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Telaprevir/boceprevir era: From bench to bed and back

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World Journal of Gastroenterology 2012年第43期18卷 6183-6188页

作者： maikel P peppelenbosch Harry LA Janssen Robert J de Knegt Department of Gastroenterology and Hepatology Erasmus MC-University Medical Center 3015 CE Rotterdam The Netherlands

Hepatitis C virus (HCV) infects approximately 200 million people worldwide. Interferon-based therapies have dominated over the past two decades. However, the overall response rates remain suboptimal. Thanks to the tremendous effort from both academia and industry, two serine protease inhibitors telaprevir and boceprevir for treating chronic hepatitis C have finally reached the clinic. Although these compounds are only approved for combination use with interferon and ribavirin in genotype 1 HCV infected chronic patients, the management of HCV patients however is now evolving incredibly. Here, we overviewed a series of landmark studies, regarding the clinical development of telaprevir and boceprevir. We discussed the mechanism-of-action of telaprevir/boceprevir and their potential application in HCV-positive liver transplantation patients. We further emphasized some emerging concerns with perspective of further development in this field.

关键词： Telaprevir Boceprevir Mechanism-of-action Clinical efficacy Liver transplantation patient Interferon Ribavirin

Bone morphogenetic protein-2 is a negative regulator of hepatocyte proliferation downregulated in the regenerating liver

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World Journal of Gastroenterology 2006年第47期12卷 7621-7625页

作者： Cui-Ping Xu Wen-Min Ji Gijs R van den Brink maikel P peppelenbosch Department of Digestive Diseases First Clinical College Shanxi Medical University Taiyuan 030001 Shanxi Province China Department of Gastroenterology & Hepatology Leiden University Medical Center Leiden The Netherlands Department of Cell Biology Faculty of Medical Sciences University of G--roningen G--roningen The Netherlands

AIM: To characterize the expression and dynamic changes of bone morphogenetic protein (BMP)-2 in hepatocytes in the regenerating liver in rats after partial hepatectomy (PH), and examine the effects of BMP-2 on proliferation of human Huh7 hepatoma cells. METHODS: Fifty-four adult male Wistar rats were randomly divided into three groups: A normal control (NC) group, a partial hepatectomized (PH) group and a sham operated (SO) group. To study the effect of liver regeneration on BMP-2 expression, rats were sacrificed before and at different time points after PH or the sham intervention (6, 12, 24 and 48 h). For each time point, six rats were used in parallel. Expression and distribution of BMP-2 protein were determined in regenerating liver tissue by Western blot analysis and immunohistochemistry. Effects of BMP-2 on cell proliferation of human Huh7 hepatoma cell line were assessed using an MTT ***: In the normal liver strong BMP-2 expression was observed around the central and portal veins. The expression of BMP-2 decreased rapidly as measured by both immunohistochemistry and Western blot analysis. This decrease was at a maximum of 3.22 fold after 12 h and returned to normal levels at 48 h after PH. No significant changes in BMP-2 immunoreactivity were observed in the SO group. BMP-2 inhibited serum induced Huh7 cell ***: BMP-2 is expressed in normal adult rat liver and negatively regulates hepatocyte proliferation. The observed down regulation of BMP-2 following partial hepatectomy suggests that such down regulation may be necessary for hepatocyte proliferation.

关键词： Bone morphogenetic protein-2 Partial hepatectomy Liver regeneration, Hepatocellular carcinoma

CD5 expression promotes IL-10 production through activation of the MAPK/Erk pathway and upregulation of TRPC1 channels in B lymphocytes

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Cellular & Molecular Immunology 2018年第2期15卷 158-170页

