Identification of potential small molecule binding pockets on Rho family GTPases

Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (.100) and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism.

La Fundación Pere Tarrés, una propuesta para el Tiempo libre familiar

La sociedad cada vez separa más a los padres de los hijos; más allá de los problemas de estructuración familiar y los nuevos modelos de familias, la realidad de trabajo del día a día, las jornadas largas de trabajo, el hecho de tener que hacer dos trabajos al mismo tiempo, pero también el concepto que tenemos de los valores y la ética que somos capaces de adquirir y creer, imposibilitan a menudo la convivencia entre padres e hijos. La Fundación Pere Tarrés hace unos años que desarrolla acciones y propuestas en este sentido, que se adapten a las nuevas realidades, y ofrece sus recursos y capital humano, para hacer posible unas vacaciones familiares en estos tiempos tan complejos que nos toca vivir

DIC.CAT. Dona, immigració i ciutadania: les dones marrquines com a generadores de ciutadania a Catalunya

DIC.CAT es centra en les contribucions a la ciutadania que realitzen les dones immigrants marroquines, sobre les quals recauen forts estereotips i imatges que, sovint, les vinculen a la passivitat i a la submissió. Partint d'aquest fet, el projecte analitza el paper d'aquetes dones com a generadores de noves formes de ciutadania a Catalunya, a partir de les seves accions en les esferes pública i privada. El projecte contribueix, d'una banda a ampliar el coneixement teòric sobre la noció de ciutadania, incorporant la dimensió del gènere i partint de la realitat multicultural actual; i de l'altra a aprofundir sobre el rol que estan exercint les doens marroquines estudiades, com agents actius de xsocialització i generadores de canvis en els formes d'exercir la ciutadania en la societat catalana. Destaquen les accions que desenvolupen des de la seva quotidianitat en relació a aspectes com el procés de reagrupació, la incorporació al mercat laboral, la transmissio de valores dins la familia, la relació amb la comunitat d'origen, les motivacions, aspiracions o els projectes professionals i personals propis. Alhora, el projecte vincula aquestes accions amb les que desenvolupen des dels espais públics en els que participen, especialment dins l'àmbit associatiu.

Gender inequality in health among elderly people in a combined framework of socioeconomic position, family characteristics and social support

This study analyses gender inequalities in health among elderly people in Catalonia (Spain) by adopting a conceptual framework that globally considers three dimensions of health determinants : socio-economic position, family characteristics and social support. Data came from the 2006 Catalonian Health Survey. For the purposes of this study a sub-sample of people aged 65–85 years with no paid job was selected (1,113 men and 1,484 women). The health outcomes analysed were self-perceived health status, poor mental health status and long-standing limiting illness. Multiple logistic regression models separated by sex were fitted and a hierarchical model was fitted in three steps. Health status among elderly women was poorer than among the men for the three outcomes analysed. Whereas living with disabled people was positively related to the three health outcomes and confidant social support was negatively associated with all of them in both sexes, there were gender differences in other social determinants of health. Our results emphasise the importance of using an integrated approach for the analysis of health inequalities among elderly people, simultaneously considering socio-economic position, family characteristics and social support, as well as different health indicators, in order fully to understand the social determinants of the health status of older men and women.

Characterization and evolution of the novel gene family FAM90A in primates originated by multiple duplication and rearrangement events

Genomic plasticity of human chromosome 8p23.1 region is highly influenced by two groups of complex segmental duplications (SDs), termed REPD and REPP, that mediate different kinds of rearrangements. Part of the difficulty to explain the wide range of phenotypes associated with 8p23.1 rearrangements is that REPP and REPD are not yet well characterized, probably due to their polymorphic status. Here, we describe a novel primate-specific gene family, named FAM90A (family with sequence similarity 90), found within these SDs. According to the current human reference sequence assembly, the FAM90A family includes 24 members along 8p23.1 region plus a single member on chromosome 12p13.31, showing copy number variation (CNV) between individuals. These genes can be classified into subfamilies I and II, which differ in their upstream and 5′-untranslated region sequences, but both share the same open reading frame and are ubiquitously expressed. Sequence analysis and comparative fluorescence in situ hybridization studies showed that FAM90A subfamily II suffered a big expansion in the hominoid lineage, whereas subfamily I members were likely generated sometime around the divergence of orangutan and African great apes by a fusion process. In addition, the analysis of the Ka/Ks ratios provides evidence of functional constraint of some FAM90A genes in all species. The characterization of the FAM90A gene family contributes to a better understanding of the structural polymorphism of the human 8p23.1 region and constitutes a good example of how SDs, CNVs and rearrangements within themselves can promote the formation of new gene sequences with potential functional consequences.

