosphate Ppeak peak power Qtw potentiated doublet force R resistance %Sat-[Hb+Mb] %Saturation-[haemoglobin+myoglobin] Tlim task failure total-[Hb+Mb] total-[haemoglobin+myoglobin] VA voluntary activation W&thinsp &prime curvature constant

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New 3,4-Secocycloartane and 3,4-Secodammarane Triterpenes from the Ecuadorian Plant Coussarea macrophylla

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CHEMISTRY & BIODIVERSITY 2015年第6期12卷 946-954页

作者： Gilardoni, Gianluca Chiriboga, Ximena finzi, Paola Vita Vidari, Giovanni Univ Pavia Dipartimento Chim IT-27100 Pavia Italy CISTRE IT-27100 Pavia Italy Univ Cent Ecuador Escuela Bioquim & Farm Fac Ciencias Quim Quito Ecuador

Coussarea macrophylla (Mart.) ***. (Rubiaceae) was collected in Ecuador, and the bark was extracted with AcOEt. Chromatographic separation afforded six novel 3,4-secocycloartane and 3,4-secodammarane triterpenes, named macrocoussaric acids A-f, together with the known metabolites secaubryenol and 3,4-secodammara-4(28), 20,24-triene-3,26-dioic acid. The structures of the new compounds were determined on the basis of their spectroscopic data. This is the first report of 3,4-secocycloartane and 3,4-secodammarane triterpenes occurring in a Coussarea species. Macrocoussaric acids A and B (2 and 3, resp.) were found to be moderately cytotoxic against five different tumor cell lines.

关键词： Coussarea macrophylla Macrocoussaric acids A&thinsp -&thinsp f Triterpenes Secodammarane triterpenes Secocycloartane triterpenes

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Snapshot of an integrated psychosocial gastroenterology service

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World Journal of Gastroenterology 2015年第6期21卷 1893-1899页

作者： Sarah W Kinsinger Sarah Ballou Laurie Keefer Division of Gastroenterology Northwestern University Feinberg School of Medicine Chicago

AIM:To characterize the patients utilizing a gastroenterology behavioral medicine service and examine the effect of treatment on health care ***:Patients were referred by their gastroenterologists for psychological treatment during a15 mo *** seen for an intake with a psychologist completed the Brief Symptom Inventory(BSI)and a checklist of psychosocial concerns.A subset of patients with functional bowel disorders also completed a disease specific quality of life *** review was conducted to obtain information on type and frequency of sessions with the psychologist,the number of outpatient gastroenterology visits,and number of gastroenterology-related medical procedures during the 6 mo following psychological ***:Of 259 patients referred for treatment,118(46%)completed an intake with a *** included:irritable bowel syndrome(42%),functional dyspepsia(20%),inflammatory bowel diseases(20%),esophageal symptoms(10%),and"other"(8%).Demographic variables and disease type did not differentiate between those who did and did not schedule an *** t-scores for the BSI global score index and the depression,anxiety,and somatization subscales fell below the cutoff for clinical significance(t=63).Treatments were predominantly gut-directed hypnosis(48%)and cognitive behavioral therapy(44%).Average length of treatment was 4 *** functional gastrointestinal(GI)patients,those patients who initiated treatment received significantly fewer GI-related medical procedures during the 6 mo following the referral than patients who did not schedule an intake[t(197)=2.69,P<0.01].CONCLUSION:Patients are receptive to psychological interventions for GI conditions and there is preliminary evidence that treatment can decrease health-care utilization among patients with functional GI conditions.

