Identification of a fibronectin interaction site in the extracellular matrix protein ameloblastin

Mammalian teeth are composed of hydroxyapatite crystals that are embedded in a rich extracellular matrix. This matrix is produced by only two cell types, the mesenchymal odontoblasts and the ectodermal ameloblasts. Ameloblasts secrete the enamel proteins amelogenin, ameloblastin, enamelin and amelotin. Odontoblasts secrete collagen type I and several calcium-binding phosphoproteins including dentin sialophosphoprotein, dentin matrix protein, bone sialoprotein and osteopontin. The latter four proteins have recently been grouped in the family of the SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) because they display similar gene structures and because they contain an RGD tripeptide sequence that binds to integrin receptors and thus mediates cell adhesion. We have prepared all the other tooth-specific proteins in recombinant form and examined whether they might also promote cell adhesion similar to the SIBLINGs. We found that only ameloblastin consistently mediated adhesion of osteoblastic and fibroblastic cells to plastic or titanium surfaces. The activity was dependent on the intact three-dimensional structure of ameloblastin and required de novo protein synthesis of the adhering cells. By deletion analysis and in vitro mutagenesis, the active site could be narrowed down to a sequence of 13 amino acid residues (VPIMDFADPQFPT) derived from exon 7 of the rat ameloblastin gene or exons 7-9 of the human gene. Kinetic studies and RNA interference experiments further demonstrated that this sequence does not directly bind to a cell surface receptor but that it interacts with cellular fibronectin, which in turn binds to integrin receptors. The identification of a fibronectin-binding domain in ameloblastin might permit interesting applications for dental implantology. Implants could be coated with peptides containing the active sequence, which in turn would recruit fibronectin from the patient's blood. The recruited fibronectin should then promote cell adhesion on the implant surface, thereby accelerating osseointegration of the implant.

Interethnic Interaction Dynamics in the Russian Federation

The collapse of the Soviet Union at the beginning of the 1990s also meant the end of the idea of a common soviet identity incarnated in the "soviet man" and the new "historic community of the soviet people". While this idea still lives on in the generations of the 1920s to 1940s, the younger generations tend to prefer identification with family, profession, ethnic group or religion. Ms. Alexakhina set out to investigate different interethnic interaction strategies in the multi-ethnic context of the Russian Federation, with an emphasis on analysing the role of cultural and ethno-demographic characteristics of minority ethnic groups. It aimed to identify those specific patterns of interaction dynamics that have emerged in response to the political and economic transformation at present under way. The basic supposition was that the size and growth of an ethnic population are defined not only by demographic features such as fertility, mortality and net migration, but are also dependent on processes interethnic interaction and ethnic transition. The central hypothesis of the project was that the multi-ethnic and multi-cultural composition of Russia is apparently manifesting itself in the ethnic minority groups in various forms, but particularly in the form of ethnic revival and/or assimilation. The results of these complex phenomena are manifested as changes in ethnic attachments (national re-identification and language behaviour (multi-lingualism, language transition and loss of the mother tongue). The stress of the political and economic crisis has stimulated significant changes in ethnographic, social and cultural characteristics of inter-ethnic dynamics such as the rate of national re-identification, language behaviour, migration activity and the spread of mixed marriages, among both those minorities with a long history of settlement in Russia and those that were annexed during the soviet period. Patterns of language behaviour and the spread of mixed marriages were taken as the main indicators of the directions of interethnic interaction described as assimilation, ethnic revival and cultural pluralism. The first stage of the research involved a statistical analysis of census data from 1959 to 1994 in order to analyse the changing demographic composition of the largest ethnic groups of the Russian Federation. Until 1989 interethnic interaction in soviet society was distinguished by the process of russification but the political and economic transformation has stimulated the process of ethnic revival, leading to an apparent fall in the size of the Russian population due to ethnic re-identification by members of other ethnic groups who had previously identified themselves as Russian. Cross-classification of nationalities by demographic, social and cultural indicators has shown that the most important determinants of the nature of interethnic interaction are cultural factors such as religion and language affiliation. The analysis of the dynamics of language shift through the study of bilingualism and the domains of language usage for different demographic groups revealed a strong correlation between recognition of Russian as a mother tongue among some non-Russian ethnic groups and the declining size of these groups. The main conclusion from this macro-analysis of census data was the hypothesis of the growing importance of social and political factors upon ethnic succession, that ethnic identity is no longer a stable characteristic but has become dynamic in nature. In order to verify this hypothesis Ms. Alexakhina conducted a survey in four regions showing different patterns of interethnic interaction: the Karelian Republic, Buryatiya, the Nenezkii Autonomous Region and Tatarstan. These represented the west, east, north and south of the Russian Federation. Samples for the survey were prepared on the basis of census lists so as to exclude mono-Russian families in favour of mixed and ethnic-minority families. The survey confirmed the significant growth in the importance of ethnic affiliation in the everyday lives of people in the Federation following the de-centralisation of the political and economic spheres. Language was shown to be a key symbol of the consciousness of national distinction, confirmed by the fact that the process of russification has been reversed by the active mastering of the languages of titular nationalities. The results also confirmed that individual ethnic identity has ceased to be a fixed personal characteristic of one's cultural and genetic belonging, and people's social adaptation to the current political, social and economic conditions is also demonstrated in changes in individual ethnic self-identification. In general terms, the dynamic nature of national identity means that ethnic identity is at present acquiring the special features of overall social identity, for which the frequent change of priorities is an inherent feature of a person's life cycle. These are mainly linked with a multi-ethnic environment and high individual social mobility. From her results Ms. Alexakhina concludes that the development of national languages and multi-lingualism, together with the preservation of Russian as a state language, seems to be the most promising path to peaceful coexistence and the development of the national cultures of different ethnic groups within the Russian Federation.

