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Origin of CD8^+ Effector and Memory T Cell Subsets

Cellular & Molecular Immunology 2007年第6期4卷 399-405页

作者： christian Stemberger Michael Neuenhahn Veit R.Buchholz Dirk h.Busch Institute for Medical Microbiology Immunology and HygieneTechnical University Munich Clinical Cooperation Group"Antigen-Specific Immunotherapy"and"Immune-Monitoring" Helmholtz Center Munich–Germany ResearchCenter for Environment Health and Technical University MunichGermany

It is well accepted that CD8＋ T cells play a pivotal role in providing protection against infection with intracellular pathogens and some tumors. In many cases protective immunity is maintained for long periods of time （immunological memory）. Over the past years, it has become evident that in order to fulfill these multiple tasks, distinct subsets of effector and memory T cells have to be generated. Until today, however, little is known about the underlying mechanisms of subset differentiation and the timing of lineage fate decisions. In this context, it is of special importance to determine at which level of clonal expansion functional and phenotypical heterogeneity is achieved. Different models for T cell subset diversification have been proposed; these differ mainly in the time point during priming and clonal expansion （prior, during, or beyond the first cell division） when differentiation programs are induced. Recently developed single-cell adoptive transfer technology has allowed us to demonstrate that individual precursor cell still bears the full plasticity to develop into a plethora different T cell subsets. This observation targets the shaping of T cell subset differentiation towards factors that are still operative beyond the first cell division. These findings have important implications for vaccine development, as the modulation of differentiation patterns towards distinct subsets could become a powerful strategy to enhance the efficacy and quality of vaccines. Cellular ＆ Molecular Immunology.

关键词： effector T cell memory T cell differentiation

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The role of the TNFα-mediated astrocyte signaling pathway in epilepsy

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Acta Epileptologica 2021年第1期3卷 163-171页

作者： Rui Chen Guofang Xue christian hölscher Shanxi Medical University Taiyuan 030001ShanxiChina Neurology Department The Second Affiliated Hospital of Shanxi Medical UniversityTaiyuan 030001ShanxiChina

Epilepsy is a common disease in the central nervous *** is growing evidence that epilepsy is associated with glial cells,including *** necrosis factorα(TNFα)is a“master regulator”of proinflammatory cytokine production and is secreted by microglia and ***αsecreted by microglia can activate ***,TNFαcan regulate neuron activity and induce epilepsy by increasing the glutamate release,reducing the expression ofγ-aminobutyric acid,inducing neuroinflammation and affecting the synaptic function in *** review summarizes the signaling pathways and receptors of TNFαacting on astrocytes that are related to epilepsy and provides insights into the potential therapeutic strategies of epilepsy for clinical practice.

关键词： Tumor necrosis factor alpha Astrocytes Inflammation Epilepsy

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Treatment of metastatic colorectal carcinomas by systemic inhibition of vascular endothelial growth factor signaling in mice

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World Journal of Gastroenterology 2005年第28期11卷 4332-4336页

作者： Volker Schmitz Miroslaw Kornek Tobias hilbert christian Dzienisowicz Esbher Raskopf christian Rabe Tilman Sauerbruch Cheng Qian Wolfgang h Caselmann Medizinische Klinik und Poliklinik I Universitatsklinikum BonnGermany Universidad de Navarra Clinica Universitaria Pamplona Spain Bavarian State Ministry of the Environment Public Health and Consumer Protection Munich 81901 Germany

