Regulatory assessment of in vitro skin corrosion and irritation data within the European framework: Workshop recommendations

Validated in vitro methods for skin corrosion and irritation were adopted by the OECD and by the European Union during the last decade. In the EU, Switzerland and countries adopting the EU legislation, these assays may allow the full replacement of animal testing for identifying and classifying compounds as skin corrosives, skin irritants, and non irritants. In order to develop harmonised recommendations on the use of in vitro data for regulatory assessment purposes within the European framework, a workshop was organized by the Swiss Federal Office of Public Health together with ECVAM and the BfR. It comprised stakeholders from various European countries involved in the process from in vitro testing to the regulatory assessment of in vitro data. Discussions addressed the following questions: (1) the information requirements considered useful for regulatory assessment; (2) the applicability of in vitro skin corrosion data to assign the corrosive subcategories as implemented by the EU Classification, Labelling and Packaging Regulation; (3) the applicability of testing strategies for determining skin corrosion and irritation hazards; and (4) the applicability of the adopted in vitro assays to test mixtures, preparations and dilutions. Overall, a number of agreements and recommendations were achieved in order to clarify and facilitate the assessment and use of in vitro data from regulatory accepted methods, and ultimately help regulators and scientists facing with the new in vitro approaches to evaluate skin irritation and corrosion hazards and risks without animal data.

A Bayesian network approach to the database serch problem in criminal proceedings

Background The 'database search problem', that is, the strengthening of a case - in terms of probative value - against an individual who is found as a result of a database search, has been approached during the last two decades with substantial mathematical analyses, accompanied by lively debate and centrally opposing conclusions. This represents a challenging obstacle in teaching but also hinders a balanced and coherent discussion of the topic within the wider scientific and legal community. This paper revisits and tracks the associated mathematical analyses in terms of Bayesian networks. Their derivation and discussion for capturing probabilistic arguments that explain the database search problem are outlined in detail. The resulting Bayesian networks offer a distinct view on the main debated issues, along with further clarity. Methods As a general framework for representing and analyzing formal arguments in probabilistic reasoning about uncertain target propositions (that is, whether or not a given individual is the source of a crime stain), this paper relies on graphical probability models, in particular, Bayesian networks. This graphical probability modeling approach is used to capture, within a single model, a series of key variables, such as the number of individuals in a database, the size of the population of potential crime stain sources, and the rarity of the corresponding analytical characteristics in a relevant population. Results This paper demonstrates the feasibility of deriving Bayesian network structures for analyzing, representing, and tracking the database search problem. The output of the proposed models can be shown to agree with existing but exclusively formulaic approaches. Conclusions The proposed Bayesian networks allow one to capture and analyze the currently most well-supported but reputedly counter-intuitive and difficult solution to the database search problem in a way that goes beyond the traditional, purely formulaic expressions. The method's graphical environment, along with its computational and probabilistic architectures, represents a rich package that offers analysts and discussants with additional modes of interaction, concise representation, and coherent communication.

The oldest Triassic platform margin reef from the Alpine - Carpathian region (Aggtelek, NE Hungary): platform evolution, reefal biota and biostratigraphic framework

The 1:10,000 scale mapping of the southern part of the Aggtelek Plateau (Western Carpathians, Silica Nappe, NE Hungary) and the study of five sections revealed two Middle Triassic reef bodies. In the late Pelsonian the uniform Steinalm Platform was drowned and dissected due to the Reifling Event. A connection with the open sea was established, indicated by the appearance of gladigondolellid conodonts from the early Illyrian. Basins and highs were formed. In the NW part of the studied area lower - middle? Illyrian basinal carbonates were followed by a platform margin reef (early? - middle Illyrian; reef stage 1) developed on a morphological high. This is the oldest known Triassic platform margin reef within the Alpine-Carpathian region. The reef association is dominated by sphinctozoans and microproblematics. The fossils are characteristic of the Wetterstein - type reef communities. Differently from this in the SE part of the studied region a basin existed from the late Pelsonian until the early Ladinian. During the late Illyrian - early Ladinian, the reef prograded to the SE, and reef stage 2 was established. Meanwhile, on the NW part of the platform a lagoon was formed behind the reef. Based on our palaeontological study the stratigraphic range of Colospongia catenulata, Follicatena cautica, Solenolmia manon manon, Vesicocaulis oenipontanus must be extended down to the middle Illyrian. Synsedimentary tectonics were detected in the 1. Binodosus Subzone, 2. Trinodosus Zone - the most part of the Reitzi Zone, 3. Avisianum Subzone.