关键词： Psychological treatment Irritable bowel syndrome f

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Selective targeting of the IL23 pathway: Generation and characterization of a novel high-affinity humanized anti-IL23A antibody

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MABS 2015年第4期7卷 778-791页

作者： Singh, Sanjaya Kroe-Barrett, Rachel R. Canada, Keith A. Zhu, Xiang Sepulveda, Eliud Wu, Helen He, Yaqin Raymond, Ernest L. Ahlberg, Jennifer frego, Lee E. Amodeo, Laura M. Catron, Katrina M. Presky, David H. Hanke, Jeffrey H. Boehringer Ingelheim Pharmaceut Inc Dept Biotherapeut Res Ridgefield CT 06877 USA Boehringer Ingelheim Pharmaceut Inc Dept Immunol Ridgefield CT USA Boehringer Ingelheim Pharmaceut Inc Global Head Biotherapeut Res Ridgefield CT USA

Herein, we describe the generation and characterization of BI 655066, a novel, highly potent neutralizing anti-interleukin-23 (IL23) monoclonal antibody in clinical development for autoimmune conditions, including psoriasis and Crohn's disease. IL23 is a key driver of the differentiation, maintenance, and activity of a number of immune cell subsets, including T helper 17 (Th17) cells, which are believed to mediate the pathogenesis of several immune-mediated disorders. Thus, IL23 neutralization is an attractive therapeutic approach. Designing an antibody for clinical activity and convenience for the patient requires certain properties, such as high affinity, specificity, and solubility. These properties were achieved by directed design of the immunization, lead identification, and humanization procedures. favorable substance and pharmacokinetic properties were established by biophysical assessments and studies in cynomolgus monkeys.

关键词： BI 655066 biophysical assessment pharmacokinetic profile humanization immunogen design IL23 Interleukin-23 Th17 T helper 17 cells IL12 Interleukin 12 IL23R IL23 receptor IL12RB1 IL12 receptor subunit beta 1 JAK2 Janus kinase 2 tyk2 tyrosine kinase 2 CDRs complementarity-determining regions V variable SPR surface plasmon resonance V-H variable heavy C-H constant region V variable kappa G glycine f phenylalanine Y tyrosine C constant kappa PK pharmacokinetic ADCC antibody-dependent cell-mediated cytotoxicity SEC size-exclusion chromatography AUC analytical ultracentrifugation HCLf high concentration liquid formulation UV ultraviolet EOf electro-osmotic flow DMf dimethylformamide GAHA goat anti-human IgG gamma antibody PBS phosphate-buffered saline RU resonance units ESI electrospray ionization CCG Chemical Computing Group

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决策神经科学与口碑再传播行为

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2017年

作者：邵长斌

本书在传统消费者决策理论的基础上，借鉴整合决策神经科学的相关理论及成果，对消费者口碑再传播评估决策机理进行了研究……

ISBN: (纸本)9787313167545

本书在传统消费者决策理论的基础上，借鉴整合决策神经科学的相关理论及成果，对消费者口碑再传播评估决策机理进行了研究……

关键词：消费者行为论研究 f

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Cetuximab and panitumumab in a patient with colon cancer and concomitant chronic skin disease:A potential beneficial effect on psoriasis vulgaris

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World Journal of Gastroenterology 2015年第12期21卷 3746-3749页

作者： Ken Okamoto Hiromichi Maeda Takeo Shiga Mai Shiga Ken Dabanaka Kazuhiro Hanazaki Michiya Kobayashi Department of Human Health and Medical Sciences Kochi Medical School Hospital Cancer Treatment Center Kochi Medical School Hospital Department of Dermatology Kochi Medical School Department of Surgery Kochi Medical School

Monoclonal antibodies against epidermal growth factor receptor(EGfR) are used in the treatment of advanced colorectal cancer. However, these agents can induce severe dermatological side effects that discourage their administration in patients with chronic dermatological disease. EGfR plays a key role in normal skin development and immunological function, and is expressed in various tissues and organs, although contrarily, it is overexpressed in psoriasis-related skin lesions. Thus, discussion is ongoing regarding the putative pathological role and therapeutic potential of this protein. We herein report on a patient with advanced colon cancer and concomitant long-standing psoriasis vulgaris who received antiEGfR antibody monotherapy as a third-line treatment for metastatic disease. One week after the initiation of treatment, the patient's skin lesions dramatically subsided and the improvement was sustained during therapy. Based on this case, we propose that anti-EGfR antibody therapy is not necessarily contraindicated in patients with psoriasis vulgaris. Moreover, the findings reaffirmed that EGfR is an important molecule in the pathology of psoriasis.