AIM： Tumor angiogenesis has been shown to be promoted by vascular endothelial growth factor （VEGF） via stimulating endothelial cell proliferation, migration, and survival. Blockade of VEGF signaling by different means has been demonstrated to result in reduced tumor growth and suppression of tumor angiogenesis in distinct tumor entities. here, we tested a recombinant adenovirus, AdsFItl-3, that encodes an antagonistically acting fragment of the VEGF receptor 1 （Fit-l）, for systemic antitumor effects in pre-established subcutaneous CRC tumors in mice.METhODS： Murine colorectal carcinoma cells （CT26） were inoculated subcutaneously into Balb/c mice for in vivo studies. Tumor size and survival were determined. 293 cell line was used for propagation of the adenoviral vectors. human lung cancer line A549 and human umbilical vein endothelial cells were transfected for in vitro experiments.RESULTS： Infection of tumor cells with AdsFlt1-3 resulted in protein secretion into cell supernatant, demonstrating correct vector function. As expected, the secreted sFlt1-3 protein had no direct effect on CT26 tumor cell proliferation in vitro, but endothelial cell function was inhibited by about 46% as compared to the AdLacZ control in a tube formation assay. When AdsFlt1-3 （5×10^9 PFU/animal） was applied to tumor bearing mice, we found a tumor inhibition by 72% at d 12 after treatment initiation, in spite of these antitumoral effects, the survival time was not improved. According to reduced intratumoral microvessel density in AdsFlt1-3-treated mice, the antitumor mechanism can be attributed to angiostatic vector effects. We did not detect increased systemic VEGF levels after AdsFlt1-3 treatment and liver toxicity was low as judged by serum alanine aminotransferase determination.CONCLUSION： In this study we confirmed the value of a systemic administration of AdsFItl-3 to block VEGF signaling as antitumor therapy in an experimental metastatic colorectal carcinoma model in mice.

关键词： Colorectal carcinomas Vascular endothelial growth factor Systemic inhibition

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Integrating geometallurgical ball mill throughput predictions into short-term stochastic production scheduling in mining complexes

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International Journal of Mining Science and Technology 2023年第2期33卷 185-199页

作者： christian Both Roussos Dimitrakopoulos COSMO–Stochastic Mine Planning Laboratory Department of Mining and Materials EngineeringMcGill UniversityMontreal H3A 0E8Canada

This article presents a novel approach to integrate a throughput prediction model for the ball mill into short-term stochastic production scheduling in mining *** datasets for the throughput prediction model include penetration rates from blast hole drilling(measurement while drilling),geological domains,material types,rock density,and throughput rates of the operating mill,offering an accessible and cost-effective method compared to other geometallurgical ***,the comminution behavior of the orebody was geostatistically simulated by building additive hardness proportions from penetration rates.A regression model was constructed to predict throughput rates as a function of blended rock properties,which are informed by a material tracking approach in the mining ***,the throughput prediction model was integrated into a stochastic optimization model for short-term production *** way,common shortfalls of existing geometallurgical throughput prediction models,that typically ignore the non-additive nature of hardness and are not designed to interact with mine production scheduling,are overcome.A case study at the Tropicana Mining Complex shows that throughput can be predicted with an error less than 30 t/h and a correlation coefficient of up to *** integrating the prediction model and new stochastic components into optimization,the production schedule achieves weekly planned production reliably because scheduled materials match with the predicted performance of the *** to optimization using conventional mill tonnage constraints reveal that expected production shortfalls of up to 7%per period can be mitigated this way.

关键词： Geometallurgy Stochastic optimization Short-term open pit mine production scheduling Measurement while drilling Non-additivity hardness

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Versatile multiplexed super-resolution imaging of nanostructures by Quencher-Exchange-PAINT

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Nano Research 2018年第12期11卷 6141-6154页

作者： Tobias Lutz Alexander h.Clowsley Ruisheng Lin Stefano Pagliara Lorenzo Di Michele christian Soeller Living Systems Institute & Biomedical Physics University of ExeterExeter EX44QDUK Cavendish Laboratory University of CambridgeCambridge CB30HEUK

