Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A.

Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.

RecA-mediated strand exchange traverses substitutional heterologies more easily than deletions or insertions.

RecA protein in bacteria and its eukaryotic homolog Rad51 protein are responsible for initiation of strand exchange between homologous DNA molecules. This process is crucial for homologous recombination, the repair of certain types of DNA damage and for the reinitiation of DNA replication on collapsed replication forks. We show here, using two different types of in vitro assays, that in the absence of ATP hydrolysis RecA-mediated strand exchange traverses small substitutional heterologies between the interacting DNAs, whereas small deletions or insertions block the ongoing strand exchange. We discuss evolutionary implications of RecA selectivity against insertions and deletions and propose a molecular mechanism by which RecA can exert this selectivity.

A member of the PLEIOTROPIC DRUG RESISTANCE family of ATP binding cassette transporters is required for the formation of a functional cuticle in Arabidopsis.

Although the multilayered structure of the plant cuticle was discovered many years ago, the molecular basis of its formation and the functional relevance of the layers are not understood. Here, we present the permeable cuticle1 (pec1) mutant of Arabidopsis thaliana, which displays features associated with a highly permeable cuticle in several organs. In pec1 flowers, typical cutin monomers, such as ω-hydroxylated fatty acids and 10,16-dihydroxypalmitate, are reduced to 40% of wild-type levels and are accompanied by the appearance of lipidic inclusions within the epidermal cell. The cuticular layer of the cell wall, rather than the cuticle proper, is structurally altered in pec1 petals. Therefore, a significant role for the formation of the diffusion barrier in petals can be attributed to this layer. Thus, pec1 defines a new class of mutants. The phenotypes of the pec1 mutant are caused by the knockout of ATP BINDING CASSETTEG32 (ABCG32), an ABC transporter from the PLEIOTROPIC DRUG RESISTANCE family that is localized at the plasma membrane of epidermal cells in a polar manner toward the surface of the organs. Our results suggest that ABCG32 is involved in the formation of the cuticular layer of the cell wall, most likely by exporting particular cutin precursors from the epidermal cell.

How political parties, rather than member-states, are building the European Union

Political party formation and coalition building in the European Parliament is being a driving force for making governance of the highly pluralistic European Union relatively effective and consensual. In spite of successive enlargements and the very high number of electoral partiesobtaining representation in the European Union institutions, the number of effective European Political Groups in the European Parliament has decreased from the first direct election in 1979 to the fifth in 1999. The formal analysis of national party¹s voting power in different Europeanparty configurations can explain the incentives for national parties to join large European Political Groups instead of forming smaller nationalistic groupings. Empirical evidence shows increasing cohesion of European Political Groups and an increasing role of the European Parliament in EU inter-institutional decision making. As a consequence of this evolution, intergovernmentalism is being replaced with federalizing relations. The analysis can support positive expectations regarding the governability of the European Union after further enlargements provided that new member states have party systems fitting the European PoliticalGroups.

On the origins of electoral systems and political parties. The role of elections in multi-member districts

The old, understudied electoral system composed of multi-member districts, open ballot and plurality rule is presented as the most remote scene of the origin of both political parties and new electoral systems. A survey of the uses of this set of electoral rules in different parts of the world during remote and recent periods shows its wide spread. A model of voting by this electoral system demonstrates that, while it can produce varied and pluralistic representation, it also provides incentives to form factional or partisan candidacies. Famous negative reactions to the emergence of factions and political parties during the 18th and 19th centuries are reinterpreted in this context. Many electoral rules and procedures invented since the second half of the 19th century, including the Australian ballot, single-member districts, limited and cumulative ballots, and proportional representation rules, derived from the search to reduce the effects of the originating multi-member district system in favor of a single party sweep. The general relations between political parties and electoral systems are restated to account for the foundational stage here discussed.

Altruism, equity and reciprocity in a gift-exchange experiment: An encompassing approach

Considerable experimental evidence suggests that non-pecuniary motivesmust be addressed when modeling behavior in economic contexts. Recentmodels of non-pecuniary motives can be classified as either altruism-based, equity-based, or reciprocity-based. We estimate and compareleading approaches in these categories, using experimental data. Wethen offer a flexible approach that nests the above three approaches,thereby allowing for nested hypothesis testing and for determiningthe relative strength of each of the competing theories. In addition,the encompassing approach provides a functional form for utility in different settings without the restrictive nature of the approaches nested within it. Using this flexible form for nested tests, we findthat intentional reciprocity, distributive concerns, and altruisticconsiderations all play a significant role in players' decisions.

Responsibility-allevation and effort provision in a gift-exchange experiment

Previous indirect evidence suggests that impulses towards pro-socialbehavior are diminished when an external authority is responsiblefor an outcome. The responsibility-alleviation effect states that ashift of responsibility to an external authority dampens internalimpulses toward honesty, loyalty, or generosity. In a gift-exchangeexperiment, we find that subjects respond with more generosity(higher effort) when a wage is determined by a random process thanwhen it is assigned by a third party, indicating that even a slightshift in perceived responsibility for the final payoffs can changebehavior. Responsibility-alleviation is a factor in economicenvironments featuring substantial personal interaction.