作者： Soizic Garaud Taher E Taher Marjolaine Debant Miguel Burgos Sarra Melayah Christian Berthou Kaushal Parikh Jacques-Olivier Pers Damien Luque-Paz Gilles Chiocchia maikel peppelenbosch David A Isenberg Pierre Youinou Olivier Mignen Yves Renaudineau Rizgar A Mageed INSERM ERI29/EA2216 réseau epigenetique and réseau canaux ioniques du Cancéropôle Grand OuestBrest University Medical SchoolBrest29609France Centre for Experimental Medicine and Rheumatology William Harvey Research InstituteBarts and the London School of Medicine and DentistryQueen Mary University of LondonLondonEC1M 6BQUK Canalopathy and Calcium Signaling INSERM UMR1078Brest29238France Centre for Experimental and Molecular Medicine Academic Medical CenterMeibergdreef 9Amsterdam1105 AZThe Netherlands Laboratory of Immunology and Immunotherapy CHU MorvanBrest29609France Institut Cochin INSERM U567Paris75014France Department of Gastroenterology and Hepatology Erasmus MCGravendijkwal 230Rotterdam015 CERotterdamThe Netherlands Centre for Rheumatology University College LondonLondonWC1E 6JFUK

CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia(CLL).Important functional properties are associated with CD5 expression in B cells,including signal transducer and activator of transcription 3 activation,IL-10 production and the promotion of B-lymphocyte survival and ***,the pathway(s)by which CD5 influences the biology of B cells and its dependence on B-cell receptor(BCR)co-signaling remain *** this study,we show that CD5 expression activates a number of important signaling pathways,including Erk1/2,leading to IL-10 production through a novel pathway independent of BCR *** pathway is dependent on extracellular calcium(Ca2+)entry facilitated by upregulation of the transient receptor potential channel 1(TRPC1)*** also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 *** this subgroup of CLL patients,small inhibitory RNA(siRNA)for CD5 reduces TRPC1 ***,siRNAs for CD5 or for TRPC1 inhibit IL-10 *** findings provide new insights into the role of CD5 in B-cell biology in health and disease and could pave the way for new treatment strategies for patients with B-CLL.

关键词： B cells calcium CD5 MAPK/Erk TRPC1

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自然免疫减弱与克罗恩病的关系

中国消化内镜 2007年第5期1卷 46-48页

作者：周璐陆星华 maikel P. peppelenbosch Department of Cell Biology University Medical Center Groningen.University of Groningen 中国医学科学院北京协和医科大学北京协和医院消化科

克罗恩病（Crohn＇s Disease）是肠道的慢性炎症性病变。其病因学的研究是目前世界范围内的科研热点之一。其中,对肠道共生细菌（Commensal Bacteria Flora）的免疫反应是否参与克罗恩病的发病更是争论不休。围绕这个论点，目前主要有... 详细信息

克罗恩病（Crohn＇s Disease）是肠道的慢性炎症性病变。其病因学的研究是目前世界范围内的科研热点之一。其中,对肠道共生细菌（Commensal Bacteria Flora）的免疫反应是否参与克罗恩病的发病更是争论不休。围绕这个论点，目前主要有两种学说：其一，具有遗传易感性的个体，肠道内的共生细菌诱导了人体过度的自然免疫（Innate Immunity），

关键词：克罗恩病自然免疫共生细菌炎症性病变遗传易感性肠道内科研热点世界范围

基于元胞自动机和流动成本场的高效降雨径流模型

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基于元胞自动机和流动成本场的高效降雨径流模型

作者： maikel Issermann 清华大学

学位级别：硕士

现今大多数的降雨径流模拟模型用浅水方程组来描述。求解浅水方程组的过程中，其微分方程用迭代法求解。迭代法是一种不断用变量的新值迭代旧值的过程，是用计算机解决问题的一种基本方法，其计算效率相对比较低。本研究提出解决这一问... 详细信息