Evidence evaluation in fingerprint comparison and automated fingerprint identification systems: modeling between finger variability

In the context of the investigation of the use of automated fingerprint identification systems (AFIS) for the evaluation of fingerprint evidence, the current study presents investigations into the variability of scores from an AFIS system when fingermarks from a known donor are compared to fingerprints that are not from the same source. The ultimate goal is to propose a model, based on likelihood ratios, which allows the evaluation of mark-to-print comparisons. In particular, this model, through its use of AFIS technology, benefits from the possibility of using a large amount of data, as well as from an already built-in proximity measure, the AFIS score. More precisely, the numerator of the LR is obtained from scores issued from comparisons between impressions from the same source and showing the same minutia configuration. The denominator of the LR is obtained by extracting scores from comparisons of the questioned mark with a database of non-matching sources. This paper focuses solely on the assignment of the denominator of the LR. We refer to it by the generic term of between-finger variability. The issues addressed in this paper in relation to between-finger variability are the required sample size, the influence of the finger number and general pattern, as well as that of the number of minutiae included and their configuration on a given finger. Results show that reliable estimation of between-finger variability is feasible with 10,000 scores. These scores should come from the appropriate finger number/general pattern combination as defined by the mark. Furthermore, strategies of obtaining between-finger variability when these elements cannot be conclusively seen on the mark (and its position with respect to other marks for finger number) have been presented. These results immediately allow case-by-case estimation of the between-finger variability in an operational setting.

A framework for assessing the scale of influence of environmental factors on ecological patterns

The distribution of living organisms, habitats and ecosystems is primarily driven by abiotic environmental factors that are spatially structured. Assessing the spatial structure of environmental factors, e.g., through spatial autocorrelation analyses (SAC), can thus help us understand their scale of influence on the distribution of organisms, habitats, and ecosystems. Yet SAC analyses of environmental factors are still rarely performed in biogeographic studies. Here, we describe a novel framework that combines SAC and statistical clustering to identify scales of spatial patterning of environmental factors, which can then be interpreted as the scales at which those factors influence the geographic distribution of biological and ecological features. We illustrate this new framework with datasets at different spatial or thematic resolutions. This framework is conceptually and statistically robust, providing a valuable approach to tackle a wide range of issues in ecological and environmental research and particularly when building predictors for ecological models. The new framework can significantly promote fundamental research on all spatially-structured ecological patterns. It can also foster research and application in such fields as global change ecology, conservation planning, and landscape management.

Modeling stochasticity and robustness in gene regulatory networks.

MOTIVATION: Understanding gene regulation in biological processes and modeling the robustness of underlying regulatory networks is an important problem that is currently being addressed by computational systems biologists. Lately, there has been a renewed interest in Boolean modeling techniques for gene regulatory networks (GRNs). However, due to their deterministic nature, it is often difficult to identify whether these modeling approaches are robust to the addition of stochastic noise that is widespread in gene regulatory processes. Stochasticity in Boolean models of GRNs has been addressed relatively sparingly in the past, mainly by flipping the expression of genes between different expression levels with a predefined probability. This stochasticity in nodes (SIN) model leads to over representation of noise in GRNs and hence non-correspondence with biological observations. RESULTS: In this article, we introduce the stochasticity in functions (SIF) model for simulating stochasticity in Boolean models of GRNs. By providing biological motivation behind the use of the SIF model and applying it to the T-helper and T-cell activation networks, we show that the SIF model provides more biologically robust results than the existing SIN model of stochasticity in GRNs. AVAILABILITY: Algorithms are made available under our Boolean modeling toolbox, GenYsis. The software binaries can be downloaded from http://si2.epfl.ch/ approximately garg/genysis.html.

Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.

Metabolic problems lead to numerous failures during clinical trials, and much effort is now devoted to developing in silico models predicting metabolic stability and metabolites. Such models are well known for cytochromes P450 and some transferases, whereas less has been done to predict the activity of human hydrolases. The present study was undertaken to develop a computational approach able to predict the hydrolysis of novel esters by human carboxylesterase hCES2. The study involved first a homology modeling of the hCES2 protein based on the model of hCES1 since the two proteins share a high degree of homology (congruent with 73%). A set of 40 known substrates of hCES2 was taken from the literature; the ligands were docked in both their neutral and ionized forms using GriDock, a parallel tool based on the AutoDock4.0 engine which can perform efficient and easy virtual screening analyses of large molecular databases exploiting multi-core architectures. Useful statistical models (e.g., r (2) = 0.91 for substrates in their unprotonated state) were calculated by correlating experimental pK(m) values with distance between the carbon atom of the substrate's ester group and the hydroxy function of Ser228. Additional parameters in the equations accounted for hydrophobic and electrostatic interactions between substrates and contributing residues. The negatively charged residues in the hCES2 cavity explained the preference of the enzyme for neutral substrates and, more generally, suggested that ligands which interact too strongly by ionic bonds (e.g., ACE inhibitors) cannot be good CES2 substrates because they are trapped in the cavity in unproductive modes and behave as inhibitors. The effects of protonation on substrate recognition and the contrasting behavior of substrates and products were finally investigated by MD simulations of some CES2 complexes.