关键词： Psoriasis Cetuximab Panitumumab Epidermal growth f

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Compositional dependence of the rheology of halogen (f, Cl) bearing aluminosilicate melts

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CHEMICAL GEOLOGY 2013年 346卷 172-183页

作者： Baasner, A. Schmidt, B. C. Webb, S. L. Univ Gottingen GZG Dept Mineral D-37077 Gottingen Germany

The rheology of three melt compositions containing different amounts of fluorine (f) and chlorine (Cl) or both was investigated with micropenetration and parallel-plate techniques. The heat capacity and configurational entropy of the melts were also determined. The observed viscosity range is between 10(5.5) and 10(13) Pa s. The melts were produced in a 1 atm furnace at temperatures between 1523 and 1923 K using oxide and carbonate compounds. The halogens were incorporated using halides and halogen-bearing ammonium compounds. The first composition is a peraluminous Na2O-CaO-Al2O3-SiO2 melt (ANCS) with an apparent NBO/T of similar to-0.08, the second composition is a peralkaline Na2O-CaO-Al2O3-SiO2 melt (NACS) (NBO/T = similar to 0.24), which is an analogue for phonolites, and the third is an aluminium-free Na2O-CaO-SiO2 melt (NCS) (NBO/T of similar to 0.68). five halogen-bearing ANCS melts with up to 1.10 mol% Cl and 1825 mol% f, 6 halogen-bearing NACS melts with up to 138 mol% Cl and 2.58 mol% f and 3 halogen-bearing NCS melts with up to 2.15 mol% Cl and 2.04 mol% f were investigated in this study. fluorine was found to decrease the viscosity for all compositions, but not with equal strength. Interpolated to 1 mol%, f decreases the viscosity by 0.31 +/- 0.08 log units in the peraluminous melt (ANCS), 0.57 +/- 0.11 log units in the peralkaline melt (NACS) and 0.47 +/- 0.14 log units in the NCS melt. The effect of Cl on rheology depends on the melt composition. Interpolated to 1 mol%, Cl decreases the viscosity by 0.57 +/- 0.13 log units in the peraluminous melt, but increases viscosity by 0.87 +/- 0.10 log units in the peralkaline melt. There is no measurable effect on viscosity due to the addition of chlorine to the aluminium-free melt. In the peraluminous melts the effects of f and Cl add almost linearly to decrease viscosity. In the peralkaline melts, Cl increases the viscosity while f decreases it, if both are present, the effects appear to balance each other;re

关键词： f Cl Viscosity Silicate melts Phonolites Parallel plate

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4P: fast computing of population genetics statistics from large DNA polymorphism panels

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ECOLOGY AND EVOLUTION 2015年第1期5卷 172-175页

作者： Benazzo, Andrea Panziera, Alex Bertorelle, Giorgio Univ Ferrara Dept Life Sci & Biotechnol I-44100 Ferrara Italy Fdn Edmund Mach Dept Biodivers & Mol Ecol I-38010 San Michele All Adige Italy

Massive DNA sequencing has significantly increased the amount of data available for population genetics and molecular ecology studies. However, the parallel computation of simple statistics within and between populations from large panels of polymorphic sites is not yet available, making the exploratory analyses of a set or subset of data a very laborious task. Here, we present 4P (parallel processing of polymorphism panels), a stand-alone software program for the rapid computation of genetic variation statistics (including the joint frequency spectrum) from millions of DNA variants in multiple individuals and multiple populations. It handles a standard input file format commonly used to store DNA variation from empirical or simulation experiments. The computational performance of 4P was evaluated using large SNP (single nucleotide polymorphism) datasets from human genomes or obtained by simulations. 4P was faster or much faster than other comparable programs, and the impact of parallel computing using multicore computers or servers was evident. 4P is a useful tool for biologists who need a simple and rapid computer program to run exploratory population genetics analyses in large panels of genomic data. It is also particularly suitable to analyze multiple data sets produced in simulation studies. Unix, Windows, and MacOs versions are provided, as well as the source code for easier pipeline implementations.

关键词： Allelic spectrum f (st) genetic indicators genetic variation NGS software

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