现今大多数的降雨径流模拟模型用浅水方程组来描述。求解浅水方程组的过程中，其微分方程用迭代法求解。迭代法是一种不断用变量的新值迭代旧值的过程，是用计算机解决问题的一种基本方法，其计算效率相对比较低。本研究提出解决这一问题的新方法，开发了立足于简化的物理机制的降雨径流模拟模型。且其主要目的在于提供一种能够进行高效计算的代码来模拟径流，当然并非从反驳对类似商业模拟软件的评价。本研究中代码是基于Python语言编写的，同时包括Python开源数学库NumPy以及Python标准扩展库。本研究开发的降雨径流模拟模型是基于元胞自动机理论。所谓元胞自动机是指一类由许多相同单元组成的，可由一些简单的邻域规则便可在系统水平上产生复杂结构和行为的时空离散模型。典型的元胞自动机模型的机理如下：将研究区域划分成若干个大小形状一致的单元，这些单元称为元胞，是元胞自动机的最基本组成单位，所有的元胞空间网点集合构成元胞空间。在元胞空间中每个元胞都具有有限个离散状态和预定义的邻居，每个元胞的当前状态以及邻居的状况决定了下一时刻该元胞的状态，即元胞状态的转变受规则控制，而且这个规则是全局一致的。本研究中元胞状态转变的规则是用离散空间的流动成本场取代了高程，这一点在元胞自动机的已有研究中涉猎较少。这一设计理念是捕捉水分移动时有效的能源消耗。为进一步与现有的元胞自动机模型比较，该降雨径流模拟模型包括根据菲利普（Philip）公式的渗透计算模块、基于Hargreaves-Samani公式的蒸散量计算模块、构筑物概化模块和一个自适应的时间步长生成模块。为了验证该降雨径流模拟模型，本文用该模型对清华大学部分区域进行降雨的径流模拟，并根据需要设置四种模拟情景。由于缺乏实测的雨径流数据，本文将同条件下模型模拟结果与MIKE21的模拟结果进行比较分析。利用英国环境局的淹没基准测试程序对两种模拟结果进行对比分析。在相同的时间序列和降雨强度下，两个模型分别选择6个样本点的水深和最终时段的淹没图进行对比。结果显示，该降雨径流模拟模型是可接受的。一方面对比模型运行的时间上，该降雨径流模拟模型在单核CPU下运行的时间比MIKE21在四核CPU条件下运行的时间还短27～63%;另一方面考虑构筑物对样本点上的影响上，该降雨径流模拟模型受到的影响比MIKE21小。不同模型的构筑物对雨水径流有明显的影响，从而导致在样本点上雨水径流出现差异。该降雨径流模拟模型在模拟屋顶上的雨水是根据时间和空间扭曲效应来收集雨水，MIKE21模拟在屋顶上雨水是平均或者瞬时分配的。最后提出通过对降雨径流模拟模型构筑物和参数化做进一步的改进，该降雨径流模拟模型的模拟运行时间还可进一步缩短。

关键词：降雨径流模型计算效率元胞自动机流动成本场

Hydrodeoxygenation of Phenol on Beta Zeolite Catalysts

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Journal of Chemistry and Chemical Engineering 2014年第12期8卷 1098-1103页

作者： Elisa Cristina Goncalves Tavares maikel Laurence Maloncy Marcelo da Silva Batista Department of Chemical Engineering and Statistic Federal University of Sao Joao del Rei Ouro Branco-MG 36420-000 Brazil Process and Food Technology The Hague University of Applied Sciences the Hague 2501 the Netherlands

Biomass is considered the largest renewable energy source and an important alternative for biofuel production. The fast pyrolysis of biomass is an economical and advantageous to get bio-oil. However, bio-oil has a large amount of oxygenated compounds and needs upgrade. The catalytic process of HDO （hydrodeoxygenation） is the most efficient way to remove oxygen from the bio-oil. In this paper, it was studied the HDO phenol （300 ℃ and 35 atm） on catalysts based on cobalt or copper oxides supported on HBeta zeolite. The catalysts were characterized by XRD （X-ray diffraction）, FTIR （infrared spectroscopy） and NH3-TPD （desorption of ammonia）. The results showed the presence of CO304 （cobalt oxide） and CuO （copper oxide）. The measurements showed the presence of acid sites weak, moderate and strong and that the impregnation of the metal oxide modifying the acidity of the support. The results showed the following order HDO conversion： CoHBeta 〉 CuHBeta 〉 HBeta. The presence of the cobalt or copper catalysts contributes to the increase in conversion due to hydrogenation. All catalysts were selective to benzene, but only the impregnated catalysts showed selectivity to cyclohexane and cyclohexene.