The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study

OBJECTIVE: To examine whether excluding patients from the analysis of randomised trials are associated with biased estimates of treatment effects and higher heterogeneity between trials. DESIGN: Meta-epidemiological study based on a collection of meta-analyses of randomised trials. DATA SOURCES: 14 meta-analyses including 167 trials that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patient reported pain as an outcome. METHODS: Effect sizes were calculated from differences in means of pain intensity between groups at the end of follow-up, divided by the pooled standard deviation. Trials were combined by using random effects meta-analysis. Estimates of treatment effects were compared between trials with and trials without exclusions from the analysis, and the impact of restricting meta-analyses to trials without exclusions was assessed. RESULTS: 39 trials (23%) had included all patients in the analysis. In 128 trials (77%) some patients were excluded from the analysis. Effect sizes from trials with exclusions tended to be more beneficial than those from trials without exclusions (difference -0.13, 95% confidence interval -0.29 to 0.04). However, estimates of bias between individual meta-analyses varied considerably (tau(2)=0.07). Tests of interaction between exclusions from the analysis and estimates of treatment effects were positive in five meta-analyses. Stratified analyses indicated that differences in effect sizes between trials with and trials without exclusions were more pronounced in meta-analyses with high between trial heterogeneity, in meta-analyses with large estimated treatment benefits, and in meta-analyses of complementary medicine. Restriction of meta-analyses to trials without exclusions resulted in smaller estimated treatment benefits, larger P values, and considerable decreases in between trial heterogeneity. CONCLUSION: Excluding patients from the analysis in randomised trials often results in biased estimates of treatment effects, but the extent and direction of bias is unpredictable. Results from intention to treat analyses should always be described in reports of randomised trials. In systematic reviews, the influence of exclusions from the analysis on estimated treatment effects should routinely be assessed.

PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature

The transmembrane ligand ephrinB2 and its cognate Eph receptor tyrosine kinases are important regulators of embryonic blood vascular morphogenesis. However, the molecular mechanisms required for ephrinB2 transduced cellular signaling in vivo have not been characterized. To address this question, we generated two sets of knock-in mice: ephrinB2DeltaV mice expressed ephrinB2 lacking the C-terminal PDZ interaction site, and ephrinB2(5F) mice expressed ephrinB2 in which the five conserved tyrosine residues were replaced by phenylalanine to disrupt phosphotyrosine-dependent signaling events. Our analysis revealed that the homozygous mutant mice survived the requirement of ephrinB2 in embryonic blood vascular remodeling. However, ephrinB2DeltaV/DeltaV mice exhibited major lymphatic defects, including a failure to remodel their primary lymphatic capillary plexus into a hierarchical vessel network, hyperplasia, and lack of luminal valve formation. Unexpectedly, ephrinB2(5F/5F) mice displayed only a mild lymphatic phenotype. Our studies define ephrinB2 as an essential regulator of lymphatic development and indicate that interactions with PDZ domain effectors are required to mediate its functions.

Simbrain: A visual framework for neural network analysis and education

Simbrain is a visually-oriented framework for building and analyzing neural networks. It emphasizes the analysis of networks which control agents embedded in virtual environments, and visualization of the structures which occur in the high dimensional state spaces of these networks. The program was originally intended to facilitate analysis of representational processes in embodied agents, however it is also well suited to teaching neural networks concepts to a broader audience than is traditional for neural networks courses. Simbrain was used to teach a course at a new university, UC Merced, in its inaugural year. Experiences from the course and sample lessons are provided.

