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News Article | May 3, 2017
Site: www.sciencedaily.com

Phthalates, which are used as plasticizers in plastics, can considerably increase the risk of allergies among children, researchers show. According to this study, an increased risk of children developing allergic asthma exists if the mother has been particularly heavily exposed to phthalates during pregnancy and breastfeeding. The mother-child cohort from the LINA study was the starting and end point of this translational study.


News Article | May 3, 2017
Site: www.eurekalert.org

Phthalates, which are used as plasticizers in plastics, can considerably increase the risk of allergies among children. This was demonstrated by UFZ researchers in conjunction with scientists from the University of Leipzig and the German Cancer Research Center (DKFZ) in a current study published in the Journal of Allergy and Clinical Immunology. According to this study, an increased risk of children developing allergic asthma exists if the mother has been particularly heavily exposed to phthalates during pregnancy and breastfeeding. The mother-child cohort from the LINA study was the starting and end point of this translational study. In our day-to-day lives, we come into contact with countless plastics containing plasticizers. These plasticizers, which also include the aforementioned phthalates, are used when processing plastics in order to make the products more flexible. Phthalates can enter our bodies through the skin, foodstuffs or respiration. "It is a well-known fact that phthalates affect our hormone system and can thereby have an adverse effect on our metabolism or fertility. But that's not the end of it," says UFZ environmental immunologist Dr Tobias Polte. "The results of our current study demonstrate that phthalates also interfere with the immune system and can significantly increase the risk of developing allergies." At the outset of the study, the team of UFZ researchers examined the urine of pregnant women from the LINA (lifestyle and environmental factors and their influence on the newborn-allergy-risk) mother-child cohort study and searched for metabolites of phthalates. The concentration level determined in each case was found to correlate with the occurrence of allergic asthma among the children. "There was a clearly discernible relationship between higher concentrations of the metabolite of benzylbutylphthalate (BBP) in the mother's urine and the presence of allergic asthma in their children", explains Dr Irina Lehmann, who heads the LINA study. Researchers were able to confirm the results from the mother-child cohort in the mouse model in collaboration with colleagues from the Medical Faculty at the University of Leipzig. In this process, mice were exposed to a certain phthalate concentration during pregnancy and the lactation period, which led to comparable concentrations of the BBP metabolite in urine to those observed in heavily exposed mothers from the LINA cohort. The offspring demonstrated a clear tendency to develop allergic asthma; even the third generation continued to be affected. Among the adult mice, on the other hand, there were no increased allergic symptoms. "The time factor is therefore decisive: if the organism is exposed to phthalates during the early stages of development, this may have effects on the risk of illness for the two subsequent generations," explains Polte. "The prenatal development process is thus clearly altered by the phthalate exposure." In order to establish precisely what may have been modified, Polte and his team, in collaboration with colleagues from the German Cancer Research Center (DKFZ), took a close look at the genes of the young mice born to exposed mothers. So-called methyl groups were found in the DNA of these genes - and to a greater extent than is usually the case. In the course of this so-called epigenetic modification of the DNA, methyl groups attach themselves to a gene like a kind of padlock and thus prevent its code from being read, meaning that the associated protein cannot be produced. After the researchers treated the mice with a special substance intended to crack the methyl "locks" on the affected genes, the mice demonstrated fewer signs of allergic asthma than before. Dr Polte concludes the following: "Phthalates apparently switch off decisive genes by means of DNA methylation, causing the activity of these genes to be reduced in the young mice." But which genes cause allergic asthma if they cannot be read? So-called T-helper 2 cells play a central part in the development of allergies. These are kept in check by special opponents (repressors). If a repressor gene cannot be read as a result of being blocked by methyl groups, the T-helper 2 cells that are conducive to the development of allergies are no longer sufficiently inhibited, meaning that an allergy is likely to develop. "We surmise that this connection is decisive for the development of allergic asthma caused by phthalates," says Polte. "Furthermore, in the cell experiment, we were able to demonstrate that there is an increased formation of T-helper 2 cells from the immune cells of the offspring of exposed mother mice than is the case for the offspring of non-exposed animals. This enabled us to establish an increased tendency towards allergies once again." In mice, the researchers were able to prove that a repressor gene that has been switched off due to DNA methylation is responsible for the development of allergic asthma. But does this mechanism also play a part in humans? In order to answer this question, the researchers consulted the LINA cohort once more. They searched for the corresponding gene among the children with allergic asthma and studied the degree of methylation and gene activity. Here, too, it became apparent that the gene was blocked by methyl groups and thus could not be read. "Thanks to our translational study approach - which led from humans via the mouse model and cellular culture back to humans again - we have been able to demonstrate that epigenetic modifications are apparently responsible for the fact that children of mothers who had a high exposure to phthalates during pregnancy and breastfeeding have an increased risk of developing allergic asthma," says Polte. "The objective of our further research will be to understand exactly how specific phthalates give rise to the methylation of genes which are relevant for the development of allergies." Susanne Jahreis, Saskia Trump, Mario Bauer, Tobias Bauer, Loreen Thu?rmann, Ralph Feltens, Qi Wang, Lei Gu, Konrad Gru?tzmann, Stefan Röder, Marco Averbeck, Dieter Weichenhan, Christoph Plass, Ulrich Sack, Michael Borte, Virginie Dubourg, Gerrit, Schu?u?rmann, Jan C. Simon, Martin von Bergen, Jörg Hackermu?ller, Roland Eils, Irina Lehmann, Tobias Polte (2017): Maternal phthalate exposure promotes allergic airway inflammation over two generations via epigenetic modifications, Journal of Allergy and Clinical Immunology; doi: 10.1016/j.jaci.2017.03.017; http://doi. PD Dr Tobias Polte Head of the Helmholtz University Research Group "Experimental Allergology and Immunology" Tel.: +49 341 235-1545 E-mail: tobias.polte@ufz.de https:/ Dr Irina Lehmann Head of the UFZ Department of Environmental Immunology Tel.: +49 341 235-1216 Email: irina.lehmann@ufz.de http://www.


Durand M.,Center Hospitalier Emile Roux | Durand M.,Jean Monnet University | Pourchez J.,LINA | Pourchez J.,French Institute of Health and Medical Research | And 7 more authors.
Rhinology | Year: 2011

Background: For many years, researchers have been interested in investigating airflow and aerosol deposition in the nasal cavities. The nasal airways appear to be a complex geometrical system. Thus, in vitro experimental studies are frequently conducted with a more or less biomimetic nasal replica. Aim: This study is devoted to the development of an anatomically realistic nose model with bilateral nasal cavities, i.e. nasal anatomy, airway geometry and aerodynamic properties as close as possible to in vivo behaviour. Methods: A specific plastination technique of cephalic extremities was developed by the Anatomy Laboratory at the Saint-Etienne University in the last 10 years. The plastinated models obtained were anatomically, geometrically and aerodynamically validated using several techniques (endoscopy, CT scans, acoustic rhinometry and rhinomanometry). Results: Our plastination model exhibited a high level of anatomic quality, including a very good mucosa preservation. Aerodynamical and geometrical investigations highlighted a global behaviour of plastinated models perfectly in accordance with a nasal decongested healthy subject. Conclusions: The present plastination model provides a realistic cast of nasal airways, and may be a useful tool for nasal flow, drug delivery and aerosol deposition studies.


Trombettoni G.,French Institute for Research in Computer Science and Automation | Araya I.,Federico Santa María Technical University | Neveu B.,University Paris Est Creteil | Chabert G.,LINA
Proceedings of the National Conference on Artificial Intelligence | Year: 2011

Researchers from interval analysis and constraint (logic) programming communities have studied intervals for their ability to manage infinite solution sets of numerical constraint systems. In particular, inner regions represent subsets of the search space in which all points are solutions. Our main contribution is the use of recent and new inner region extraction algorithms in the upper bounding phase of constrained global optimization. Convexification is a major key for efficiently lower bounding the objective function. We have adapted the convex interval taylorization proposed by Lin & Stadtherr for producing a reliable outer and inner polyhedral approximation of the solution set and a linearization of the objective function. Other original ingredients are part of our optimizer, including an efficient interval constraint propagation algorithm exploiting monotonicity of functions. We end up with a new framework for reliable continuous constrained global optimization. Our interval B&B is implemented in the interval-based explorer Ibex and extends this free C++ library. Our strategy significantly outperforms the best reliable global optimizers. Copyright © 2011, Association for the Advancement of Artificial Intelligence. All rights reserved.


Porumbel D.C.,University of Angers | Hao J.-K.,University of Angers | Kuntz P.,LINA
Computers and Operations Research | Year: 2010

We present a diversity-oriented hybrid evolutionary approach for the graph coloring problem. This approach is based on both generally applicable strategies and specifically tailored techniques. Particular attention is paid to ensuring population diversity by carefully controlling spacing among individuals. Using a distance measure between potential solutions, the general population management strategy decides whether an offspring should be accepted in the population, which individual needs to be replaced and when mutation is applied. Furthermore, we introduce a special grouping-based multi-parent crossover operator which relies on several relevant features to identify meaningful building blocks for offspring construction. The proposed approach can be generally characterized as "well-informed", in the sense that the design of each component is based on the most pertinent information which is identified by both experimental observation and careful analysis of the given problem. The resulting algorithm proves to be highly competitive when it is applied on the whole set of the DIMACS benchmark graphs. © 2010 Elsevier Ltd. All rights reserved.


Porumbel D.C.,University of Angers | Hao J.-K.,University of Angers | Kuntz P.,LINA
Computers and Operations Research | Year: 2010

We present a search space analysis and its application in improving local search algorithms for the graph coloring problem. Using a classical distance measure between colorings, we introduce the following clustering hypothesis: the high quality solutions are not randomly scattered in the search space, but rather grouped in clusters within spheres of specific diameter. We first provide intuitive evidence for this hypothesis by presenting a projection of a large set of local minima in the 3D space. An experimental confirmation is also presented: we introduce two algorithms that exploit the hypothesis by guiding an underlying Tabu Search (TS) process. The first algorithm (TS-Div) uses a learning process to guide the basic TS process toward as-yet-unvisited spheres. The second algorithm (TS-Int) makes deep investigations within a bounded region by organizing it as a tree-like structure of connected spheres. We experimentally demonstrate that if such a region contains a global optimum, TS-Int does not fail in eventually finding it. This pair of algorithms significantly outperforms the underlying basic TS algorithm; it can even improve some of the best-known solutions ever reported in the literature (e.g. for dsjc 1000.9). © 2009 Elsevier Ltd. All rights reserved.


PubMed | Ecole Nationale Superieure des Mines de Saint - Etienne CMP and LINA
Type: Journal Article | Journal: Langmuir : the ACS journal of surfaces and colloids | Year: 2015

Carbon nanotube (CNT) cytotoxicity is frequently investigated using in vitro classical toxicology assays. However, these cellular tests, usually based on the use of colorimetric or fluorimetric dyes, were designed for chemicals and may not be suitable for nanosized materials. Indeed, because of their unique physicochemical properties CNT can interfere with the assays and bias the results. To get accurate data and draw reliable conclusions, these artifacts should be carefully taken into account. The aim of this study was to evaluate qualitatively and quantitatively the interferences occurring between CNT and the commonly used lactate dehydrogenase (LDH) assay. Experiments under cell-free conditions were performed, and it was clearly demonstrated that artifacts occurred. They were due to the intrinsic absorbance of CNT on one hand and the adsorption of LDH at the CNT surface on the other hand. The adsorption of LDH on CNT was modeled and was found to fit the Langmuir model. The K(ads) and n(eq) constants were defined, allowing the correction of results obtained from cellular experiments to get more accurate data and lead to proper conclusions on the cytotoxicity of CNT.


Nair-Benrekia N.-Y.,Orange Group | Kuntz P.,LINA | Meyer F.,Orange Group
Studies in Classification, Data Analysis, and Knowledge Organization | Year: 2015

Interactive classification-based systems engage users to coach learning algorithms to take into account their own individual preferences. However most of the recent interactive systems limit the users to a single-label classification, which may be not expressive enough in some organization tasks such as film classification, where a multi-label scheme is required. The objective of this paper is to compare the behaviors of 12 multi-label classification methods in an interactive framework where “good” predictions must be produced in a very short time from a very small set of multi-label training examples. Experimentations highlight important performance differences for four complementary evaluation measures (Log-Loss, Ranking-Loss, Learning and Prediction Times). The best results are obtained for Multi-label k Nearest Neighbors (ML-kNN), ensemble of classifier chains (ECC), and ensemble of binary relevance (EBR). © Springer-Verlag Berlin Heidelberg 2015.


Petit T.,Worcester Polytechnic Institute | De Nantes M.,LINA | Trapp A.C.,Worcester Polytechnic Institute
IJCAI International Joint Conference on Artificial Intelligence | Year: 2015

A number of effective techniques for constraintbased optimization can be used to generate either diverse or high-quality solutions independently, but no framework is devoted to accomplish both simultaneously. In this paper, we tackle this issue with a generic paradigm that can be implemented in most existing solvers. We show that our technique can be specialized to produce diverse solutions of high quality in the context of over-constrained problems. Furthermore, our paradigm allows us to consider diversity from a different point of view, based on generic concepts expressed by global constraints.


Carbonnel C.,CNRS Laboratory for Analysis and Architecture of Systems | Vismara P.,Montpellier SupAgro | Trombettoni G.,Montpellier University | Chabert G.,LINA
Proceedings of the National Conference on Artificial Intelligence | Year: 2014

Given a set of axis-parallel n-dimensional boxes, the q- interseetion is defined as the smallest box encompassing all the points that belong to at least q boxes. Computing the q- intersection is a combinatorial problem that allows us to handle robust parameter estimation with a numerical constraint programming approach. The q-intersection can be viewed as a filtering operator for soft constraints that model measurements subject to outliers. This paper highlights the equivalence of this operator with the search of q-cliques in a graph whose boxicity is bounded by the number of variables in the constraint network. We present a computational study of the q-intersection. We also propose a fast heuristic and a sophisticated exact q-intersection algorithm. First experiments show that our exact algorithm outperforms the existing one while our heuristic performs an efficient filtering on hard problems. Copyright © 2014, Association for the Advancement of Artificial Intelligence (www.aaai.org). All rights reserved.

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