关键词： HDO catalysts beta zeolite biofuel

Production of Pequi Powder by Drying Pulp

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Agricultural Sciences 2018年第8期9卷 1047-1057页

作者： Aluizio Paulo Rodrigues Silva Welisson Martins Rocha David maikel Fernandes José Roberto Delalibera Finzer Faculty of Chemical Engineering-UNIUBE Uberaba MG Brazil

The pequi tree is a native plant of the Brazilian cerrado, and the scientific name is Caryocar brasiliense, whose fruits are called pequi, appreciated for its pleasant peculiarities of color, aroma and flavor. The objective of this work is to transform pequi pulp into powder, aiming at maintaining the flavor. By using the convection drying technique, the product is converted from the fluid state to the solid state in the form of a powder. Experiments were performed with drying at the following temperatures: 40°C, 50°C, 60°C, 90°C and 105°C. Interpretations were made of the experimental drying and milling results. It was verified that for all the experimental temperatures, there was no loss of the sensory characteristics of pequi. The drying of the pequi pulp in a greenhouse at 105°C consisted of a good result of preservation of the characteristics of the fruit: color, aroma and flavor. Using the Trojan Powder Coating scale, it is found that pequi powder, dried at 105°C, differs little in terms of the color of the fruit in nature.

关键词： Pequi Drying Brazilian Cerrado

Tuf m RNA rather than 16S r RNA is associated with culturable Staphylococcus aureus

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World Journal of Clinical Infectious Diseases 2015年第4期5卷 86-93页

作者： Anne JM Loonen Petra FG Wolffs maikel de Bresser Maurice Habraken Cathrien A Bruggeman Mirjam HA Hermans Adriaan JC van den Brule Laboratory for Molecular Diagnostics Department of Medical Microbiology and Pathology Jeroen Bosch Hospital Department of Medical Molecular Diagnostics Fontys University of Applied Sciences Department of Medical Microbiology CAPHRI Maastricht University Medical Centre

AIM: To study the presence of various nucleic acids targets of Staphylococcus aureus(S. aureus) during bacterial growth and antibiotic induced killing in relation to ***: S. aureus was cultured to log phase and spiked in Todd Hewitt(TH) broth and whole blood of healthy human volunteers. Viability of S. aureus after flucloxacillin treatment(0, 1, 3 and 6 d) was assessed by culture on bloodagar plates. DNA and RNA were isolated from 200 μL. c DNA synthesis was performed by using random primers. The presence of S. aureus DNA, r RNA, and m RNA were determined by real-time polymerase chain reaction of the 16 S r DNA and tuf gene(elongation factor Tu).RESULTS: S. aureus spiked in TH broth without antibiotics grew from day 0-6 and DNA(tuf and 16S), and 16 S r RNA remained detectable during this whole period. During flucloxacillin treatment S. aureus lost viability from day 3 onwards, while the 16 S r RNA-gene and its RNA transcripts remained detectable. DNA andr RNA can be detected in flucloxacillin treated S. aureus cultures that do not further contain culturable ***, tuf m RNA became undetectable from day 3onwards. Tuf m RNA can only be detected from samples with culturable bacteria. When spiking S. aureus in whole blood instead of broth no bacterial growth was seen, neither in the absence nor in the presence of flucloxacillin. Accordingly, no increase in DNA and RNA levels of both 16 S r DNA and the tuf gene were detected. CONCLUSION: Tuf m RNA expression is associated with culturable S. aureus and might be used to monitor antibiotic effects.

关键词： Bloodstream infection Staphylococcus aureus Viability mRNA Polymerase chain reaction Sepsis Molecular diagnostics Blood

Characterization of the potential energy surface for reaction of C24H12 with NO2+: A model reaction to study graphene oxidation in acid medium

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Characterization of the potential energy surface for reactio...