In Silico Logical Modelling to Uncover Cooperative Interactions in Cancer

The multistep development of cancer involves the cooperation between multiple molecular lesions, as well as complex interactions between cancer cells and the surrounding tumour microenvironment. The search for these synergistic interactions using experimental models made tremendous contributions to our understanding of oncogenesis. Yet, these approaches remain labour-intensive and challenging. To tackle such a hurdle, an integrative, multidisciplinary effort is required. In this article, we highlight the use of logical computational models, combined with experimental validations, as an effective approach to identify cooperative mechanisms and therapeutic strategies in the context of cancer biology. In silico models overcome limitations of reductionist approaches by capturing tumour complexity and by generating powerful testable hypotheses. We review representative examples of logical models reported in the literature and their validation. We then provide further analyses of our logical model of Epithelium to Mesenchymal Transition (EMT), searching for additional cooperative interactions involving inputs from the tumour microenvironment and gain of function mutations in NOTCH.     

Ontology-driven analysis of UML-based collaborative processes using OWL-DL and CPN

A key ingredient in system and organization modeling is modeling business processes that involve the collaborative participation of different teams within and outside the organization. Recently, the use of the Unified Modeling Language (UML) for collaborative business modeling has been increasing, thanks to its human-friendly visual representation of a rich set of structural and behavioral views, albeit its unclear semantics. In the meantime, the use of the Web Ontology Language (OWL) has also been emerging, thanks to its clearly-defined semantics, hence being amenable to automatic analysis and reasoning, although it is less human friendly than, and also perhaps not as rich as, the UML notation — especially concerning processes, or activities. In this paper, we view the UML and the OWL as being complementary to each other, and exploit their relative strengths. We provide a mapping between the two, through a set of mapping rules, which allow for the capture of UML activity diagrams in an OWL-ontology. This mapping, which results in a formalization of collaborative processes, also sets a basis for subsequent construction of executable models using the Colored Petri Nets (CPN) formalism. For this purpose, we also provide appropriate mappings from OWL-based ontological elements into CPN elements. A case study of a mortgage granting system is described, along with the potential benefits and limitations of our proposal.     

Assessing the capabilities of the zonal model to predict the isothermal airflow induced by a linear ceiling diffuser

The objective of this work is to evaluate the quality of the zonal airflow predictions compared to those provided by computational fluid dynamics (CFD) tools for an isothermal airflow induced in a room by a linear ceiling diffuser. This comparative analysis was conducted for a typical rectangular office designed for two people, considering two different arrangements of obstacles within the room volume. The ventilation was provided by a four-way ceiling diffuser type with large aspect ratio slots, the outlet integrated into it, operating in a three-way mode with slot Reynolds number of 2700. As a result, the airflow was transitional or weakly turbulent. The airflow patterns obtained with the zonal models were first compared qualitatively with the CFD computations. A quantitative comparison based on the mean velocities at the interface of the zonal grid was then carried out. The characteristic features of the zonal predictions are shown and the limitations of the zonal and CFD approaches are discussed.     

Sequestration and metabolism of protoxic pyrrolizidine alkaloids by larvae of the leaf beetle Platyphora boucardi and their transfer via pupae into defensive secretions of adults

Several neotropical leaf-beetles of the genus Platyphora ingest and specifically metabolize plant acquired pyrrolizidine alkaloids (PAs) of the lycopsamine type (e.g., rinderine or intermedine) and enrich the processed alkaloids in their exocrine defensive secretions. In contrast to the related palaearctic leaf beetles of the genus Oreina, which absorb and store only the non-toxic alkaloid N-oxides, Platyphora sequesters PAs exclusively as protoxic tertiary amines. In this study, the ability of P. boucardi larvae to accumulate PAs was investigated. Tracer studies with [¹⁴C]rinderine and its N-oxide revealed that P. boucardi larvae, like adult beetles, utilize the two alkaloidal forms with the same efficiency, but accumulate the alkaloid as a tertiary amine exclusively. Ingested rinderine is rapidly epimerized to intermedine, which is localized in the hemolymph and all other tissues; it is also detected on the larval surface. Like adults, larvae are able to synthesize their own alkaloid esters (beetle PAs) from orally administered [¹⁴C]retronecine and endogenous aliphatic 2-hydroxy acids. These retronecine esters show the same tissue distribution as intermedine. A long-term feeding experiment lasting for almost four months revealed that retronecine esters synthesized from [¹⁴C]retronecine in the larvae are transferred from larvae via pupae into the exocrine glands of adult beetles. Pupae contain ca. 45% of the labeled retronecine originally ingested, metabolized, and stored by larvae; ca. 12% of larval radioactivity could be recovered from the defensive secretions of adults sampled successively over two and a half months. Almost all of this radioactivity is found in the insect-made retronecine esters that are highly enriched in the defensive secretions, i.e., more than 200-fold higher concentration compared to pupae.     

An exact calculation of the voltage-dependent tunnelling current in simple one-dimensional models: comparison with the Bardeen perturbation approach

In this paper we present an exact calculation of the tunnelling current for two different one-dimensional barrier potentials. The purpose is twofold: First, we demonstrate the feasibility of applying the new method of C. Noguera as a direct analytical tool for solving tunnelling problems in the case of independent electrons. In this approach, the tunnelling current is expressed in terms of the logarithmic derivative of the Green's function which must be evaluated at the cutting surface. This can be done analytically in the one-dimensional case. Secondly, we compare these results with the corresponding tunnelling current obtained using the Bardeen perturbation method, valid only in the large barrier limit. In particular, we investigate the use of the Bardeen approach in describing tunnelling spectroscopy. The dynamic conductance dI/dV, as a function of bias and barrier width, is compared in both cases.     

Attentional orienting within visual field in a lexical decision task.

The influence of spatial attention on lexical decisions to lateralized target letter-strings appearing either along with a distractor (Experiment 1) or in an otherwise empty field (Experiments 2–6) was examined. Attentional orienting was controlled by peripheral (Experiments 1, 2, 3, and 6) and central (Experiments 4–5) cuing methods. Manipulations of spatial attention, including cue validity and cue–target stimulus onset asynchrony, were combined with manipulations of word frequency in Experiments 3-6. All the attentional manipulations were effective, but they did not modify the right visual field advantage in word performance, In addition, the attentional effects did not interact with either the presence or absence of distractors or with stimulus familiarity. Implications of these results regarding the influence of spatial attention (the posterior attention system) on word processing are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

D.C. scanning thermal microscopy: Characterisation and interpretation of the measurement

The used Scanning Thermal Microscopy (SThM) probe is a thin Pt resistance wire acting as a heat source and as a detector simultaneously. Its energetic balance is investigated by the study of the temperature profile along the probe. A theoretical approach of the measurement, based on this investigation, is then proposed. Simulations with this modelling are shown to predict how the heat, electrically produced in the probe, is dissipated in the probe-sample system. In particular, it is shown that the steady-state of conduction losses to the thermal element support varies versus the thermal conductivity of the sample and can lead to bad interpretations of the measurement.