Improved Time-related Checking in Routing Solvers

To solve routing problems with given constraints, an initial routing solution is obtained in a construction phase and iteratively improved in a subsequent improvement phase. With O(1) time complexity to check for constraint satisfaction per change with p being the total length of all paths changed between a known solution and a new candidate solution, current approaches have O(p²) time and space complexity when replacing the current solution with a new one. This does not scale when routing problems involve paths that have hundreds of nodes. This disclosure describes techniques to perform efficient pre-computations to reduce the time and space complexity to O(p log p), thus significantly saving time and resources. The pre-computations check constraint satisfaction for new candidate solutions generated with small variations from a current solution that is known to respect the constraints. The new candidate solutions are described by the chains of their paths that are changed in comparison to the current solution. The checking and pre-computations are performed with a general algorithm and associated query scheme for each subproblem, and run in linear time in the number of chains. As a result, the time and space complexity of the operation is reduced to O(p log p), where p is the total length of all changed paths in the new solution

An imPRESsive mimic

Received for publication April 22, 2009; revision received June 18, 2009; and accepted June 19, 2009.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78628/1/j.1537-2995.2009.02362.x.pd

Subgraph Epimorphisms: Theory and Application to Model Reductions in Systems Biology

This thesis develops a framework of graph morphisms and applies it to model reductionin systems biology. We are interested in the following problem: the collection of systemsbiology models is growing, but there is no formal relation between models in this collection.Thus, the task of organizing the existing models, essential for model refinement andcoupling, is left to the modeler. In mathematical biology, model reduction techniques havebeen studied for a long time, however these techniques are far too restrictive to be appliedon the scales required by systems biology.We propose a model reduction framework based solely on graphs, allowing to organizemodels in a partial order. Systems biology models will be represented by their reactiongraphs. To capture the process of reduction itself, we study a particular kind of graph morphisms:subgraph epimorphisms, which allow both vertex merging and deletion. We firstanalyze the partial order emerging from the merge/delete graph operations, then developtools to solve computational problems raised by this framework, and finally show both thecomputational feasibility of the approach and the accuracy of the reaction graphs/subgraphepimorphisms framework on a large repository of systems biology models.Cette th`ese d´eveloppe une m´ethode de morphismes de graphes et l’applique `a la r´eductionde mod`eles en biologie des syst`emes. Nous nous int´eressons au probl`eme suivant: l’ensembledes mod`eles en biologie des syst`emes est en expansion, mais aucune relation formelle entreles mod`eles de cet ensemble n’a ´et´e entreprise. Ainsi, la tˆache d’organisation des mod`elesexistants, qui est essentielle pour le raffinement et le couplage de mod`eles, doit ˆetre effectu´eepar le mod´elisateur. En biomath´ematiques, les techniques de r´eduction de mod`elesont ´etudi´ees depuis longtemps, mais ces techniques sont bien trop restrictives pour ˆetreappliqu´ees aux ´echelles requises en biologie des syst`emes.Nous proposons un cadre de r´eduction de mod`ele, bas´e uniquement sur des graphes, quipermet d’organiser les mod`eles en un ordre partiel. Les mod`eles de biologie des syst`emesseront repr´esent´es par leur graphe de r´eaction. Pour capturer le processus de r´eduction luimˆeme,nous ´etudierons un type particulier de morphismes de graphes: les ´epimorphismesde sous-graphe, qui permettent la fusion et l’effacement de sommets. Nous commenceronsen analysant l’ordre partiel qui ´emerge des op´erations de fusion et d’effacement, puis nousd´evelopperons des outils th´eoriques pour r´esoudre les probl`emes calculatoires de notrem´ethode, et pour finir nous montrerons la faisabilit´e de l’approche et la pr´ecision du cadre“graphes de r´eactions/´epimorphismes de sous-graphe”, en utilisant un d´epˆot de mod`elesde biologie des syst`emes

Automatic Curation of SBML Models based on their ODE Semantics

Many models in Systems Biology are described as a system of Ordinary Differential Equations. The fact that the Systems Biology Markup Language SBML has become a standard for sharing and publishing models, has helped in making modelers formalize the structure of the reactions and use structure-related methods for reasoning about models. Unfortunately, SBML does not enforce any coherence between the structure and the kinetics of a reaction. Therefore the structural interpretation of models transcribed in SBML may vary according to different choices of representation of the original model and may be incorrect for some analyses. The first contribution of this paper is to propose a general compatibility condition between the kinetic expression and the structure of a reaction. We show that these well-formedness conditions are satisfied by standard kinetics and that they entail a property of independence from the kinetic expressions for the influence graph associated to the ODEs. We present a heuristic algorithm of low computational complexity for, given an ODE system, inferring a reaction model that preserves the ODE semantics and infers well-formed reactions whenever possible. This algorithm can be used for not only checking whether the network and ODE structures of an SBML model are consistent but also automatically curating SBML models by exporting them as ODE systems and then importing them as well-formed reaction models. We show how this strategy is capable of automatically curating SBML models on a large scale and provide some statistics figures obtained on the whole biomodels.net repository. The algorithms described in this paper are implemented in the open-source software modeling platform BIOCHAM [Fages and Soliman, 2008a, Calzone et al., 2006] available at http://contraintes.inria.fr/biocham The models used in the experiments are available from http://www.biomodels.net

