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  • 1
    Abstract: BACKGROUND: We suggest a new type of modeling approach for the coarse grained, particle-based spatial simulation of combinatorially complex chemical reaction systems. In our approach molecules possess a location in the reactor as well as an orientation and geometry, while the reactions are carried out according to a list of implicitly specified reaction rules. Because the reaction rules can contain patterns for molecules, a combinatorially complex or even infinitely sized reaction network can be defined. For our implementation (based on LAMMPS), we have chosen an already existing formalism (BioNetGen) for the implicit specification of the reaction network. This compatibility allows to import existing models easily, i.e., only additional geometry data files have to be provided. RESULTS: Our simulations show that the obtained dynamics can be fundamentally different from those simulations that use classical reaction-diffusion approaches like Partial Differential Equations or Gillespie-type spatial stochastic simulation. We show, for example, that the combination of combinatorial complexity and geometric effects leads to the emergence of complex self-assemblies and transportation phenomena happening faster than diffusion (using a model of molecular walkers on microtubules). When the mentioned classical simulation approaches are applied, these aspects of modeled systems cannot be observed without very special treatment. Further more, we show that the geometric information can even change the organizational structure of the reaction system. That is, a set of chemical species that can in principle form a stationary state in a Differential Equation formalism, is potentially unstable when geometry is considered, and vice versa. CONCLUSIONS: We conclude that our approach provides a new general framework filling a gap in between approaches with no or rigid spatial representation like Partial Differential Equations and specialized coarse-grained spatial simulation systems like those for DNA or virus capsid self-assembly.
    Type of Publication: Journal article published
    PubMed ID: 20529264
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  • 2
    Keywords: CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; PATHWAYS ; imaging ; PROTEIN ; PROTEINS ; METABOLISM ; TIME ; MECHANISM ; DOMAIN ; mechanisms ; DYNAMICS ; BIOLOGY ; ALPHA ; AGE ; RATES ; DNA-DAMAGE ; MAMMALIAN-CELLS ; EXCHANGE ; ONCOGENE ; KINETICS ; GREEN FLUORESCENT PROTEIN ; DOMAINS ; NUCLEAR-BODIES ; Sp100 ; ACUTE PROMYELOCYTIC LEUKEMIA ; BODIES ; RE ; ASSEMBLIES ; assembly ; INCREASE ; LEVEL ; NUCLEAR ; ANOMALOUS DIFFUSION ; ENGLAND ; CAJAL BODY COMPONENTS ; modeling ; TURNOVER ; SUMO ; SPIN ; FCS ; CELL BIOLOGY ; dynamic ; live cell imaging ; nuclear body ; promyelocytic leukemia ; SECONDS ; INTERACTING PROTEIN KINASE-2 ; FRAP ; PHOTOBLEACHING RECOVERY ; CELL-NUCLEUS ; kinetics modeling ; RAR alpha ; RECEPTOR-ALPHA
    Abstract: PML nuclear bodies (NBs) are involved in the regulation of key nuclear pathways but their biochemical function in nuclear metabolism is unknown. In this study PML NB assembly dynamics were assessed by live cell imaging and mathematic modeling of its major component parts. We show that all six nuclear PML isoforms exhibit individual exchange rates at NBs and identify PML V as a scaffold subunit. SPIN exchanges at least five times faster at NBs than PML proteins. Turnover dynamics of PML and SPIN at NBs is modulated by SUMOylation. Exchange is not temperature-dependent but depletion of cellular ATP levels induces protein immobilization at NBs. The PML-RAR alpha oncogene exhibits a strong NB retention effect on wild-type PML proteins. HIPK2 requires an active kinase for PML NB targeting and elevated levels of PML IV increase its residence time. DAXX and BLM turn over rapidly and completely at PML NBs within seconds. These findings provide a kinetics model for factor exchange at PML NBs and highlight potential mechanisms to regulate intranuclear trafficking of specific factors at these domains
    Type of Publication: Journal article published
    PubMed ID: 18664490
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  • 3
