330 research outputs found
TIde: a software for the systematic scanning of drug targets in kinetic network models
<p>Abstract</p> <p>Background</p> <p>During the stages of the development of a potent drug candidate compounds can fail for several reasons. One of them, the efficacy of a candidate, can be estimated <it>in silico </it>if an appropriate ordinary differential equation model of the affected pathway is available. With such a model at hand it is also possible to detect reactions having a large effect on a certain variable such as a substance concentration.</p> <p>Results</p> <p>We show an algorithm that systematically tests the influence of activators and inhibitors of different type and strength acting at different positions in the network. The effect on a quantity to be selected (e.g. a steady state flux or concentration) is calculated. Moreover, combinations of two inhibitors or one inhibitor and one activator targeting different network positions are analysed. Furthermore, we present TIde (Target Identification), an open source, platform independent tool to investigate ordinary differential equation models in the common systems biology markup language format. It automatically assigns the respectively altered kinetics to the inhibited or activated reactions, performs the necessary calculations, and provides a graphical output of the analysis results. For illustration, TIde is used to detect optimal inhibitor positions in simple branched networks, a signalling pathway, and a well studied model of glycolysis in <it>Trypanosoma brucei</it>.</p> <p>Conclusion</p> <p>Using TIde, we show in the branched models under which conditions inhibitions in a certain pathway can affect a molecule concentrations in a different. In the signalling pathway we illuminate which inhibitions have an effect on the signalling characteristics of the last active kinase. Finally, we compare our set of best targets in the glycolysis model with a similar analysis showing the applicability of our tool.</p
SBMLmerge, a System for Combining Biochemical Network Models
The Systems Biology Markup Language (SBML) is an XML-based format for representing mathematical models of biochemical reaction networks, and it is likely to become a main standard in the systems biology community. As published mathematical models in cell biology are growing in number and size, modular modelling approaches will gain additional importance. The main issue to be addressed in computer-assisted model combination is the specification and handling of model semantics. The software SBMLmerge assists the user in combining models of biological subsystems to larger biochemical networks. First, the program helps the user in annotating all model elements with unique identifiers pointing to databases such as KEGG or Gene Ontology. Second, during merging, SBMLmerge detects and resolves various syntactic and semantic problems. Typical problems are conflicting variable names, elements which appear in more than one input model, and mathematical problems arising from the combination of equations. If the input models make contradicting statements about a biochemical quantity, the user is asked to choose between them. In the end the merging process results in a new, valid SBML model
Fkh1 and Fkh2 associate with Sir2 to control <em>CLB2</em> transcription under normal and oxidative stress conditions
Coupling biochemistry and mechanics in cell adhesion: a model for inhomogeneous stress fiber contraction
Biochemistry and mechanics are closely coupled in cell adhesion. At sites of
cell-matrix adhesion, mechanical force triggers signaling through the
Rho-pathway, which leads to structural reinforcement and increased
contractility in the actin cytoskeleton. The resulting force acts back to the
sites of adhesion, resulting in a positive feedback loop for mature adhesion.
Here we model this biochemical-mechanical feedback loop for the special case
when the actin cytoskeleton is organized in stress fibers, which are
contractile bundles of actin filaments. Activation of myosin II molecular
motors through the Rho-pathway is described by a system of reaction-diffusion
equations, which are coupled into a viscoelastic model for a contractile actin
bundle. We find strong spatial gradients in the activation of contractility and
in the corresponding deformation pattern of the stress fiber, in good agreement
with experimental findings.Comment: Revtex, 35 pages, 13 Postscript figures included, in press with New
Journal of Physics, Special Issue on The Physics of the Cytoskeleto
Measurement in biological systems from the self-organisation point of view
Measurement in biological systems became a subject of concern as a
consequence of numerous reports on limited reproducibility of experimental
results. To reveal origins of this inconsistency, we have examined general
features of biological systems as dynamical systems far from not only their
chemical equilibrium, but, in most cases, also of their Lyapunov stable states.