Semiotic Analysis in the Study of Social Work

Research and professional practices have the joint aim of re-structuring the preconceived notions of reality. They both want to gain the understanding about social reality. Social workers use their professional competence in order to grasp the reality of their clients, while researchers’ pursuit is to open the secrecies of the research material. Development and research are now so intertwined and inherent in almost all professional practices that making distinctions between practising, developing and researching has become difficult and in many aspects irrelevant. Moving towards research-based practices is possible and it is easily applied within the framework of the qualitative research approach (Dominelli 2005, 235; Humphries 2005, 280). Social work can be understood as acts and speech acts crisscrossing between social workers and clients. When trying to catch the verbal and non-verbal hints of each others’ behaviour, the actors have to do a lot of interpretations in a more or less uncertain mental landscape. Our point of departure is the idea that the study of social work practices requires tools which effectively reveal the internal complexity of social work (see, for example, Adams & Dominelli & Payne 2005, 294 – 295). The boom of qualitative research methodologies in recent decades is associated with much profound the rupture in humanities, which is called the linguistic turn (Rorty 1967). The idea that language is not transparently mediating our perceptions and thoughts about reality, but on the contrary it constitutes it was new and even confusing to many social scientists. Nowadays we have got used to read research reports which have applied different branches of discursive analyses or narratologic or semiotic approaches. Although differences are sophisticated between those orientations they share the idea of the predominance of language. Despite the lively research work of today’s social work and the research-minded atmosphere of social work practice, semiotics has rarely applied in social work research. However, social work as a communicative practice concerns symbols, metaphors and all kinds of the representative structures of language. Those items are at the core of semiotics, the science of signs, and the science which examines people using signs in their mutual interaction and their endeavours to make the sense of the world they live in, their semiosis. When thinking of the practice of social work and doing the research of it, a number of interpretational levels ought to be passed before reaching the research phase in social work. First of all, social workers have to interpret their clients’ situations, which will be recorded in the files. In some very rare cases those past situations will be reflected in discussions or perhaps interviews or put under the scrutiny of some researcher in the future. Each and every new observation adds its own flavour to the mixture of meanings. Social workers have combined their observations with previous experience and professional knowledge, furthermore, the situation on hand also influences the reactions. In addition, the interpretations made by social workers over the course of their daily working routines are never limited to being part of the personal process of the social worker, but are also always inherently cultural. The work aiming at social change is defined by the presence of an initial situation, a specific goal, and the means and ways of achieving it, which are – or which should be – agreed upon by the social worker and the client in situation which is unique and at the same time socially-driven. Because of the inherent plot-based nature of social work, the practices related to it can be analysed as stories (see Dominelli 2005, 234), given, of course, that they are signifying and told by someone. The research of the practices is concentrating on impressions, perceptions, judgements, accounts, documents etc. All these multifarious elements can be scrutinized as textual corpora, but not whatever textual material. In semiotic analysis, the material studied is characterised as verbal or textual and loaded with meanings. We present a contribution of research methodology, semiotic analysis, which has to our mind at least implicitly references to the social work practices. Our examples of semiotic interpretation have been picked up from our dissertations (Laine 2005; Saurama 2002). The data are official documents from the archives of a child welfare agency and transcriptions of the interviews of shelter employees. These data can be defined as stories told by the social workers of what they have seen and felt. The official documents present only fragmentations and they are often written in passive form. (Saurama 2002, 70.) The interviews carried out in the shelters can be described as stories where the narrators are more familiar and known. The material is characterised by the interaction between the interviewer and interviewee. The levels of the story and the telling of the story become apparent when interviews or documents are examined with the use of semiotic tools. The roots of semiotic interpretation can be found in three different branches; the American pragmatism, Saussurean linguistics in Paris and the so called formalism in Moscow and Tartu; however in this paper we are engaged with the so called Parisian School of semiology which prominent figure was A. J. Greimas. The Finnish sociologists Pekka Sulkunen and Jukka Törrönen (1997a; 1997b) have further developed the ideas of Greimas in their studies on socio-semiotics, and we lean on their ideas. In semiotics social reality is conceived as a relationship between subjects, observations, and interpretations and it is seen mediated by natural language which is the most common sign system among human beings (Mounin 1985; de Saussure 2006; Sebeok 1986). Signification is an act of associating an abstract context (signified) to some physical instrument (signifier). These two elements together form the basic concept, the “sign”, which never constitutes any kind of meaning alone. The meaning will be comprised in a distinction process where signs are being related to other signs. In this chain of signs, the meaning becomes diverged from reality. (Greimas 1980, 28; Potter 1996, 70; de Saussure 2006, 46-48.) One interpretative tool is to think of speech as a surface under which deep structures – i.e. values and norms – exist (Greimas & Courtes 1982; Greimas 1987). To our mind semiotics is very much about playing with two different levels of text: the syntagmatic surface which is more or less faithful to the grammar, and the paradigmatic, semantic structure of values and norms hidden in the deeper meanings of interpretations. Semiotic analysis deals precisely with the level of meaning which exists under the surface, but the only way to reach those meanings is through the textual level, the written or spoken text. That is why the tools are needed. In our studies, we have used the semiotic square and the actant analysis. The former is based on the distinctions and the categorisations of meanings, and the latter on opening the plotting of narratives in order to reach the value structures.

Genome-wide analysis in German shepherd dogs reveals association of a locus on CFA 27 with atopic dermatitis

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1 × 10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n cases = 91, n controls = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0 × 10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (praw = 3.1 × 10(-7), pgenome = 0.03). The total associated region was defined as a ~1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The ~209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

La ciudad como texto. Consideraciones teóricas y metodológicas para el estudio de la percepción lingüística en el espacio urbano. El ejemplo de la Ciudad de Buenos Aires

La ciudad en tanto espacio amplio, heterogéneo y densificado ocupa un lugar particular en el estudio de fenómenos sociales. La tensión entre procesos intrínsecos, marcados por la transformación histórica de la ciudad, y tendencias globales como gentrificación y segregación del espacio urbano crea una compleja dinámica multidimensional que no solo se manifiesta en el aspecto físico, sino también en el imaginario colectivo del espacio urbano. Desde esta perspectiva del espacio-ciudad entendido como construcción social (en el sentido de la «producción del espacio social» de Lefèbvre 1974), percibido, concebido y vivido por quienes habitan en él, sus experiencias compartidas y sus objetivos comunes (Johnstone 2004: 69), la lengua adquiere un papel fundamental como medio de expresión y reflejo de las identidades urbanas. La ciudad se convierte en texto, en semiótica espacial. Las variedades en el uso de la lengua se convierten en símbolos espaciales, valorados e interpretados por los hablantes a base de un proceso perceptivo-selectivo y de sus representaciones extralingüísticas. Sirven, consciente o inconscientemente, para posicionarse dentro de la jerarquía urbana, provocan actitudes lingüísticas positivas o negativas. Por lo tanto, como ya lo hizo constar Labov en los años setenta, los habitantes de los grandes metrópolis se definen mucho más por sus actitudes y perjuicios lingüísticos marcados y persistentes que por las variedades que objetivamente hablan. Por eso, la perspectiva subjetiva de los hablantes, es decir, su percepción del espacio y de las diferencias en el uso de la lengua se considera cada vez más importante. El objetivo de esta ponencia es presentar consideraciones teóricas y metodológicas para el análisis de la percepción lingüística en el espacio urbano desde un enfoque interdisciplinario, poniendo en discusión conceptos de la Sociolingüística y de la Geografía Humana, como por ejemplo el uso de mapas cognitivos como representaciones del imaginario social, sobre el modelo del Área Metropolitana de Buenos Aires, ciudad que, como es sabido, destaca por la identificación geográfica y la conciencia lingüística de sus habitantes.

Die Sprache als Element sozialräumlicher Identitätskonstruktion im urbanen Raum. Das Beispiel Buenos Aires

Die dicht besiedelten lateinamerikanischen Metropolräume zeichnen sich heutzutage durch eine komplexe Dynamik der urbanen Sozialstruktur aus. Räumliche und soziokulturelle Segregationsprozesse – ausgelöst durch politische und ökonomische Umstrukturierungen und verstärkt durch die Einflüsse der Globalisierung – führten zu einer ausgeprägten Fragmentierung des urbanen Raumes. Soziale Ausgrenzung einerseits und bewusste Abschottung andererseits lassen innerhalb der einzelnen, immer stärker getrennten Stadtteile einen Drang zur Homogenisierung und Konzentration von Bevölkerungsgruppen mit ähnlichem sozioökonomischen Status feststellen. Im Zuge dieser urbanen Transformationen kommt der Identifikation mit einem bestimmten Ort innerhalb der Stadt eine stets größere Bedeutung zu. Dieses räumliche Verhalten ist Teil eines Lebensstils als ganzheitliches und vielschichtiges Phänomen (Auer 2007: 11), welches neben der Ortsgebundenheit auch durch soziokulturelle Verhaltensmuster, durch Konsumverhalten und schließlich durch den Sprachgebrauch zum Ausdruck kommt. Sprachliche Varietäten oder Merkmale als semiotisches Element konstituieren zusammen mit weiteren Faktoren den Lebensstil sozialer Gruppen im Raum und bilden demnach sowohl eine zentrale Komponente als auch ein Medium der sozialräumlichen Identitätskonstruktion. Unterschiede im Sprachgebrauch werden als Teil einer (räumlichen) Identität wahrgenommen, in Abhängigkeit der Repräsentationen und mentalen Bildern der Sprecher bezüglich des urbanen Raumes beurteilt und schließlich stilisiert. So spielen sie eine zentrale Rolle beim Ausdruck von Abgrenzung oder Zugehörigkeit zu einer sozialen Gruppe und geben vor dem historischen und geopolitischen Hintergrund einer Stadt Aufschluss über deren Sozialstruktur. Ausgehend von diesem konstruktivistischen Verständnis des Raumes als mehrdimensionales soziales Produkt im Sinne von Lefebvre (1974) werden an dem für die Entwicklungen der lateinamerikanischen Städte paradigmatischen Beispiel von Buenos Aires theoretische Überlegungen und methodische Herangehensweisen für die Erforschung des Zusammenhangs von sprachlicher Variation und sozialräumlicher Segregation dargestellt.

La estilización lingüística y espacial en Buenos Aires – huellas para el estudio de la transformación urbana

En las grandes metrópolis latinoamericanas, de las cuales la Región Metropolitana de Buenos Aires es ejemplo paradigmático, la polarización tradicional ha sido reemplazada por una fragmentación social, funcional y geográfica muy marcada del espacio urbano. Desde el punto de vista del espacio urbano entendido como construcción social (en el sentido de la «producción del espacio social» de Lefèbvre 1974), percebido, concebido y vivido por quienes habitan en él, sus experiencias compartidas y sus objetivos comunes (Johnstone 2004: 69), la lengua adquiere un papel fundamental como medio de expresión y reflejo de las identidades urbanas. A raíz de la redistribución en la estructura socio-urbana, el sentido de pertenencia a un lugar se hace cada vez más importante, lo cual se manifiesta tanto en preferencias de consumo como en actitudes sociales y lingüísticas, y no en último término en el uso de la lengua. La práctica lingüística revela la práctica social, de modo que determinados rasgos lingüísticos alcanzan un valor socio-indexical, es decir, actúan como elementos lingüísticos capaces de crear o constituir un significado social. Por un lado, un hablante se identifica y se asocia a un determinado grupo mediante el uso de determinados rasgos lingüísticos y crea, así, su identidad social a través de la lengua. Por otro lado, determinados rasgos lingüísticos se atribuyen de manera metonímica y generalizada a un determinado grupo, asociado, a su vez, a un lugar dentro del espacio urbano. Un rasgo indicador de un grupo social se convierte, según la terminología de Labov, en un estereotipo cuando clasifica de manera categórica a un grupo dado. Estas variantes estereotipadas muchas veces perduran como rastros en el ámbito de la lengua, viéndose reforzadas constantemente también por la representación de los medios de comunicación, factor determinante e ineludible en la construcción del espacio social actual. El objetivo de esta comunicación es, pues, proponer un planteamiento teórico y metodológico que permita analizar los estereotipos lingüísticos y espaciales que se observan en el área metropolitana de Buenos Aires y que, al estar tan vinculados con los desarrollos socio-espaciales, nos servirán como fuente de información para el estudio de los procesos urbanos.

Genome-wide gene-gene interaction analysis for cardiovascular disease

Numerous studies have been carried out to try to better understand the genetic predisposition for cardiovascular disease. Although it is widely believed that multifactorial diseases such as cardiovascular disease is the result from effects of many genes which working alone or interact with other genes, most genetic studies have been focused on identifying of cardiovascular disease susceptibility genes and usually ignore the effects of gene-gene interactions in the analysis. The current study applies a novel linkage disequilibrium based statistic for testing interactions between two linked loci using data from a genome-wide study of cardiovascular disease. A total of 53,394 single nucleotide polymorphisms (SNPs) are tested for pair-wise interactions, and 8,644 interactions are found to be significant with p-values less than 3.5×10-11. Results indicate that known cardiovascular disease susceptibility genes tend not to have many significantly interactions. One SNP in the CACNG1 (calcium channel, voltage-dependent, gamma subunit 1) gene and one SNP in the IL3RA (interleukin 3 receptor, alpha) gene are found to have the most significant pair-wise interactions. Findings from the current study should be replicated in other independent cohort to eliminate potential false positive results.^