Therapeutic target discovery using Boolean network attractors: avoiding pathological phenotypes

Target identification, one of the steps of drug discovery, aims at identifying biomolecules whose function should be therapeutically altered in order to cure the considered pathology. This work proposes an algorithm for in silico target identification using Boolean network attractors. It assumes that attractors of dynamical systems, such as Boolean networks, correspond to phenotypes produced by the modeled biological system. Under this assumption, and given a Boolean network modeling a pathophysiology, the algorithm identifies target combinations able to remove attractors associated with pathological phenotypes. It is tested on a Boolean model of the mammalian cell cycle bearing a constitutive inactivation of the retinoblastoma protein, as seen in cancers, and its applications are illustrated on a Boolean model of Fanconi anemia. The results show that the algorithm returns target combinations able to remove attractors associated with pathological phenotypes and then succeeds in performing the proposed in silico target identification. However, as with any in silico evidence, there is a bridge to cross between theory and practice, thus requiring it to be used in combination with wet lab experiments. Nevertheless, it is expected that the algorithm is of interest for target identification, notably by exploiting the inexpensiveness and predictive power of computational approaches to optimize the efficiency of costly wet lab experiments.Comment: Since the publication of this article and among the possible improvements mentioned in the Conclusion, two improvements have been done: extending the algorithm for multivalued logic and considering the basins of attraction of the pathological attractors for selecting the therapeutic bullet

Control of embryonic Xenopus morphogenesis by a Ral-GDS/Xral branch of the Ras signalling pathway.

Ras proteins mediate biological responses through various effectors and play a key role in relaying the Fibroblast Growth Factor (FGF) mesoderm induction signal during embryogenesis of the frog, Xenopus laevis. One Ras effector pathway involves the activation of the small G protein Ral. In the present study, we have investigated the role of key components in the Ral branch of FGF and Ras signalling during early Xenopus development. Treatment of animal caps with bFGF, which converts prospective ectoderm to mesoderm, activates Xral. The Ras mutant 12V37G, which can bind to Ral-GDS but not Raf, also activates Xral as well as causing developmental defects and cortical F-actin disassembly. A similar phenotype is induced by Ral-GDS itself. FGF-induced expression of several signature mesodermal genes, by contrast, is independent of Xral signalling. This and other data suggest that the RalB branch of Ras and FGF signalling regulates the actin cytoskeleton and morphogenesis in a transcriptionally independent manner. We also find Xral to be specifically activated in the marginal zone of Xenopus embryos, and find that disruption of the Ral pathway in this region prevents closure of the blastopore during gastrulation. We conclude that Ral signalling is autonomously required by mesodermal cells to effect essential morphogenetic changes during Xenopus gastrulation

Revisiting the relationship between baseline risk and risk under treatment

<p>Abstract</p> <p>Background</p> <p>In medical practice, it is generally accepted that the 'effect model' describing the relationship between baseline risk and risk under treatment is linear, i.e. 'relative risk' is constant. Absolute benefit is then proportional to a patient's baseline risk and the treatment is most effective among high-risk patients. Alternatively, the 'effect model' becomes curvilinear when 'odds ratio' is considered to be constant. However these two models are based on purely empirical considerations, and there is still no theoretical approach to support either the linear or the non-linear relation.</p> <p>Presentation of the hypothesis</p> <p>From logistic and sigmoidal Emax (Hill) models, we derived a phenomenological model which includes the possibility of integrating both beneficial and harmful effects. Instead of a linear relation, our model suggests that the relationship is curvilinear i.e. the moderate-risk patients gain most from the treatment in opposition to those with low or high risk.</p> <p>Testing the hypothesis</p> <p>Two approaches can be proposed to investigate in practice such a model. The retrospective one is to perform a meta-analysis of clinical trials with subgroups of patients including a great range of baseline risks. The prospective one is to perform a large clinical trial in which patients are recruited according to several prestratified diverse and high risk groups.</p> <p>Implications of the hypothesis</p> <p>For the quantification of the treatment effect and considering such a model, the discrepancy between odds ratio and relative risk may be related not only to the level of risk under control conditions, but also to the characteristics of the dose-effect relation and the amount of dose administered. In the proposed approach, OR may be considered as constant in the whole range of <it>Rc</it>, and depending only on the intrinsic characteristics of the treatment. Therefore, OR should be preferred rather than RR to summarize information on treatment efficacy.</p

RLIP mediates downstream signalling from RalB to the actin cytoskeleton during Xenopus early development.