Thus, in biological experiments, we do not observe states, but distinct
trajectories followed by the examined organism. If one of the possible
sequences is selected, a minute sub-section of the whole problem is obtained,
sometimes in a seemingly highly reproducible manner. But the state of the
organism is known only if a complete set of possible trajectories is known. And
this is often practically impossible. Therefore, we propose a different
framework for reporting and analysis of biological experiments, respecting the
view of non-linear mathematics. This view should be used to avoid
overoptimistic results, which have to be consequently retracted or largely
complemented. An increase of specification of experimental procedures is the
way for better understanding of the scope of paths, which the biological system
may be evolving. And it is hidden in the evolution of experimental protocols.Comment: 13 pages, 5 figure
Controlling complex networks: How much energy is needed?
The outstanding problem of controlling complex networks is relevant to many
areas of science and engineering, and has the potential to generate
technological breakthroughs as well. We address the physically important issue
of the energy required for achieving control by deriving and validating scaling
laws for the lower and upper energy bounds. These bounds represent a reasonable
estimate of the energy cost associated with control, and provide a step forward
from the current research on controllability toward ultimate control of complex
networked dynamical systems.Comment: 4 pages paper + 5 pages supplement. accepted for publication in
Physical Review Letters;
http://link.aps.org/doi/10.1103/PhysRevLett.108.21870
Sic1 plays a role in timing and oscillatory behaviour of B-type cyclins
Budding yeast cell cycle oscillates between states of low and high cyclin-dependent kinase activity, driven by association of Cdk1 with B-type (Clb) cyclins. Various Cdk1-Clb complexes are activated and inactivated in a fixed, temporally regulated sequence, inducing the behaviour known as "waves of cyclins". The transition from low to high Clb activity is triggered by degradation of Sic1, the inhibitor of Cdk1-Clb complexes, at the entry to S phase. The G(1) phase is characterized by low Clb activity and high Sic1 levels. High Clb activity and Sic1 proteolysis are found from the beginning of the S phase until the end of mitosis. The mechanism regulating the appearance on schedule of Cdk1-Clb complexes is currently unknown. Here, we analyse oscillations of Clbs, focusing on the role of their inhibitor Sic1. We compare mathematical networks differing in interactions that Sic1 may establish with Cdk1-Clb complexes. Our analysis suggests that the wave-like cyclins pattern derives from the binding of Sic1 to all Clb pairs rather than from Clb degradation. These predictions are experimentally validated, showing that Sic1 indeed interacts and coexists in time with Clbs. Intriguingly, a sic1Delta strain looses cell cycle-regulated periodicity of Clbs, which is observed in the wild type, whether a SIC1-0P strain delays the formation of Clb waves. Our results highlight an additional role for Sic1 in regulating Cdk1-Clb complexes, coordinating their appearance
A Clb/Cdk1-mediated regulation of Fkh2 synchronizes CLB expression in the budding yeast cell cycle
Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations
Metabolic reprogramming is as a hallmark of cancer, and several studies have reported that BRAF and KRAS tumors may be accompanied by a deregulation of cellular metabolism. We investigated how BRAF(V600E) and KRAS(G12V) affect cell metabolism, stress resistance and signaling in colorectal carcinoma cells driven by these mutations. KRAS(G12V) expressing cells are characterized by the induction of glycolysis, accumulation of lactic acid and sensitivity to glycolytic inhibition. Notably mathematical modelling confirmed the critical role of MCT1 designating the survival of KRAS(G12V) cells. Carcinoma cells harboring BRAF(V600E) remain resistant towards alterations of glucose supply or application of signaling or metabolic inhibitors. Altogether these data demonstrate that an oncogene-specific decoupling of mTOR from AMPK or AKT signaling accounts for alterations of resistance mechanisms and metabolic phenotypes. Indeed the inhibition of mTOR in BRAF(V600E) cells counteracts the metabolic predisposition and demonstrates mTOR as a potential target in BRAF(V600E)-driven colorectal carcinomas
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