Explaining Fiscal Balances with a Simultaneous Equation Model of Revenue and Expenditure : A Case Study of Swiss Cantons Using Panel Data

Empirical literature on the analysis of the efficiency of measures for reducing persistent government deficits has mainly focused on the direct explanation of deficit. By contrast, this paper aims at modeling government revenue and expenditure within a simultaneous framework and deriving the fiscal balance (surplus or deficit) equation as the difference between the two variables. This setting enables one to not only judge how relevant the explanatory variables are in explaining the fiscal balance but also understand their impact on revenue and/or expenditure. Our empirical results, obtained by using a panel data set on Swiss Cantons for the period 1980-2002, confirm the relevance of the approach followed here, by providing unambiguous evidence of a simultaneous relationship between revenue and expenditure. They also reveal strong dynamic components in revenue, expenditure, and fiscal balance. Among the significant determinants of public fiscal balance we not only find the usual business cycle elements, but also and more importantly institutional factors such as the number of administrative units, and the ease with which people can resort to political (direct democracy) instruments, such as public initiatives and referendum.

The cover basement contact beneath the Rawil axial depression (Western Alps) - True amplitude seismic processing, petrophysical properties, and modeling

Since 1986, several near-vertical seismic reflection profiles have been recorded in Switzerland in order to map the deep geologic structure of the Alps. One objective of this endeavour has been to determine the geometries of the autochthonous basement and of the external crystalline massifs, important elements for understanding the geodynamics of the Alpine orogeny. The PNR-20 seismic line W1, located in the Rawil depression of the western Swiss Alps, provides important information on this subject. It extends northward from the `'Penninic front'' across the Helvetic nappes to the Prealps. The crystalline massifs do not outcrop along this profile. Thus, the interpretation of `'near-basement'' reflections has to be constrained by down-dip projections of surface geology, `'true amplitude'' processing, rock physical property studies and modelling. 3-D seismic modelling has been used to evaluate the seismic response of two alternative down-dip projection models. To constrain the interpretation in the southern part of the profile, `'true amplitude'' processing has provided information on the strength of the reflections. Density and velocity measurements on core samples collected up-dip from the region of the seismic line have been used to evaluate reflection coefficients of typical lithologic boundaries in the region. The cover-basement contact itself is not a source of strong reflections, but strong reflections arise from within the overlaying metasedimentary cover sequence, allowing the geometry of the top of the basement to be determined on the basis of `'near-basement'' reflections. The front of the external crystalline massifs is shown to extend beneath the Prealps, about 6 km north of the expected position. A 2-D model whose seismic response shows reflection patterns very similar to the observed is proposed.

Conceptual framework and pilot study to benchmark phylogenomic databases based on reference gene trees.

Phylogenomic databases provide orthology predictions for species with fully sequenced genomes. Although the goal seems well-defined, the content of these databases differs greatly. Seven ortholog databases (Ensembl Compara, eggNOG, HOGENOM, InParanoid, OMA, OrthoDB, Panther) were compared on the basis of reference trees. For three well-conserved protein families, we observed a generally high specificity of orthology assignments for these databases. We show that differences in the completeness of predicted gene relationships and in the phylogenetic information are, for the great majority, not due to the methods used, but to differences in the underlying database concepts. According to our metrics, none of the databases provides a fully correct and comprehensive protein classification. Our results provide a framework for meaningful and systematic comparisons of phylogenomic databases. In the future, a sustainable set of 'Gold standard' phylogenetic trees could provide a robust method for phylogenomic databases to assess their current quality status, measure changes following new database releases and diagnose improvements subsequent to an upgrade of the analysis procedure.

Lifelong dynamics of human CD4+CD25+ regulatory T cells: insights from in vivo data and mathematical modeling.

Despite their limited proliferation capacity, regulatory T cells (T(regs)) constitute a population maintained over the entire lifetime of a human organism. The means by which T(regs) sustain a stable pool in vivo are controversial. Using a mathematical model, we address this issue by evaluating several biological scenarios of the origins and the proliferation capacity of two subsets of T(regs): precursor CD4(+)CD25(+)CD45RO(-) and mature CD4(+)CD25(+)CD45RO(+) cells. The lifelong dynamics of T(regs) are described by a set of ordinary differential equations, driven by a stochastic process representing the major immune reactions involving these cells. The model dynamics are validated using data from human donors of different ages. Analysis of the data led to the identification of two properties of the dynamics: (1) the equilibrium in the CD4(+)CD25(+)FoxP3(+)T(regs) population is maintained over both precursor and mature T(regs) pools together, and (2) the ratio between precursor and mature T(regs) is inverted in the early years of adulthood. Then, using the model, we identified three biologically relevant scenarios that have the above properties: (1) the unique source of mature T(regs) is the antigen-driven differentiation of precursors that acquire the mature profile in the periphery and the proliferation of T(regs) is essential for the development and the maintenance of the pool; there exist other sources of mature T(regs), such as (2) a homeostatic density-dependent regulation or (3) thymus- or effector-derived T(regs), and in both cases, antigen-induced proliferation is not necessary for the development of a stable pool of T(regs). This is the first time that a mathematical model built to describe the in vivo dynamics of regulatory T cells is validated using human data. The application of this model provides an invaluable tool in estimating the amount of regulatory T cells as a function of time in the blood of patients that received a solid organ transplant or are suffering from an autoimmune disease.