The optical super-resolution technique DNA-PAINT (Point Accumulation Imaging in Nanoscale Topography) provides a flexible way to achieve imaging of nanoscale structures at ∼10-nanometer resolution. In DNA-PAINT, fluorescently labeled DNA “imager” strands bind transiently and with high specificity to complementary target “docking” strands anchored to the structure of interest. The localization of single binding events enables the assembly of a super-resolution image, and this approach effectively circumvents photobleaching. The solution exchange of imager strands is the basis of Exchange-PAINT, which enables multiplexed imaging that avoids chromatic aberrations. Fluid exchange during imaging typically requires specialized chambers or washes, which can disturb the sample. Additionally, diffusional washout of imager strands is slow in thick samples such as biological tissue slices. here, we introduce Quencher-Exchange-PAINT—a new approach to Exchange-PAINT in regular open-top imaging chambers—which overcomes the comparatively slow imager strand switching via diffusional imager washout. Quencher-Exchange-PAINT uses “quencher” strands, i.e., oligonucleotides that prevent the imager from binding to the targets, to rapidly reduce unwanted single-stranded imager concentrations to negligible levels, decoupled from the absolute imager concentration. The quencher strands contain an effective dye quencher that reduces the fluorescence of quenched imager strands to negligible levels. We characterized Quencher-Exchange-PAINT when applied to synthetic, cellular, and thick tissue samples. Quencher-Exchange-PAINT opens the way for efficient multiplexed imaging of complex nanostructures, e.g., in thick tissues, without the need for washing steps.

关键词： super-resolution microscopy fluorescence imaging DNA nanotechnology DNA-PAINT fluorescence quencher

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CYLD deletion triggers nuclear factor-κB-signaling and increases cell death resistance in murine hepatocytes

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World Journal of Gastroenterology 2014年第45期20卷 17049-17064页

作者： Toni Urbanik Bruno christian Koehler Laura Wolpert Christin Elbner Anna-Lena Scherr Thomas Longerich Nicole Kautz Stefan Welte Nadine hovelmeyer Dirk Jager Ari Waisman henning schulze-Bergkamen National Center for Tumor Diseases Department of Medical Oncology University Clinic of heidelberg 69120 HeidellbergBade-WuerrtembergGermany Institute of Pathology University hospital heidelberg 69120 HeidelbergBaden-WuerrtembergGermany Institute for Molecular Medicine Johannes Gutenberg-University Mainz 55131 MainzRheinland-PalatlnateGemany

AIM:To analyze the role of CYLD for receptor-mediated cell death of murine hepatocytes in acute liver injury ***:hepatocyte cell death in CYLD knockout mice(CYLD-/-)was analyzed by application of liver injury models for CD95-(Jo2)and tumor necrosis factor(TNF)-α-[D-Gal N/lipopolysaccharide(LPS)]induced *** injury was assessed by measurement of serum transaminases and histological *** induction was quantified by cleaved PARP staining and Western blotting of activated *** factor(NF)-κB,ERK,Akt and jun amino-terminal kinases signaling were *** hepatocytes were isolated by two step-collagenase perfusion and treated with recombinant TNF-αand with the CD95-ligand *** viability was analyzed by ***:Livers of CYLD-/-mice showed increased anti-apoptotic NF-κB *** both applied liver injury models CYLD-/-mice showed a significantly reduced apoptosis *** D-Gal N/LPS treatment CYLD-/-mice exhibited significantly lower levels of alanine aminotransferase(ALT)(295 U/L vs 859 U/L,Phowed 2-fold lower ALT(50 U/L vs 110 U/L,Phepatocytes(PMh)were less sensitive towards death receptor-mediated apoptosis and showed increased levels of Bcl-2,XIAP,c IAP1/2,survivin and c-FLIP expression upon TNF-and CD95-receptor triggering,*** of NF-κB activation by the inhibitor of NF-κB phosphorylation inhibitor BAY 11-7085 inhibited the expression of antiapoptotic proteins and re-sensitized CYLD-/-PMh towards TNF-and CD95-receptor mediated cell ***:CYLD is a central regulator of apoptotic cell death in murine hepatocytes by controlling NF-κB dependent anti-apoptotic signaling.

