A functional genomics approach reveals novel quantitative trait loci associated with platelet signalling pathways

Platelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet function (P < .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3' untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca2+ levels after activation with ADP (P < .004). These data provide novel insights into key hubs within platelet signaling networks.

Casimir effect for the scalar field under Robin boundary conditions: a functional integral approach

In this work we show how to define the action of a scalar field such that the Robin boundary condition is implemented dynamically, i.e. as a consequence of the stationary action principle. We discuss the quantization of that system via functional integration. Using this formalism, we derive an expression for the Casimir energy of a massless scalar field under Robin boundary conditions on a pair of parallel plates, characterized by constants c(1) and c(2). Some special cases are discussed; in particular, we show that for some values of cl and c(2) the Casimir energy as a function of the distance between the plates presents a minimum. We also discuss the renormalization at one-loop order of the two-point Green function in the philambda(4) theory subject to the Robin boundary condition on a plate.

A cognitive approach to Berber-Tamazight sociocultural reality : the bioconceptual organization of Izri poetics by Tarifit-speaking Riffian women

Programa de doctorado: Nuevas perspectivas cognitivas en los estudios de lengua, litaretura y traducción.

Novel functional profiling approach combining reverse phase protein microarrays and human 3-D ex vivo tissue cultures: expression of apoptosis-related proteins in human colon cancer

Cancer is caused by a complex pattern of molecular perturbations. To understand the biology of cancer, it is thus important to look at the activation state of key proteins and signaling networks. The limited amount of available sample material from patients and the complexity of protein expression patterns make the use of traditional protein analysis methods particularly difficult. In addition, the only approach that is currently available for performing functional studies is the use of serial biopsies, which is limited by ethical constraints and patient acceptance. The goal of this work was to establish a 3-D ex vivo culture technique in combination with reverse-phase protein microarrays (RPPM) as a novel experimental tool for use in cancer research. The RPPM platform allows the parallel profiling of large numbers of protein analytes to determine their relative abundance and activation level. Cancer tissue and the respective corresponding normal tissue controls from patients with colorectal cancer were cultured ex vivo. At various time points, the cultured samples were processed into lysates and analyzed on RPPM to assess the expression of carcinoembryonic antigen (CEA) and 24 proteins involved in the regulation of apoptosis. The methodology displayed good robustness and low system noise. As a proof of concept, CEA expression was significantly higher in tumor compared with normal tissue (p<0.0001). The caspase 9 expression signal was lower in tumor tissue than in normal tissue (p<0.001). Cleaved Caspase 8 (p=0.014), Bad (p=0.007), Bim (p=0.007), p73 (p=0.005), PARP (p<0.001), and cleaved PARP (p=0.007) were differentially expressed in normal liver and normal colon tissue. We demonstrate here the feasibility of using RPPM technology with 3-D ex vivo cultured samples. This approach is useful for investigating complex patterns of protein expression and modification over time. It should allow functional proteomics in patient samples with various applications such as pharmacodynamic analyses in drug development.

Identification of eIF2Bγ and eIF2γ as cofactors of hepatitis C virus internal ribosome entry site-mediated translation using a functional genomics approach

The 5′-untranslated region of hepatitis C virus (HCV) is highly conserved, folds into a complex secondary structure, and functions as an internal ribosome entry site (IRES) to initiate translation of HCV proteins. We have developed a selection system based on a randomized hairpin ribozyme gene library to identify cellular factors involved in HCV IRES function. A retroviral vector ribozyme library with randomized target recognition sequences was introduced into HeLa cells, stably expressing a bicistronic construct encoding the hygromycin B phosphotransferase gene and the herpes simplex virus thymidine kinase gene (HSV-tk). Translation of the HSV-tk gene was mediated by the HCV IRES. Cells expressing ribozymes that inhibit HCV IRES-mediated translation of HSV-tk were selected via their resistance to both ganciclovir and hygromycin B. Two ribozymes reproducibly conferred the ganciclovir-resistant phenotype and were shown to inhibit IRES-mediated translation of HCV core protein but did not inhibit cap-dependent protein translation or cell growth. The functional targets of these ribozymes were identified as the gamma subunits of human eukaryotic initiation factors 2B (eIF2Bγ) and 2 (eIF2γ), respectively. The involvement of eIF2Bγ and eIF2γ in HCV IRES-mediated translation was further validated by ribozymes directed against additional sites within the mRNAs of these genes. In addition to leading to the identification of cellular IRES cofactors, ribozymes obtained from this cellular selection system could be directly used to specifically inhibit HCV viral translation, thereby facilitating the development of new antiviral strategies for HCV infection.

Token codeswitching and language alternation in narrative discourse: a functional-pragmatic approach

This study is concerned with two phenomena of language alternation in biographic narrations in Yiddish and Low German, based on spoken language data recorded between 1988 and 1995. In both phenomena language alternation serves as an additional communicative tool which can be applied by bilingual speakers to enlarge their set of interactional devices in order to ensure a smoother or more pointed processing of communicative aims. The first phenomenon is a narrative strategy I call Token Cod-eswitching: In a bilingual narrative culminating in a line of reported speech, a single element of L2 indicates the original language of the reconstructed dialogue – a token for a quote. The second phenomenon has to do with directing procedures, carried out by the speaker and aimed at guiding the hearer's attention, which are frequently carried out in L2, supporting the hearer's attention at crucial points in the interaction. Both phenomena are analyzed following a model of narrative discourse as proposed in the framework of Functional Pragmatics. The model allows the adoption of an integral approach to previous findings in code-switching research.

Metaphor and translation:Some implications of a cognitive approach

Metaphor has been widely discussed within the discipline of Translation Studies, predominantly with respect to translatability and transfer methods. It has been argued that metaphors can become a translation problem, since transferring them from one language and culture to another one may be hampered by linguistic and cultural differences. A number of translation procedures for dealing with this problem have been suggested, e.g., substitution (metaphor into different metaphor), paraphrase (metaphor into sense), or deletion. Such procedures have been commented on both in normative models of translation (how to translate metaphors) and in descriptive models (how metaphors have been dealt with in actual translations). After a short overview of how metaphor has been dealt with in the discipline of Translation Studies, this paper discusses some implications of a cognitive approach to metaphors for translation theory and practice. Illustrations from authentic source and target texts (English and German, political discourse) show how translators handled metaphorical expressions, and what effects this had for the text itself, for text reception by the addressees, and for subsequent discursive developments. © 2004 Elsevier B.V. All right reserved.

Seminar 1 impurity in the tomonaga-luttinger model:a functional integral approach

This chapter explains a functional integral approach about impurity in the Tomonaga–Luttinger model. The Tomonaga–Luttinger model of one-dimensional (1D) strongly correlates electrons gives a striking example of non-Fermi-liquid behavior. For simplicity, the chapter considers only a single-mode Tomonaga–Luttinger model, with one species of right- and left-moving electrons, thus, omitting spin indices and considering eventually the simplest linearized model of a single-valley parabolic electron band. The standard operator bosonization is one of the most elegant methods developed in theoretical physics. The main advantage of the bosonization, either in standard or functional form, is that including the quadric electron–electron interaction does not substantially change the free action. The chapter demonstrates the way to develop the formalism of bosonization based on the functional integral representation of observable quantities within the Keldysh formalism.

Cognitive Approach to e-Learning in Sciences and Technologies

This article describes the approach adopted and the results obtained by the international team developing WBLST (Web Based Learning in Sciences and Technologies) a Web-based application for e-learning, developed for the students of “UVPL: Université Virtuelle des Pays de la Loire”. The developed e-learning system covers three levels of learning activities - content, exercises, and laboratory. The delivery model is designed to operate with domain concepts as relevant providers of semantic links. The aim is to facilitate the overview and to help the establishment of a mental map of the learning material. The implemented system is strongly based on the organization of the instruction in virtual classes. The obtained quality of the system is evaluated on the bases of feedback form students and professors.

Cognitive Approach in Castings’ Quality Control

Every year production volume of castings grows, especially grows production volume of non-ferrous metals, thanks to aluminium. As a result, requirements to castings quality also increase. Foundry men from all over the world put all their efforts to manage the problem of casting defects. In this article the authors present an approach based on the use of cognitive models that help to visualize inner cause-and-effect relations leading to casting defects in the foundry process. The cognitive models mentioned comprise a diverse network of factors and their relations, which together thoroughly describe all the details of the foundry process and their influence on the appearance of castings’ defects and other aspects.. Moreover, the article contains an example of a simple die casting model and results of simulation. Implementation of the proposed method will help foundry men reveal the mechanism and the main reasons of casting defects formation.

Evaluating green infrastructure in urban environments using a multi-taxa and functional diversity approach

Forested areas within cities host a large number of species, responsible for many ecosystem services in urban areas. The biodiversity in these areas is influenced by human disturbances such as atmospheric pollution and urban heat island effect. To ameliorate the effects of these factors, an increase in urban green areas is often considered sufficient. However, this approach assumes that all types of green cover have the same importance for species. Our aim was to show that not all forested green areas are equal in importance for species, but that based on a multi-taxa and functional diversity approach it is possible to value green infrastructure in urban environments. After evaluating the diversity of lichens, butterflies and other-arthropods, birds and mammals in 31 Mediterranean urban forests in south-west Europe (Almada, Portugal), bird and lichen functional groups responsive to urbanization were found. A community shift (tolerant species replacing sensitive ones) along the urbanization gradient was found, and this must be considered when using these groups as indicators of the effect of urbanization. Bird and lichen functional groups were then analyzed together with the characteristics of the forests and their surroundings. Our results showed that, contrary to previous assumptions, vegetation density and more importantly the amount of urban areas around the forest (matrix), are more important for biodiversity than forest quantity alone. This indicated that not all types of forested green areas have the same importance for biodiversity. An index of forest functional diversity was then calculated for all sampled forests of the area. This could help decision-makers to improve the management of urban green infrastructures with the goal of increasing functionality and ultimately ecosystem services in urban areas.