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Search Results: 1 - 10 of 3506 matches for " Stephan Diekmann "
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In-Silico Modeling of the Mitotic Spindle Assembly Checkpoint
Bashar Ibrahim, Stephan Diekmann, Eberhard Schmitt, Peter Dittrich
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001555
Abstract: Background The Mitotic Spindle Assembly Checkpoint (MSAC) is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer. Principle Findings We have constructed and validated for the human MSAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the MSAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the “Dissociation” and the “Convey” model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments. Conclusion Only in the controlled case, our models show MSAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for MSAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.
Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts
Sascha Sch?uble, Karolin Klement, Shiva Marthandan, Sandra Münch, Ines Heiland, Stefan Schuster, Peter Hemmerich, Stephan Diekmann
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042150
Abstract: Primary human fibroblasts in tissue culture undergo a limited number of cell divisions before entering a non-replicative “senescent” state. At early population doublings (PD), fibroblasts are proliferation-competent displaying exponential growth. During further cell passaging, an increasing number of cells become cell cycle arrested and finally senescent. This transition from proliferating to senescent cells is driven by a number of endogenous and exogenous stress factors. Here, we have developed a new quantitative model for the stepwise transition from proliferating human fibroblasts (P) via reversibly cell cycle arrested (C) to irreversibly arrested senescent cells (S). In this model, the transition from P to C and to S is driven by a stress function γ and a cellular stress response function F which describes the time-delayed cellular response to experimentally induced irradiation stress. The application of this model based on senescence marker quantification at the single-cell level allowed to discriminate between the cellular states P, C, and S and delivers the transition rates between the P, C and S states for different human fibroblast cell types. Model-derived quantification unexpectedly revealed significant differences in the stress response of different fibroblast cell lines. Evaluating marker specificity, we found that SA-β-Gal is a good quantitative marker for cellular senescence in WI-38 and BJ cells, however much less so in MRC-5 cells. Furthermore we found that WI-38 cells are more sensitive to stress than BJ and MRC-5 cells. Thus, the explicit separation of stress induction from the cellular stress response, and the differentiation between three cellular states P, C and S allows for the first time to quantitatively assess the response of primary human fibroblasts towards endogenous and exogenous stress during cellular ageing.
Premitotic Assembly of Human CENPs -T and -W Switches Centromeric Chromatin to a Mitotic State
Lisa Prendergast,Chelly van Vuuren,Agnieszka Kaczmarczyk,Volker Doering,Daniela Hellwig,Nadine Quinn,Christian Hoischen,Stephan Diekmann,Kevin F. Sullivan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001082
Abstract: Centromeres are differentiated chromatin domains, present once per chromosome, that direct segregation of the genome in mitosis and meiosis by specifying assembly of the kinetochore. They are distinct genetic loci in that their identity in most organisms is determined not by the DNA sequences they are associated with, but through specific chromatin composition and context. The core nucleosomal protein CENP-A/cenH3 plays a primary role in centromere determination in all species and directs assembly of a large complex of associated proteins in vertebrates. While CENP-A itself is stably transmitted from one generation to the next, the nature of the template for centromere replication and its relationship to kinetochore function are as yet poorly understood. Here, we investigate the assembly and inheritance of a histone fold complex of the centromere, the CENP-T/W complex, which is integrated with centromeric chromatin in association with canonical histone H3 nucleosomes. We have investigated the cell cycle regulation, timing of assembly, generational persistence, and requirement for function of CENPs -T and -W in the cell cycle in human cells. The CENP-T/W complex assembles through a dynamic exchange mechanism in late S-phase and G2, is required for mitosis in each cell cycle and does not persist across cell generations, properties reciprocal to those measured for CENP-A. We propose that the CENP-A and H3-CENP-T/W nucleosome components of the centromere are specialized for centromeric and kinetochore activities, respectively. Segregation of the assembly mechanisms for the two allows the cell to switch between chromatin configurations that reciprocally support the replication of the centromere and its conversion to a mitotic state on postreplicative chromatin.
Premitotic Assembly of Human CENPs -T and -W Switches Centromeric Chromatin to a Mitotic State
Lisa Prendergast,Chelly van Vuuren,Agnieszka Kaczmarczyk,Volker Doering,Daniela Hellwig,Nadine Quinn,Christian Hoischen,Stephan Diekmann,Kevin F. Sullivan
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1001082
Abstract: Centromeres are differentiated chromatin domains, present once per chromosome, that direct segregation of the genome in mitosis and meiosis by specifying assembly of the kinetochore. They are distinct genetic loci in that their identity in most organisms is determined not by the DNA sequences they are associated with, but through specific chromatin composition and context. The core nucleosomal protein CENP-A/cenH3 plays a primary role in centromere determination in all species and directs assembly of a large complex of associated proteins in vertebrates. While CENP-A itself is stably transmitted from one generation to the next, the nature of the template for centromere replication and its relationship to kinetochore function are as yet poorly understood. Here, we investigate the assembly and inheritance of a histone fold complex of the centromere, the CENP-T/W complex, which is integrated with centromeric chromatin in association with canonical histone H3 nucleosomes. We have investigated the cell cycle regulation, timing of assembly, generational persistence, and requirement for function of CENPs -T and -W in the cell cycle in human cells. The CENP-T/W complex assembles through a dynamic exchange mechanism in late S-phase and G2, is required for mitosis in each cell cycle and does not persist across cell generations, properties reciprocal to those measured for CENP-A. We propose that the CENP-A and H3-CENP-T/W nucleosome components of the centromere are specialized for centromeric and kinetochore activities, respectively. Segregation of the assembly mechanisms for the two allows the cell to switch between chromatin configurations that reciprocally support the replication of the centromere and its conversion to a mitotic state on postreplicative chromatin.
Step-Wise Assembly, Maturation and Dynamic Behavior of the Human CENP-P/O/R/Q/U Kinetochore Sub-Complex
Anja Eskat, Wen Deng, Antje Hofmeister, Sven Rudolphi, Stephan Emmerth, Daniela Hellwig, Tobias Ulbricht, Volker D?ring, James M. Bancroft, Andrew D. McAinsh, M. Cristina Cardoso, Patrick Meraldi, Christian Hoischen, Heinrich Leonhardt, Stephan Diekmann
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044717
Abstract: Kinetochores are multi-protein megadalton assemblies that are required for attachment of microtubules to centromeres and, in turn, the segregation of chromosomes in mitosis. Kinetochore assembly is a cell cycle regulated multi-step process. The initial step occurs during interphase and involves loading of the 15-subunit constitutive centromere associated complex (CCAN), which contains a 5-subunit (CENP-P/O/R/Q/U) sub-complex. Here we show using a fluorescent three-hybrid (F3H) assay and fluorescence resonance energy transfer (FRET) in living mammalian cells that CENP-P/O/R/Q/U subunits exist in a tightly packed arrangement that involves multifold protein-protein interactions. This sub-complex is, however, not pre-assembled in the cytoplasm, but rather assembled on kinetochores through the step-wise recruitment of CENP-O/P heterodimers and the CENP-P, -O, -R, -Q and -U single protein units. SNAP-tag experiments and immuno-staining indicate that these loading events occur during S-phase in a manner similar to the nucleosome binding components of the CCAN, CENP-T/W/N. Furthermore, CENP-P/O/R/Q/U binding to the CCAN is largely mediated through interactions with the CENP-N binding protein CENP-L as well as CENP-K. Once assembled, CENP-P/O/R/Q/U exchanges slowly with the free nucleoplasmic pool indicating a low off-rate for individual CENP-P/O/R/Q/U subunits. Surprisingly, we then find that during late S-phase, following the kinetochore-binding step, both CENP-Q and -U but not -R undergo oligomerization. We propose that CENP-P/O/R/Q/U self-assembles on kinetochores with varying stoichiometry and undergoes a pre-mitotic maturation step that could be important for kinetochores switching into the correct conformation necessary for microtubule-attachment.
Features of an Experimental Station at an International Agricultural Research Center that Enhance Regional Impact
John Ryan,Colin Norwood,Juergen Diekmann
Sustainable Agriculture Research , 2012, DOI: 10.5539/sar.v1n2p88
Abstract: Adequately equipped field stations are essential for any institution involved with applied agricultural research. The field station is particularly crucial to the functioning of the network of global international research centers. The International Center for Agricultural Research in the Dry Areas addresses issues mainly related to dryland cropping system of the West Asia and North Africa region. It extends its effectiveness in northern Syria through a range of sub-stations and on-farm sites across the rainfall transect (150-600 mm). This article describes the environment and management of the Center that backstops its applied and adaptive research. Particular strengths of the station are highlighted. Unique features of the station that further the technology generation and transfer are described. While some aspects of international research station management are generic, there are considerations described that are specific to an evolving dryland research center in a rapidly changing region.
Organic Field-Effect-Transistors with Pentacene for radio-controlled-price-tag applications
C. Pannemannn,T. Diekmann,U. Hilleringmann
Advances in Radio Science : Kleinheubacher Berichte , 2003,
Abstract: This letter presents organic thin-film-transistors (OTFT) using the small organic molecule Pentacene targeting applications like radio controlled identification tags. Simple OTFTs as well as inverter circuits based on a pconducting silicon wafer substrate are presented. Comparing PECVD oxide and LTO as dielectric, only LTO deposited layers provide sufficient electrical stability. PECVD oxides show defects called “pin-holes", leading to short circuiting through the gate dielectrics. OTFTs of L=1μm/W=1000μm were prepared providing Ids = 61μA at –40Vds and –40Vgs, a subthreshold slope of 10.3 V/dec and an on-offratio of 102. The inverter circuits using insulated gate contacts switch from VA=–10V to VA=–3V output voltage when the input voltage is varied from VE=0V to VE=–8V at a supplied voltage of VB=–10V.
Functional Characterisation of the Maturation of the Blood-Brain Barrier in Larval Zebrafish
Angeleen Fleming, Heike Diekmann, Paul Goldsmith
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077548
Abstract: Zebrafish are becoming increasingly popular as an organism in which to model human disease and to study the effects of small molecules on complex physiological and pathological processes. Since larvae are no more than a few millimetres in length, and can live in volumes as small as 100 microliters, they are particularly amenable to high-throughput and high content compound screening in 96 well plate format. There is a growing literature providing evidence that many compounds show similar pharmacological effects in zebrafish as they do in mammals, and in particular humans. However, a major question regarding their utility for small molecule screening for neurological conditions is whether a molecule will reach its target site within the central nervous system. Studies have shown that Claudin-5 and ZO-1, tight-junction proteins which are essential for blood-brain barrier (BBB) integrity in mammals, can be detected in some cerebral vessels in zebrafish from 3 days post-fertilisation (d.p.f.) onwards and this timing coincides with the retention of dyes, immunoreactive tracers and fluorescent markers within some but not all cerebral vessels. Whilst these findings demonstrate that features of a BBB are first present at 3 d.p.f., it is not clear how quickly the zebrafish BBB matures or how closely the barrier resembles that of mammals. Here, we have combined anatomical analysis by transmission electron microscopy, functional investigation using fluorescent markers and compound uptake using liquid chromatography/tandem mass spectrometry to demonstrate that maturation of the zebrafish BBB occurs between 3 d.p.f. and 10 d.p.f. and that this barrier shares both structural and functional similarities with that of mammals.
Structures and Stabilities of H3+(H2)n Clusters (n=1-11)
B. Diekmann,P. Borrmann,E. R. Hilf
Physics , 1994,
Abstract: Geometries and energies for H3+(H2)n clusters (n = 0, ..., 11) have been calculated using standard "ab initio" methods. Up to clusters with n = 6, four different Pople basis sets (DZ, TZ, TZP) have been used in the calculations. For larger cluster sizes, the calculations have been carried out with one basis set (DZ) using the HF/CISD method. We discuss here only the nice counterplay of polarisation effects between the central H3+ ion and the adsorbed H2 molecules, which naturally governs both the geometric structure and the energy of the clusters.
Directed Security Policies: A Stateful Network Implementation
Cornelius Diekmann,Lars Hupel,Georg Carle
Computer Science , 2014, DOI: 10.4204/EPTCS.150.3
Abstract: Large systems are commonly internetworked. A security policy describes the communication relationship between the networked entities. The security policy defines rules, for example that A can connect to B, which results in a directed graph. However, this policy is often implemented in the network, for example by firewalls, such that A can establish a connection to B and all packets belonging to established connections are allowed. This stateful implementation is usually required for the network's functionality, but it introduces the backflow from B to A, which might contradict the security policy. We derive compliance criteria for a policy and its stateful implementation. In particular, we provide a criterion to verify the lack of side effects in linear time. Algorithms to automatically construct a stateful implementation of security policy rules are presented, which narrows the gap between formalization and real-world implementation. The solution scales to large networks, which is confirmed by a large real-world case study. Its correctness is guaranteed by the Isabelle/HOL theorem prover.
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