关键词： CYLD Apoptosis Nuclear factor-κB Tumo rnecrosis factor-α CD95 Liver

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Clinical characteristics and outcome of a cohort of 101 patients with hepatocellular carcinoma

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World Journal of Gastroenterology 2001年第2期7卷 208-215页

作者： christian Rabe Tillmann Pilz Christoph Klostermann Marc Berna hans h.Schild Tilman Sauerbruch Wolfgang h.Caselmann Department of Medicine I Department of RadiologyUniversity of BonnGermany

AIM: To conduct a cohort study of 101 patients with hepatocellular carcinoma (hCC) presenting to a tertiary care medical referral center in Germany between 1997 and 1999. METhODS AND RESULTS: Data were retrospectively analyzed by chart review. In 95 cases (72 males and 23 females) sufficient data were available for analysis. Twenty five (29%) of 85 patients were hBsAg or anti hBc positive, 21/85 (25%) were anti hCV positive, and 6/85 (7%) were positive for both hBV and hCV-markers. Age was significantly lower in hBV positive patients than in the other two groups. Thirty one (34%) of 90 patients had histories of alcohol abuse. In 79/94 (84%) patients, cirrhosis was diagnosed. Of these cirrhotic patients, 29/79 (37%) belonged to Child Pugh's group (ChILD) A, 32/79 (40%) to ChILD B, and 18/79 (23%) to ChILD C. AFP was elevated in 61/91 (67%) patients. A single tumor nodule was found in 38/94 (40%), more than one nodule in 31/94 (34%), and 25/94 (26%) had a diffusely infiltrating tumor, i.e. the tumor margins could not be seen on imaging procedures. Portal vein thrombosis was present in 19/94 (20%). Imaging data consistent with lymph node metastases were found in 10/92 (11%), while distant metastases were found in 8/93 (9%). According to Okuda 28/94 (30%) were grouped to stage I, 53/94 (56%) were grouped to stage II, and 13/94 (14%) were grouped to stage II. Survival data were available for 83 patients. The Kaplan-Meier estimate for median survival was 8 4 months. Factors influencing survival were the Okuda score, the presence of portal vein thrombosis, and the presence of ascites. The presence of non complicated liver cirrhosis by itself, distant metastases, or infection with hepatitis viruses did not influence survival. AFP positivity by itself did not influence survival, though patients with an AFP value greater than 100 microg/L did experience shortened survival. Treatment besides tamoxifen or supportive care was associated with prolonged survival. The influence of

关键词： Adult Aged Aged, 80 and over Carcinoma, hepatocellular Cohort Studies Female Germany hepatitis B hepatitis C humans Liver Cirrhosis, Alcoholic Liver Neoplasms Male Middle Aged Research Support, Non-U.S. Gov't Retrospective Studies Risk Factors Survival Analysis

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抗糖尿病药物有助于治疗阿尔茨海默病和帕金森病(英文)

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生理学报 2014年第5期66卷 497-510页

作者： christian hlscher 兰卡斯特大学生物医学和生命科学学院

2型糖尿病已被证实是阿尔茨海默病(Alzheimer’s disease,AD)和帕金森病(Parkinson’s disease,PD)的一个危险因素。已有报道表明,AD和PD患者脑内的胰岛素信号转导受到损害。这一发现使抗糖尿病药物的应用有了新的研究,并显示出良好效... 详细信息

2型糖尿病已被证实是阿尔茨海默病(Alzheimer’s disease,AD)和帕金森病(Parkinson’s disease,PD)的一个危险因素。已有报道表明,AD和PD患者脑内的胰岛素信号转导受到损害。这一发现使抗糖尿病药物的应用有了新的研究,并显示出良好效应。临床前期试验表明,胰岛素或长效肠促胰岛素肽(incretin peptide)类似物具有良好的神经保护作用。在AD和PD转基因模型动物中,胰高血糖素样肽1(GLP-1,一种肠促胰岛素的类似物)阻止了神经退行性变进程,改善了神经元和突触的功能,并减轻了疾病的症状。在AD转基因小鼠模型中,GLP-1类似物阻止了淀粉样斑块的沉积、突触的丧失以及认知功能的损害;在PD动物模型中,GLP-1类似物改善了多巴胺能神经传递和运动功能。在此基础上,临床试验也在进行之中,并显示出令人鼓舞的结果。在AD患者中的初步研究表明,鼻腔给予胰岛素可改善患者的认知功能并减少脑内的AD标志物。对PD患者的初步研究也表明,目前已经上市用于治疗2型糖尿病的一种GLP-1受体激动剂(exendin-4,Byetta)对PD病人具有良好的疗效。另一种上市用于治疗糖尿病的GLP-1类似物(liraglutide,Victoza)也正在AD患者中进行临床测试。最近,第三种GLP-1受体激动剂(Lixisenatide,Lyxumia)已经在欧洲被批准上市,该药物也显示了良好的神经保护作用。本文将就以上抗糖尿病药物的神经保护作用进行归纳。可见,GLP-1类似物所显示的神经保护乃至神经再生作用为AD和PD提供了一种新的治疗手段,这些作用是当前其它药物所不具备的。

关键词：糖尿病记忆帕金森病神经退行性变神经生长因子胰岛素阿尔茨海默病神经毒性

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Second premolar agenesis is associated with mandibular form： a geometric morphometric analysis of mandibular cross-sections

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International Journal of Oral Science 2016年第4期8卷 254-260页

作者： Michael h Bertl Kristina Bertl Manuel Wagner Andre Gahleitner Andreas Stavropoulos christian Ulm Philipp Mitteroecker Division of Orthodontics School of Dentistry Medical University of Vienna Vienna Austria Department of Periodontology Faculty of Odontology University of Malmo MalmoSweden Division of Oral Surgery School of Dentistry Medical University of Vienna Vienna Austria Department of Diagnostic Radiology Division of Osteoradiology General Hospital Medical University of Vienna Vienna Austria Department of Theoretical Biology University of Vienna Vienna Austria

The aim of this study was to compare mandibular form （i.e., size and shape） between patients with agenesis of the lower second premolar （P2） and a control group with no agenesis. Three hypotheses were tested：（h1） agenesis causes a change in mandibular morphology because of inadequate alveolar ridge development in the area of the missing tooth （mandibular plasticity）; （h2） agenesis is caused by spatial limitations within the mandible （dental plasticity）; and （h3） common genetic/ epigenetic factors cause agenesis and affect mandibular form （pleiotropy）. A geometric morphometric analysis was applied to cross-sectional images of computed tomography （CT） scans of three matched groups （n= 50 each）：（1） regularly erupted P2; （2） agenesis of P2 and the primary second molar in situ; and （3） agenesis of P2 and the primary second molar missing for 〉3 months. Cross-sections of the three areas of interest （first premolar, P2, first molar） were digitized with 23 landmarks and superimposed by a generalized Procrustes analysis. On average, the mandibular cross-sections were narrower and shorter in patients with P2 agenesis compared with that in the control group. Both agenesis groups featured a pronounced submandibular fossa. These differences extended at least one tooth beyond the agenesis-affected region. Taken together with the large interindividual variation that resulted in massively overlapping group distributions, these findings support genetic and/or epigenetic pleiotropy （h3） as the most likely origin of the observed covariation between mandibular form and odontogenesis. Clinically, reduced dimensions and greater variability of mandibular form, as well as a pronounced submandibular fossa, should be expected during the treatment planning of patients with P2 agenesis.

关键词： agenesis cross-sections geometric morphometrics mandibular form

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Existence of global solutions to isentropic gas dynamics equations with a source term

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Science China Mathematics 2010年第1期53卷 115-124页

作者： KLINGENBERG christian Institut fr angewandte Mathematik Universitt WrzburgAm Hubland97074 WrzburgGermany

In this paper we prove existence of isentropic gas dynamic equations with a source term (1.2). To this end we construct a sequence of regular hyperbolic systems (1.1) to approximate the inhomogeneous system of isentropic gas dynamics (1.2). First,for each fixed approximation parameter δ and very general condition on P (ρ),we establish the existence of entropy solutions for the Cauchy problem (1.1) with bounded initial date (1.4). Second,letting=o(δ),we obtain a complete proof of the h-1loc compactness of weak entropy pairs of system (1.2) in the form η(ρ,u) =ρh(ρ,u) given in Chen-LeFloch (2003). Finally,for the conditions of P(ρ) given in Chen-LeFloch (2003),applied to the results in Theorems 1 and 2,we obtain the global existence of entropy solutions for the Cauchy problem (1.2) with bounded initial date (1.4).

关键词： isentropic gas dynamics system global entropy solution compactness in h-loc1 compensated compactness method

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