The Sudden Death of the Nearest Quasar

Galaxy formation is significantly modulated by energy output from supermassive black holes at the centers of galaxies which grow in highly efficient luminous quasar phases. The timescale on which black holes transition into and out of such phases is, however, unknown. We present the first measurement of the shutdown timescale for an individual quasar using X-ray observations of the nearby galaxy IC 2497, which hosted a luminous quasar no more than 70,000 years ago that is still seen as a light echo in `Hanny's Voorwerp', but whose present-day radiative output is lower by at least 2 and more likely by over 4 orders of magnitude. This extremely rapid shutdown provides new insights into the physics of accretion in supermassive black holes, and may signal a transition of the accretion disk to a radiatively inefficient state.Comment: 4 pages, 2 figures. Astrophysical Journal Letters, in pres

Solving Subgraph Epimorphism Problems using CLP and SAT

International audienceIn this work, we compare CLP and SAT solvers on the NP-complete problem of deciding the existence of a subgraph epimorphism between two graphs. Our interest in this variant of graph matching problem stems from the study of model reductions in systems biology, where large systems of biochemical reactions can be naturally represented by bipartite digraphs of species and reactions. In this setting, model reduction can be formalized as the existence of a sequence of vertex, species or reaction, deletion and merge operations which transforms a first reaction graph into a second graph. This problem is in turn equivalent to the existence of a subgraph (corresponding to delete operations) epimorphism (i.e. surjective homomorphism, corresponding to merge operations) from the first graph to the second. We show how subgraph epimorphism problems can be modeled as Boolean constraint satisfaction problems, and we compare CLP and SAT solvers on a large benchmark of reaction graphs from systems biology

O-GlcNAc modifications regulate cell survival and epiboly during zebrafish development

<p>Abstract</p> <p>Background</p> <p>The post-translational addition of the monosaccharide O-linked β-<it>N</it>-acetylglucosamine (O-GlcNAc) regulates the activity of a wide variety of nuclear and cytoplasmic proteins. The enzymes O-GlcNAc Transferase (Ogt) and O-GlcNAcase (Oga) catalyze, respectively, the attachment and removal of O-GlcNAc to target proteins. In adult mice, Ogt and Oga attenuate the response to insulin by modifying several components of the signal transduction pathway. Complete loss of <it>ogt </it>function, however, is lethal to mouse embryonic stem cells, suggesting that the enzyme has additional, unstudied roles in development. We have utilized zebrafish as a model to determine role of O-GlcNAc modifications in development. Zebrafish has two <it>ogt </it>genes, encoding six different enzymatic isoforms that are expressed maternally and zygotically.</p> <p>Results</p> <p>We manipulated O-GlcNAc levels in zebrafish embryos by overexpressing zebrafish <it>ogt</it>, human <it>oga </it>or by injecting morpholinos against <it>ogt </it>transcripts. Each of these treatments results in embryos with shortened body axes and reduced brains at 24 hpf. The embryos had 23% fewer cells than controls, and displayed increased rates of cell death as early as the mid-gastrula stages. An extensive marker analysis indicates that derivatives of three germ layers are reduced to variable extents, and the embryos are severely disorganized after gastrulation. Overexpression of Ogt and Oga delayed epiboly and caused a severe disorganization of the microtubule and actin based cytoskeleton in the extra-embryonic yolk syncytial layer (YSL). The cytoskeletal defects resemble those previously reported for embryos lacking function of the Pou5f1/Oct4 transcription factor <it>spiel ohne grenzen</it>. Consistent with this, Pou5f1/Oct4 is modified by O-GlcNAc in human embryonic stem cells.</p> <p>Conclusion</p> <p>We conclude that O-GlcNAc modifications control the activity of proteins that regulate apoptosis and epiboly movements, but do not seem to regulate germ layer specification. O-GlcNAc modifies the transcription factor Spiel ohne grenzen/Pou5f1 and may regulate its activity.</p

A proposal for curriculum content in transfusion medicine and blood banking education in pathology residency programs

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71606/1/j.1537-2995.2007.01417.x.pd