The Ras protein activates at least three different pathways during early development. Two of them regulate mesodermal gene expression and the third is thought to participate in the control of actin cytoskeleton dynamics via the Ral protein. From a yeast two-hybrid screen of a Xenopus maternal cDNA library, we identified the Xenopus orthologue of the Ral interacting protein (RLIP, RIP1 or RalBP1), a putative effector of small G protein Ral. Previously we observed that a constitutively activated form of Ral GTPase (XralB G23V) induced bleaching of the animal hemisphere and disruption of the cortical actin cytoskeleton. To demonstrate that RLIP is the effector of RalB in early development, we show that the artificial targeting of RLIP to the membrane induces a similar phenotype to that of activated RalB. We show that overexpression of the Ral binding domain (RalBD) of XRLIP, which binds to the effector site of Ral, acts in competition with the endogenous effector of Ral and protects against the destructive effect of XralB G23V on the actin cytoskeleton. In contrast, the XRLIP has a synergistic effect on the activated form of XralB, which is dependent on the RalBD of RLIP. We provide evidence for the involvement of RLIP by way of its RalBD on the dynamics of the actin cytoskeleton and propose that signalling from Ral to RLIP is required for gastrulation

Collaborative Knowledge Framework for Mediation Information System Engineering

With the worldwide interenterprise collaboration and interoperability background, automatic collaborative business process deduction is crucial and imperative researching subject. A methodology of deducing collaborative process is designed by collecting collaborative knowledge. Due to the complexity of deduction methodology, a collaborative knowledge framework is defined to organize abstract and concrete collaborative information. The collaborative knowledge framework contains three dimensions: elements, levels, and life cycle. To better define the framework, the relations in each dimension are explained in detail. They are (i) relations among elements, which organize the gathering orders and methods of different collaborative elements, (ii) relations among life cycle, which present modeling processes and agility management, and (iii) relations among levels, which define relationships among different levels of collaborative processes: strategy, operation, and support. This paper aims to explain the collaborative knowledge framework and the relations inside

Jean-Pierre Jessenne (dir.), Vers un ordre bourgeois ? Révolution française et changement social

« État bourgeois ! Espèce d’étudiants bourgeois !… » Toutes ces exclamations entendues ici et là traitent toujours d’une même partie de la société : la bourgeoisie. Cependant qu’est ce qu’un bourgeois ? Comment le définit-on ? Cette question Jean-Pierre Jessenne et ses collègues historiens, ont essayé d’y répondre dans un colloque en janvier 2006 à Lille dans un cadre chronologique assez vaste : avant, pendant et largement après la Révolution Française. Cet ouvrage constitue la publication de..

Requirement of Dynactin p150Glued Subunit for the Functional Integrity of the Keratinocyte Microparasol

The keratinocyte microparasol, composed of a perinuclear microtubular/melano–phagolysosomal complex, protects the nucleus from UV-induced DNA damage. We have previously demonstrated that cytoplasmic dynein is the motor involved in the perinuclear-directed aggregation of phagocytosed melanosomes. Dynactin, of which p150Glued is the major subunit, can link directly to microtubules and links organelles to dynein at different domains. To further define the mechanism of the microparasol, we transfected siRNA targeted against p150Glued into human keratinocytes cultured with 0.5mm fluorescent microspheres and performed time-lapse analysis, confocal immunolocalization, and Western immunoblotting after 24 and 48 hours. Western blots revealed a significant knockdown of the p150Glued subunit. The knockdown decreased p150Glued colocalization with microtubules and decreased perinuclear positioning of the convergent microtubular framework. It also inhibited perinuclear aggregation of phagocytosed fluorescent microspheres and reduced mean centripetal microsphere displacement. The findings provide evidence that dynactin p150Glued plays an important role in the functional integrity of the keratinocyte microparasol