Analysis of the multi-copy gene family FAM90A as a copy number variant in different ethnic backgrounds

Copy number variants contribute extensively to inter-individual genomic differences, but little is known about their inter-population variability and diversity. In a previous study (Bosch et al., 2007; 16:2572-2582), we reported that the primate-specific gene family FAM90A, which accounts for as many as 25 members in the human reference assembly, has expanded the number of FAM90A clusters across the hominoid lineage. Here we examined the copy number variability of FAM90A genes in 260 HapMap samples of European, African, and Asian ancestry, and showed significant inter-population differences (p<0.0001). Based on the recent study of Stranger et al. (2007; 315:848-853), we also explored the correlation between copy number variability and expression levels of the FAM90A gene family. Despite the high genomic variability, we found a low correlation between FAM90A copy number and expression levels, which could be due to the action of independent trans-acting factors. Our results show that FAM90A is highly variable in copy number between individuals and between populations. However, this variability has little impact on gene expression levels, thus highlighting the importance of genomic variability for genes located in regions containing segmental duplications.

Unstable equilibrium: young adult women in family and career formation in Southern Europe

The paper examines the relationship between family formation (i.e., living with a partner and having children) and women’s occupational career in southern Europe (i.e., Greece, Italy, Portugal and Spain). The relationship is explored by analysing the impact that different family structures and male [nvolvement in caring activities have on women’s early occupational trajectories (i.e., remaining in the same occupational status, experiencing downward or upward mobility, or withdrawing from paid work). This research shows that male involvement in caring activities does not really push women ahead in their career, but the absolute lack of male support seems to negatively affect women’s permanence in paid work. These results apply to all southern European countries except Portugal, where the absolute absence of the partners’ support in caring activities does not seem to alter women’s determination to remain in paid work. The methodology applied consists of the estimation of multinomial logit regression models and the analysis is based on eight waves (1994-2001) of the European Community Household Panel (ECHP).

What made him change? an individual and national analysis of men's participation in housework in 26 countries

We offer new evidence on multi-level determinants of the gender division of housework. Using data from the 2004 European Social Survey (ESS) for 26 European, we study the micro and macro-level factors which increase the likelihood of men doing an equal or greater share of housework than their female partners. A sample of 11,915 young men and women is analysed with a multi-level logistic regression in order to test at individual level the classic relative-income, time-availability and gender-role values, and a new couple conflict hypothesis. At individual level we find significant relationships between relative resources, values, couple's disagreement, and the division of housework which support more economic dependency than "doing gender" perspectives. At the macro-level, we find important composition effects and also support for gender empowerment, family model and social stratification explanations of cross-country differences.

A reassessment of family reunification in Europe. The case of Senegalese couples

Contemporary policy makers in most European destination countriesexpress a great concern about reunification of migrants’ families. Newrestrictions multiply in almost all countries, on the grounds thatmigrants would take advantage of a too lax system and that it wouldfoster an influx of non-desirable migrants. So far, quantitative evidenceis scarce on migrants’ practices in matter of family reunification.Taking advantage of a unique longitudinal dataset that includesSenegalese individuals surveyed both at origin (in Senegal) and inEurope (France, Italy and Spain), we perform event-history analyses toshow three things. First, couple separation is very often a long lastingsituation. Second, when separated because of international migration,wives and husbands do not only reunify in Europe but quite commonlyin Senegal. And third, those who reunify in Europe are those who arethe most adapted or adaptable to the European culture and economy.

The Generational contract in the family : explaining regime differences in financial transfers from parents to children in Europe

The exchange of social and economic support between the generationsis one of the main pillars of both family life and welfare systems. Thedebate on how to reform the generational contract is still truncated, however, by focusing on its public dimension only, especially on pensions and health care provisions. For a full account, the transfer of resources between adult generations in the family needs to be included as well. In our previous research we have shown that intergenerationalexchange is more likely to take place but less intense in the Nordicwelfare regime than in the Continental and Southern ones. In thepresent paper we analyze the social mechanisms that create and explain this nexus between patterns of intergenerational transfers and welfare regimes. The notion that Southern European family support networksare stronger and more effective than those of Continental and Northern European countries is only partially confirmed. In Southern (and partly in Continental) countries, children are mostly supported by means of co-residence with their parents till their complete economicindependence. However, once they have left the parental home thereare fewer transfers; support tends to be restricted to children who have special needs (such as for the formation of their own family), and depends more on their parents’ resources. In the Nordic countries, in contrast, transfers are less driven by children’s needs and parentalresources.

Organisational Values as "Attractors of Chaos": An Emerging Cultural Change to Manage Organisational Complexity

Business organisations are excellent representations of what in physics and mathematics are designated "chaotic" systems. Because a culture of innovation will be vital for organisational survival in the 21st century, the present paper proposes that viewing organisations in terms of "complexity theory" may assist leaders in fine-tuning managerial philosophies that provide orderly management emphasizing stability within a culture of organised chaos, for it is on the "boundary of chaos" that the greatest creativity occurs. It is argued that 21st century companies, as chaotic social systems, will no longer be effectively managed by rigid objectives (MBO) nor by instructions (MBI). Their capacity for self-organisation will be derived essentially from how their members accept a shared set of values or principles for action (MBV). Complexity theory deals with systems that show complex structures in time or space, often hiding simple deterministic rules. This theory holds that once these rules are found, it is possible to make effective predictions and even to control the apparent complexity. The state of chaos that self-organises, thanks to the appearance of the "strange attractor", is the ideal basis for creativity and innovation in the company. In this self-organised state of chaos, members are not confined to narrow roles, and gradually develop their capacity for differentiation and relationships, growing continuously toward their maximum potential contribution to the efficiency of the organisation. In this way, values act as organisers or "attractors" of disorder, which in the theory of chaos are equations represented by unusually regular geometric configurations that predict the long-term behaviour of complex systems. In business organisations (as in all kinds of social systems) the starting principles end up as the final principles in the long term. An attractor is a model representation of the behavioral results of a system. The attractor is not a force of attraction or a goal-oriented presence in the system; it simply depicts where the system is headed based on its rules of motion. Thus, in a culture that cultivates or shares values of autonomy, responsibility, independence, innovation, creativity, and proaction, the risk of short-term chaos is mitigated by an overall long-term sense of direction. A more suitable approach to manage the internal and external complexities that organisations are currently confronting is to alter their dominant culture under the principles of MBV.

The Economic Effects of Christian Moralities

This article examines the different influences that Catholicism and Protestantism exert on economically relevant values. It argues that Catholic theology and practice facilitate personal transactions while Protestantism favors values and types of moral and legal enforcement better adapted for impersonal trade. Protestantism may thus be more conducive to economic growth through anonymous exchange while Catholicism may provide better support for personal contracting. Several components of this hypothesis are confirmed using statistical models with data from the 1998 ISSP international survey on religion. These show that Protestants are more trusting of anonymous counter parties, develop more reliable institutions for legal enforcement and are more willing to spend resources on monitoring and punishing other members of the community. Catholicism is more protective of the family and small-group relationships, and provides more tolerant and less motivating beliefs. Relatively smaller and less consistent differences appear in terms of worldly personal success and incentives.

The role of moral values in the economic analysis of crime: A general equilibrium approach

In this paper, we develop a general equilibrium model of crime and show thatlaw enforcement has different roles depending on the equilibrium characterization and the value of social norms. When an economy has a unique stable equilibrium where a fraction of the population is productive and the remaining predates, the government can choose an optimal law enforcement policy to maximize a welfare function evaluated at the steady state. If such steady state is not unique, law enforcement is still relevant but in a completely different way because the steady state that prevails depends on the initial proportions of productive and predator individuals in the economy. The relative importance of these proportions can be changed through law enforcement policy.

Power transformations in correspondence analysis

Power transformations of positive data tables, prior to applying the correspondence analysis algorithm, are shown to open up a family of methods with direct connections to the analysis of log-ratios. Two variations of this idea are illustrated. The first approach is simply to power the original data and perform a correspondence analysis this method is shown to converge to unweighted log-ratio analysis as the power parameter tends to zero. The second approach is to apply the power transformation to thecontingency ratios, that is the values in the table relative to expected values based on the marginals this method converges to weighted log-ratio analysis, or the spectral map. Two applications are described: first, a matrix of population genetic data which is inherently two-dimensional, and second, a larger cross-tabulation with higher dimensionality, from a linguistic analysis of several books.

Organisational values as "attractors of chaos": An emerging cultural change to manage organisational complexity

Business organisations are excellent representations of what in physics and mathematics are designated "chaotic" systems. Because a culture of innovation will be vital for organisational survival in the 21st century, the present paper proposes that viewing organisations in terms of "complexity theory" may assist leaders in fine-tuning managerial philosophies that provide orderly management emphasizing stability within a culture of organised chaos, for it is on the "boundary of chaos" that the greatest creativity occurs. It is argued that 21st century companies, as chaotic social systems, will no longer be effectively managed by rigid objectives (MBO) nor by instructions (MBI). Their capacity for self-organisation will be derived essentially from how their members accept a shared set of values or principles for action (MBV). Complexity theory deals with systems that show complex structures in time or space, often hiding simple deterministic rules. This theory holds that once these rules are found, it is possible to make effective predictions and even to control the apparent complexity. The state of chaos that self-organises, thanks to the appearance of the "strange attractor", is the ideal basis for creativity and innovation in the company. In this self-organised state of chaos, members are not confined to narrow roles, and gradually develop their capacity for differentiation and relationships, growing continuously toward their maximum potential contribution to the efficiency of the organisation. In this way, values act as organisers or "attractors" of disorder, which in the theory of chaos are equations represented by unusually regular geometric configurations that predict the long-term behaviour of complex systems. In business organisations (as in all kinds of social systems) the starting principles end up as the final principles in the long term. An attractor is a model representation of the behavioral results of a system. The attractor is not a force of attraction or a goal-oriented presence in the system; it simply depicts where the system is headed based on its rules of motion. Thus, in a culture that cultivates or shares values of autonomy, responsibility, independence, innovation, creativity, and proaction, the risk of short-term chaos is mitigated by an overall long-term sense of direction. A more suitable approach to manage the internal and external complexities that organisations are currently confronting is to alter their dominant culture under the principles of MBV.