Monetary policy and exchange rate volatility in a small open economy

We lay out a small open economy version of the Calvo sticky price model, and show how the equilibrium dynamics can be reduced to simple representation in domestic inflation and the output gap. We use the resulting framework to analyze the macroeconomic implications of three alternative rule-based policy regimes for the small open economy: domestic inflation and CPI-based Taylor rules, and an exchange rate peg. We show that a key difference amongthese regimes lies in the relative amount of exchange rate volatility that they entail. We also discuss a special case for which domestic inflation targeting constitutes the optimal policy, and where a simple second order approximation to the utility of the representative consumer can be derived and used to evaluate the welfare losses associated with the suboptimal rules.

Earnings management in Spain. Some evidence from companies quoted in the Spanish stock exchange

After the accounting scandals that have taken place mainly in the UnitedStates during the last years, some Spanish leading authorities havedefended the idea that this kind of accounting problems cannot happen inSpain. They argue that accounting regulation in Europe, and specificallyin Spain, make more difficult the use of creative accounting practices.The objective of this paper is to identify some evidence about thesituacion in Spain. The study tries to demonstrate that some accountingpractices of several of the companies quoted in the Spanish Stock Exchangecould be qualified as earnings management.To carry out this study, the authors have analysed the accounts of the 35companies included in the stock market index IBEX 35. This index iscalculated with the share prices variations of the most importantcompanies quoted in the Spanish Stock Exchange.

Productivity growth and the exchange rate regime: The role of financial development

This paper offers empirical evidence that a country's choice of exchange rate regime can have a signifficant impact on its medium-term rate of productivity growth. Moreover, the impact depends critically on the country's level of financial development, its degree of market regulation, and its distance from the global technology frontier. We illustrate how each of these channels may operate in a simple stylized growth model in which real exchange rate uncertainty exacerbates the negative investment e¤ects of domestic credit market constraints. The empirical analysis is based on an 83 country data set spanning the years 1960-2000. Our approach delivers results that are in striking contrast to the vast existing empirical exchange rate literature, which largely finds the effects of exchange rate volatility on real activity to be relatively small and insignificant.

Molecular mechanisms of insulin exocytosis role of small monomeric GTP-ASES

SUMMARYInsulin secretion from pancreatic beta-cells is a fundamental condition for the maintenance of blood glucose levels. During the last decades, important components of the molecular machinery controlling hormone release have been characterized. My PhD thesis was dedicated to the study of new signaling pathways regulating insulin exocytosis and in particular to the role of small monomelic guanine triphosphatase or GTPases controlling the last events of hormone release.The first part of my thesis focused on Ras-like (Ral) RalA and RalB proteins. We investigated the mechanisms leading to activation of Ral proteins in pancreatic beta-cells and analyzed their impact on different steps of the insulin-secretory process. Our results have shown that RalA is the predominant isoform expressed in pancreatic islets and insulin-secreting cell lines. Silencing of this GTPase in INS-IE cells by RNA interference led to a decrease in secretagogue-induced hormone release. The activation of the GTPase, followed by FRET imaging, is triggered by increases in intracellular Ca and cAMP. Defective insulin release in cells lacking RalA is associated with a decrease in the secretory granules docked at the plasma membrane, detected by TIRF microscopy and with strong impairment in PLD1 activation in response to secretagogues. RalA was found to be activated by the exchange factor RalGDS, which regulates hormone secretion induced by secretagogues and the docking step of insulin-containing granules at the plasma membrane. In the second part of this work we have shown that a member of the Rab family, Rab37, is present on insulin-containing secretory granules of pancreatic beta-cells. In addition, our experiments have suggested that Rab37 is required to obtain an optimal insulin secretory response induced by secretogogues and is important for the docking step of insulin-containing granules at the plasma membrane.

The forensic radiographer: a new member in the medicolegal team.

Multidetector computed tomography is becoming more widespread in forensic medicine. In most services, autopsy assistants perform the radiological examination. We introduced professional radiographers into the legal medicine service and hypothesized they would also be able to take over duties currently reserved for other specialists. The aims of this study were to evaluate if radiographers could be trained as "forensic radiographers" by (1) integrating graduated medical radiographers into the legal medicine service, (2) investigating the advantages of this collaboration, and (3) defining the duties of the forensic radiographers.The study was performed prospectively on a group of 8 recruited radiographers who underwent a testing period with special training. They learned the basics of medicolegal case treatment, the autonomous execution of postmortem computed tomography angiography, and postprocessing of data. Seven of 8 radiographers finished the training and were integrated into our service. