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Microsystems & Nanoengineering 2018年第1期4卷 325-336页

作者： Ketki Chawla Sebastian C.Bürgel Gregor W.Schmidt hans-michael kaltenbach Fabian Rudolf Olivier Frey Andreas Hierlemann ETH Zurich Department of Biosystems Science and EngineeringBio Engineering LaboratoryBaselSwitzerland ETH Zurich Department of Biosystems Science and EngineeringComputational Systems Biology GroupBaselSwitzerland

Growth rate is a widely studied parameter for various cell-based biological *** rates of cell populations can be monitored in chemostats and micro-chemostats,where nutrients are continuously ***,we present an integrated microfluidic platform that enables long-term culturing of non-adherent cells as well as parallel and mutually independent continuous monitoring of(i)growth rates of cells by means of impedance measurements and of(ii)specific other cellular events by means of high-resolution optical or fluorescence *** colonies were grown in a monolayer under culturing pads,which enabled high-resolution microscopy,as all cells were in the same focal *** cell growth and division,cells leaving the culturing area passed over a pair of electrodes and were counted through impedance *** impedance data could then be used to directly determine the growth rates of the cells in the culturing *** integration of multiple culturing chambers with sensing electrodes enabled multiplexed long-term monitoring of growth rates of different yeast strains in *** a demonstration,we modulated the growth rates of engineered yeast strains using *** results indicated that impedance measurements provide a label-free readout method to continuously monitor the changes in the growth rates of the cells without compromising high-resolution optical imaging of single cells.

关键词： impedance continuously culture

A simple human cell model for TAU trafficking and tauopathy-related TAU pathology

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Neural Regeneration Research 2022年第4期17卷 770-772页

作者： michael Bell hans Zempel Institute of Human Genetics Faculty of Medicine and University Hospital CologneUniversity of CologneCenter for Molecular Medicine Cologne(CMMC)University of CologneCologneGermany

The microtubule(MT)-associated protein TAU is highly abundant in the axon of human brain neurons,where it binds to and stabilizes MT ***,TAU regulates the dynamic(dis)assembly of MT strands and is involved in a wide range of neuronal *** Alzheimer's disease(AD)and other tauopathies,TAU is missorted into the somatodendritic *** missorting is accompanied by(or leads to)abnormal TAU phosphorylation,MT destabilization,and loss of dendritic spines and mitochondria,eventually resulting in TAU aggregation,neuronal dysfunction and cell death(Arendt et al.,2016).Strikingly,the mechanisms of TAU sorting,and the detrimental cascade upon its failure,are still not fully understood.

关键词： tau sorting eventually

General Regulatory Patterns of Plant Mineral Nutrient Depletion as Revealed by serat Quadruple Mutants Disturbed in Cysteine Synthesis

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Molecular Plant 2010年第2期3卷 438-466页

作者： Mutsumi Watanabe hans-michael Hubberten Kazuki Saito Rainer Hoefgen Graduate School of Pharmaceutical Sciences Chiba University 1-33 Yayoi-cho Inage-ku Chiba 263-8522 Japan Max-Planck-lnstitut fuer Molekulare Pflanzenphysiologie Wissenschaftspark Golm Am Muehlenberg 1 14476 Potsdam-Golm RIKEN Plant Science Center Tsurumi-ku Yokohama 230-0045 Japan

Sulfate is an essential macronutrient for plants. Plants have developed strategies to cope with sulfate deficiency, and other nutrient ion limitations. However, the regulation of these adaptive responses and the coordinating signals that underlie them are still poorly characterized. O-acetylserine （OAS） is a marker metabolite of sulfate starvation and has been speculated to have a signaling function. OAS is synthesized by the enzyme serine acetyltransferase （SERAT）, which is encoded by five distinct genes in Arabidopsis. We investigated quadruple knockout mutants of SERAT that retained only one functional isoform. These mutants displayed symptoms of sulfate starvation. Furthermore, some of them displayed phenotypes typical of prolonged sulfate starvation, in particular, developmental programs associated with senescence or stress responses. Thus, we compared metabolite and transcriptome data from these mutants with N-, P-, K-, and S-depleted plants. This revealed many similarities with general nutrient-depletion-induced senescence （NuDIS）, in- dicating the recruitment of existing regulatory programs for nutrient-starvation responses. Several candidate genes that could be involved in these processes were identified, including transcription factors and other regulatory proteins, as well as the functional categories of their target genes. These results outline components of the regulatory network controlling plant development under sulfate stress, forming a basis for further investigations to elucidate the complete network. In turn, this will advance our broader understanding of plant responses to a range of other nutrient stresses.

关键词： Abiotic/environmental stress ion/metabolite sensing senescence functional genomics Arabidopsis sulfur.

Targeted medical therapy of biliary tract cancer:Recent advances and future perspectives

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World Journal of Gastroenterology 2008年第46期14卷 7021-7032页

作者： michael Hpfner Detlef Schuppan hans Scherübl Institute of Physiology Charité-Universittsmedizin BerlinCampus Benjamin Franklin Beth Israel Deaconess Medical Center and Harvard Medical School Klinik für Innere Medizin Gastroenterologieund Gastrointestinale OnkologieKlinikum am Urban Vivantes Netzwerk für Gesundheit10967 BerlinGermany

The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biological features of these neoplasms led to the development of new targeted therapies, which take the abundant expression of several growth factors and cognate tyrosine kinase receptors into account. This review will briefly summarize the status and future perspectives of antiangiogenic and growth factor receptor-based pharmacological approaches for the treatment of biliary tract and gallbladder cancers. In view of multiple novel targeted approaches, the rationale for innovative therapies, such as combinations of growth factor (receptor)-targeting agents with cytotoxic drugs or with other novel anticancer drugs will be highlighted.

关键词： Growth factor receptor Biliary tract cancer Small molecule inhibitor lonoclonal antibody Innovative cancer treatment Sorafenib Bevacizumab Erlotinib

Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: Recent advances and future perspectives

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World Journal of Gastroenterology 2008年第16期14卷 2461-2473页

作者： michael Hpfner Detlef Schuppan hans Scherübl Institute of Physiology Charité-Universitts-medizin Berlin Campus Benjamin Franklin Beth Israel Deaconess Medical Center and Harvard Medical School Klinik für Innere Medizin Gastroenterologie und Gastrointestinale Onkologie Klinikum am Urban Vivantes Netzwerk für Gesundheit

The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.

关键词： Growth factor receptor Neuroendocrinegastrointestinal tumor Small molecule inhibitor lonoclonal antibody Multi kinase inhibition

Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer

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World Journal of Gastroenterology 2008年第1期14卷 1-14页

作者： michael Hpfner Detlef Schuppan hans Scherübl Institute of Physiology Charité-Universittsmedizin Berlin Campus Benjamin Franklin Berlin 12200 Germany Beth Israel Deaconess Medical Center Harvard Medical School Boston MA 02215 United States Klinik für Innere Medizin Gastroenterologie und Gastrointestinale Onkologie Klinikum am Urban Vivantes Netzwerk für Gesundheit Berlin 10967 Germany

Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer （HCC）. Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors （＂small molecule inhibitors＂） and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin （mTOR） upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation, roTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.

关键词： Growth factor receptor Hepatocellular cancer Small molecule inhibitor Monoclonal antibody Innovative cancer treatment Sorafenib Bevacizumab Erlotinib

CALCULATION OF THE YOUNG'S MODULUS OF AN ADSORBED POLYMER LAYER

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Chinese Journal of Polymer Science 2007年第1期25卷 95-105页

作者： Rüdiger Stark michael Kappl hans-Jürgen Butt Max-Planck-Institute for Polymer Research Ackermannweg 1055128 MainzGermany

Polymer layers adsorbed to a surface or in a confined environment often change their mechanical properties. There is even the possibility of solidification of the confined layer. To judge the stiffness of such a layer, we used the Hertz model to calculate the Young＇s modulus of the polymer layer in the confinement of AFM experiments with silicon nitride tip with a radius of curvature ofR ≈ 50 nm and a glass sphere attached to the cantilever R =5 μm. Since there is no visible indentation of the layer in the AFM experiments, the layer is either penetrated very easily, or the indentation is too small to be seen in a force curve. The latter would be the case for a polymer layer with a Young＇s modulus above 4 × 10^8 Pa in case of an experiment with a silicon nitride tip and 4×10^5 Pa in case of a glass sphere.

关键词： AFM PDMS PI Confined polymer Young's modulus Solidification.

Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells

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World Journal of Gastroenterology 2007年第33期13卷 4458-4466页

作者： Viola Baradari michael Hpfner Alexander Huether Detlef Schuppan hans Scherübl Institute of Physiology Charité-Universit?tsmedizin Berlin CampusBenjamin Franklin Berlin Germany Division of Gastroenterology Beth Israel Deaconess Medical Center Harvard Medical School Boston United States Klinik für Gastroenterologie und Gastrointestinale Onkologie Klinikum Am Urban Vivantes Netzwerk fürGesundheit Berlin Germany

AIM: To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or the novel anticancer agents sorafenib or bortezomib. METHODS: Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow ***: MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21Waf/CIP1. Furthermore, additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multi-kinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic ***: The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new, targeted anticancer agents.

关键词： Apoptosis Cholangiocarcinoma Bortezomib Combination treatment Histone deacetylase inhibitor MS-275 Proteasome inhibitor Sorafenib

Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer

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World Journal of Gastroenterology 2006年第35期12卷 5635-5643页

作者： michael Hpfner Andreas P Sutter Alexander Huether Viola Baradari hans Scherübl Charité-Universittsmedizin Berlin Campus Benjamin Franklin Medical Clinic I Gastroenterology/Infectious Diseases/ Rheumatology Berlin Germany Klinik für Gastroenterologie und Gastrointestinale Onkologie Vivantes-Klinikum Am Urban Dieffenbachstr. 1 Berlin 10967 Germany

AIM： To investigate the antineoplastic potency of the novel insulin-like growth factor 1 receptor （IGF-1R） tyrosine kinase inhibitor （TKI） NVP-AEW541 in cell lines and primary cell cultures of human colorectal cancer （CRC）. METHODS： Cells of primary colorectal carcinomas were from 8 patients. Immunostaining and crystal violet staining were used for analysis of growth factor receptor protein expression and detection of cell number changes, respectively. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase （LDH）. The proportion of apoptotic cells was determined by quantifying the percentage of sub-G1 （hypodiploid） cells. Cell cycle status reflected by the DNA content of the nuclei was detected by flow cytometry. RESULTS： NVP-AEW541 dose-dependently inhibited the proliferation of colorectal carcinoma cell lines and primary cell cultures by inducing apoptosis and cell cycle arrest. Apoptosis was characterized by caspase-3 activation and nuclear degradation. Cell cycle was arrested at the G1/S checkpoint. The NVP-AEW541-mediated cell cycle-related signaling involved the inactivation of Akt and extracellular signal-regulated kinase （ERK） 1/2, the upregulation of the cyclin-dependent kinase inhibitors p21^waf1/CIP1 and p27^kjp1, and the downregulation of the cell cycle promoter cyclin D1. Moreover, BAX was upregulated during NVP-AEW541-induced apoptosis, whereas Bcl-2 was downregulated. Measurement of LDH release showed that the antineoplastic effect of NVP-AEW541 was not due to general cytotoxicity of the compound. However, augmented antineoplastic effects were observed in combination treatments of NVP-AEW541 with either 5-FU, or the EGFR-antibody cetuximab, or the HMG-CoA-reductase inhibitor fluvastatin. CONCLUSION： IGF-1R-TK inhibition is a promising novel approach for either monoor combination treatment strategies of colorectal carcinoma and even for CRC chemoprevention.

关键词： Insulin-like growth factor receptor Tyrosine kinase Colorectal cancer Apoptosis Cell cycle arrest

Timanide(Ediacaran–Early Cambrian) Metamorphism at the Transition from Eclogite to Amphibolite Facies in the Beloretsk Complex,SW-Urals,Russia

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Journal of Earth Science 2019年第6期30卷 1144-1165页

作者： Arne P.Willner michael Gopon Johannes Glodny Victor N.Puchkov hans-Peter Schertl Institute of Geology Mineralogy and GeophysicsRuhr-University BochumD-44780 BochumGermany College of Earth Science and Engineering Shandong University of Science and TechnologyQingdao 266590China Deutsches Geoforschungszentrum GFZ、Telegrafenberg 14473 Potsdam、Germany Institute of Geology and Geochemistry Uralian Branch of Russian Academy of Science、620016 EkaterinburgRussia

The Beloretsk Metamorphic Complex in the SW Urals formed at a convergent eastern margin of Baltica during the Neoproterozoic–Early Cambrian Timanide *** comprises three major units with lenses of facies-critical metabasites within metasedimentary rocks:A lowermost eclogite unit,an intermediate garnet amphibolite unit and an upper amphibolite-greenschist ***(P)-temperature(T)-paths of four rocks from the two lowermost units were determined mainly by PT pseudosection techniques showing similar clockwise loops at different peak metamorphic,watersaturated conditions:A phengite-bearing eclogite shows peak PT conditions of 16.5–18.5 kbar/525–550℃(stage I)followed by stage II at 11.5–13.0 kbar/585–615℃.A garnet amphibolite from the intermediate unit yields lower peak conditions of 11.7–14.5 kbar/480–510℃(stage I)followed by stage II at 9.5–11.0 kbar/535–560℃.However,a granite gneiss in the eclogite unit shows similar maximum pressures as the eclogite,but higher temperatures at 15.6–16.2 kbar/660–675℃,whereas a garnet micaschist contains comparable high pressure relicts,but underwent an advanced midcrustal reequilibration at 7.5–9.0 kbar/555–610℃.We dated the eclogite by a 7-point Rb/Sr mineral isochron(phengite,omphacite,apatite)at 532.2±9.1 Ma interpreted as age of crystallisation of the eclogitic peak PT *** age is the youngest compared to the known Timanide metamorphic and magmatic ages.

关键词： Urals eclogite high pressure metamorphism Timanide orogeny Rb-Sr dating PT pseudosections PT-path