    Keywords: ENVIRONMENT ; IN-VITRO ; INHIBITOR ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; VITRO ; VIVO ; SITES ; PROTEIN ; ACTIVATION ; MECHANISM ; mechanisms ; DYNAMICS ; SIMULATION ; BINDING ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; RATES ; REQUIRES ; LOCALIZATION ; PARAMETERS ; KINETICS ; MITOSIS ; DIFFUSION ; CHROMOSOMES ; FRAMEWORK ; assembly ; CHECKPOINT ; BINDING-SITE ; USA ; MITOTIC-SPINDLE ; BINDING-SITES ; ANEUPLOIDY ; MAINTENANCE ; CHROMOSOME SEGREGATION ; signaling networks ; IN-SILICO ; BINDING SITE ; MITOTIC SPINDLE ; SEGREGATION ; ANAPHASE ; computational systems biology ; KINETOCHORE-MICROTUBULE INTERFACE ; MAD2 ; spatial simulation ; spindle assembly checkpoint ; TEMPLATE
    Abstract: The mitotic spindle assembly checkpoint ((M)SAC) is an important regulatory mechanism of the cell cycle, ensuring proper chromosome segregation in mitosis. It delays the transition to anaphase until all chromosomes are properly attached to the mitotic spindle by emitting a diffusible "wait anaphase"-signal from unattached kinetochores. Current models of the checkpoint disregard important spatial properties like localization, diffusion and realistic numbers of kinetochores. To allow for in silico studies of the dynamics of these models in a more realistic environment, we introduce a mathematical framework for quasi-spatial simulation of localized biochemical processes that are typically observed during checkpoint activation and maintenance. The "emitted inhibition" model of the (M)SAC by Doncic et al. (Proc Natl Acad Sci USA 2005; 102: 6332-7) assumes instantaneous activation of the diffusible "wait anaphase"-signal upon kinetochore encounter. We modify this model to account for binding kinetics with finite rates and use the developed framework to determine the feasible range of the binding parameters. We find that for proper activation, the binding rate constant has to be fast and above a critical value. Furthermore, this critical value depends significantly on the amount of local binding sites at each kinetochore. The critical values lie in a physiological realistic regime (10(4)-10(6) M(-1)s(-1)). We also determine the feasible parameter range for fast checkpoint activation of the "Mad2 template" model, for which the kinetic parameters have recently been studied in vitro by Simonetta et al. (PLoS Biology 2009; 7: 1000010). We find critical values for binding and catalysis rate constants, both significantly higher than the measured values. Our results suggest that yet unknown mechanisms at the kinetochores facilitate binding and catalysis in vivo. We conclude that quantitative models of the (M)SAC have to account for the limited availability of binding sites at kinetochores
    Type of Publication: Journal article published
    PubMed ID: 19657233
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  • 4
    Keywords: SACCHAROMYCES-CEREVISIAE ; COMPLEXES ; GTPASE-ACTIVATING PROTEIN ; fluorescent proteins ; IN-VITRO REGULATION ; TEM1 GTPASE ; PHOSPHATASE CDC14 ; mitotic exit network ; KINASE KIN4 ; SPINDLE POSITION CHECKPOINT ; ASSEMBLY CHECKPOINT ; Bfa1 ; BUDDING-YEAST ; MITOTIC EXIT-NETWORK ; modeling and simulation ; Tem1
    Abstract: The orientation of the mitotic spindle with respect to the polarity axis is crucial for the accuracy of asymmetric cell division. In budding yeast, a surveillance mechanism called the spindle position checkpoint (SPOC) prevents exit from mitosis when the mitotic spindle fails to align along the mother-to-daughter polarity axis. SPOC arrest relies upon inhibition of the GTPase Tem1 by the GTPase-activating protein (GAP) complex Bfa1-Bub2. Importantly, reactions signaling mitotic exit take place at yeast centrosomes (named spindle pole bodies, SPBs) and the GAP complex also promotes SPB localization of Tem1. Yet, whether the regulation of Tem1 by Bfa1-Bub2 takes place only at the SPBs remains elusive. Here, we present a quantitative analysis of Bfa1-Bub2 and Tem1 localization at the SPBs. Based on the measured SPB-bound protein levels, we introduce a dynamical model of the SPOC that describes the regulation of Bfa1 and Tem1. Our model suggests that Bfa1 interacts with Tem1 in the cytoplasm as well as at the SPBs to provide efficient Tem1 inhibition.
    Type of Publication: Journal article published
    PubMed ID: 22580890
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  • 5
    Keywords: MODEL ; COMPLEX ; ORIENTATION ; POLARITY ; IN-SILICO ; BIOLOGICAL NETWORKS ; SPINDLE-ASSEMBLY CHECKPOINT ; POSITION CHECKPOINT ; ORGANIZATION THEORY ; MAD2 ACTIVATION
    Abstract: Cycles are abundant in most kinds of networks, especially in biological ones. Here, we investigate their role in the evolution of a chemical reaction system from one self-sustaining composition of molecular species to another and their influence on the stability of these compositions. While it is accepted that, from a topological standpoint, they enhance network robustness, the consequence of cycles to the dynamics are not well understood. In a former study, we developed a necessary criterion for the existence of a fixed point, which is purely based on topological properties of the network. The structures of interest we identified were a generalization of closed autocatalytic sets, called chemical organizations. Here, we show that the existence of these chemical organizations and therefore steady states is linked to the existence of cycles. Importantly, we provide a criterion for a qualitative transition, namely a transition from one self-sustaining set of molecular species to another via the introduction of a cycle. Because results purely based on topology do not yield sufficient conditions for dynamic properties, e.g. stability, other tools must be employed, such as analysis via ordinary differential equations. Hence, we study a special case, namely a particular type of reflexive autocatalytic network. Applications for this can be found in nature, and we give a detailed account of the mitotic spindle assembly and spindle position checkpoints. From our analysis, we conclude that the positive feedback provided by these networks' cycles ensures the existence of a stable positive fixed point. Additionally, we use a genome-scale network model of the Escherichia coli sugar metabolism to illustrate our findings. In summary, our results suggest that the qualitative evolution of chemical systems requires the addition and elimination of cycles.
    Type of Publication: Journal article published
    PubMed ID: 23071525
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  • 6
    ISSN: 1439-0973
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Ceftriaxon und Natrium-Penicillin G sind gegenBorrelia burgdorferi in vitro wirksam. Zur Pharmakokinetik beider Substanzen im Liquor cerebrospinalis von Kindern ist hingegen wenig bekannt. 75 Kinder im Alter von 10 bis 176 Monaten (Median 96) mit einer definitiven oder möglichen Neuroborreliose wurden intravenös mit Ceftriaxon (1×50–90 mg/kg/Tag) oder Penicillin G (4×80000–120000 I.E./kg/Tag) behandelt. Am 10. Therapietag wurden die Liquor-Spiegel von Penicillin G (1, 1.5, 2, 3, 4, 5, oder 6 Stunden nach Gabe) bzw. Ceftriaxon (1, 2, 4, 6, 12, oder 24 Stunden nach Gabe) in Serum und Liquor aus gepaarten Proben mittels einer Mikroagar Diffusions-Methode gemessen. Die Ergebnisse zeigen, daß Penicillin G 5 Stunden nach Gabe noch über der minimalen Hemmkonzentration lag, daß aber 6 Stunden nach Gabe die Konzentration des Antibiotikums in 60% der Liquorproben bereits unterhalb der Meßgrenze lag. Die Ceftriaxon Liquorspiegel lagen durchwegs über der MHK — auch noch 24 Stunden nach der letzten Gabe. Die Serumkonzentrationen von Penicillin G lagen zwischen 46,6 und 0.1 mg/l, die Serumkonzentrationen von Ceftriaxon zwischen 261 und 5 mg/l. Die vorgestellten Ergebnisse werden im Hinblick auf den Stellenwert der beiden Antibiotika in der Therapie der Neuroborreliose im Kindesalter diskutiert.
    Notes: Summary In vitro β-lactam antibiotics like ceftriaxone and penicillin G sodium have been shown to be active againstBorrelia burgdorferi. Results of quantitative determinations of both antibiotic substances in the CSF for children are limited. Seventy-five children (median age 96 months, range 10 to 176 months) with probable or definite neuroborreliosis were treated with ceftriaxone (1×50–90 mg/kg/day) or penicillin G sodium (4×80,000–120,000 IU/kg/day) intravenously. On day 10 of therapy levels of penicillin G sodium (1, 1.5, 2, 3, 4, 5, or 6 h after i.v. administration), and ceftriaxone (1, 2, 4, 6, 12 or 24 h after i.v. administration) in serum and CSF were measured with a micro agar diffusion bioassay. Results demonstrate that after 5 h penicillin G sodium in CSF was above the minimal inhibitory concentration (MIC) but after 6 h penicillin G sodium levels were below the determination limit in 60% of the cases. All ceftriaxone results in CSF — even after 24 h — were above MIC. Penicillin G sodium serum values ranged from 46.6 to 0.1 mg/l (1 to 6 h post dose) and ceftriaxone serum values from 261 to 5 mg/l (1 to 24 h post dose). The role of penicillin G sodium and ceftriaxone and administration intervals of both antibiotics in the therapy of neuroborreliosis in children are discussed.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Description / Table of Contents: Zusammenfassung Chromosomen aus peripherem Blut und direkten Knochenmarkspräparaten von Patienten unter Azathioprin-Therapie wurden verglichen mit solchen von gesunden Kontrollpersonen und urämischen Patienten ohne Azathioprin-Einnahme. Die Ergebnisse sprechen für eine toxische Chromosomenschädigung sowohl durch Azathioprin als auch die urämische Stoffwechsellage. Die Bedeutung dieser Befunde, insbesondere im Zusammenhang mit mehrfach berichteten malignen Prozessen nach Azathioprin-Einnahme, wird diskutiert. Unsere Ergebnisse lassen eher einen Zusammenhang zwischen Immunosuppression und malignem Geschehen vermuten als eine direkte cancerogen Wirkung von Azathioprin.
    Notes: Summary Chromosomes from leukocyte cultures and direct bone marrow preparations from patients under Azathioprine treatment were examined and compared with those from uremic patients and normal controls not taking Azathioprine. The results indicate a toxic effect of the drug, as well as an effect of uremia on the chromosome complement. The significance of these findings is discussed, especially in relation to several reports concerning malignant processes arising during or after Azathioprine intake. According to our findings, a relation between immunosuppression and malignancy seems more likely than a direct cancerogenicity of Azathioprine.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Planta 134 (1977), S. 69-75 
    ISSN: 1432-2048
    Keywords: CO2 fixation ; Commelina communis ; Epidermis ; Stomata ; Tulipa gesneriana
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Isolated epidermes of Tulipa gesneriana L. and Commelian communis L. were exposed to 14CO2 in the light and in darkness, when stomata were either closed or open. The labelling patterns did not differ: the main products of CO2 fixation were malate and aspartate. Small amounts of radioactivity appeared also in acids of the tricarboxylic-acid cycle and their transamination products. Since the capacity of epidermis to assimilate CO2 is known to reside in the guard cells, we can state that guard cells continuously take up CO2 if present, and are thus able to recognize the presence of CO2 in their environment at all times. Epidermal samples exposed to 14CO2 in the light contained only small amounts of radioactive 3-phosphoglyceric acid (3-PGA) and sugar phosphates, or none at all. Epidermal samples from Commelina communis did not contain labelled 3-PGA if all adhering mesophyll cells had been removed before exposure to 14CO2. Homogenates of clean epidermal strips of Commelina communis were able to convert exogenous ribulose diphosphate to 3-PGA at a low rate, but could not catalyze the conversion of exogenous ribulose-5-phosphate to ribulose diphosphate. Guard cells of Commelina communis, and probably also those of Tulipa gesneriana, appear not to possess the reductive pentosephosphate pathway, despite the presence of chloroplasts. In such species, the guard cells will have to rely on import in order to maintain their carbon balance. Earlier findings of photosynthetic reduction of CO2 by epidermal tissues were probably obtained with samples that were contaminated with mesophyll cells.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-2048
    Keywords: Commelina communis ; Epidermis ; Gluconeogenesis ; Malic acid ; Stomatal movement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Epidermal strips with closed stomata were exposed to malic acid labelled with 14C either uniformly or in 4-C only. During incubation with [U-14C]malate, radioactivity appeared in products of the tricarboxylic-acid cycle and in transamination products within 10 min, in sugars after 2 h. Hardly any radioactivity was found in sugars if [4-14C]malate had been offered. This difference in the degree of labelling of sugars indicates that gluconeogenesis can occur in epidermal tissue, involving the decarboxylation of malate. Epidermis incubated with labelled malate was hydrolyzed after extraction with aqueous ethanol. The hydrolysate contained glucose as the only radioactive product, indicating that starch had been formed from malate. Microautoradiograms were black above stomatal complexes, showing that the latter were sites of starch formation. In order to follow the fate of malate during stomatal closure, malate was labelled in guard cells by exposing epidermes with open stomata to 14CO2 and then initiating stomatal closure. Of the radioactive fixation products of CO2 only malate was released into the water on which the epidermal samples floated; the epidermal strips retained some of the malate and all of its metabolites. In the case of rapid stomatal closure initiated by abscisic acid and completed within 5 min, 63% of the radioactivity was in the malate released, 22% in the malate retained, the remainder in aspartate, glutamate, and citrate. We conclude that during stomatal closing guard cells can dispose of malate by release, gluconeogenesis, and consumption in the tricarboxylic-acid cycle.
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  • 10
    ISSN: 1432-2048
    Keywords: Amylases ; Crassulacean acid metabolism ; Kalanchoë ; Maltose phosphorylase ; Phosphorylase ; Starch metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The degradation of starch by a protein fraction of Kalanchoë daigremontiana Hamet et Perrier, obtained by ammoniumsulfate precipitation (30–70%), was found to be catalyzed by α-and β-amylase (EC 3.2.1.1 and EC 3.2.1.2, respectively) and by starch phosphorylase (EC 2.4.1.1). The activity of these enzymes was determined by chromatographic analysis of the reaction products; separation and identification of α-amylase was accomplished by heat-inactivation of β-amylase and α-glucosidase. When the interaction of amylolytic and phosphorolytic enzymes was comparatively studied, it was found that without inorganic phosphorus in the reaction mixture, 14C-starch was converted predominantly to maltose and glucose; supplementation with 1–10 mM orthophosphate (Pi) resulted in an increase in glucose-1-phosphate formation and a concomitant reduction of maltose production. Since the total volume of starch degradation remained approximately constant, Pi apparently inhibits β-amylase (Ki about 3 mM Pi). Thus, free Pi in the cell participates in the regulation of starch catabolism, serving as a substrate for starch phosphorylase while simultaneously reducing the production of maltose. With respect to glucan synthesis, adenosinediphosphoglucose-α-1,4-glucosyltransferase (EC 2.4.1.22), maltose phosphorylase and maltoseglucosyltransferase were also found to be active. The last-named enzyme catalyzes an exchange between dextrins and is considered to provide primer carbohydrates for the synthesis of polyglucans.
    Type of Medium: Electronic Resource
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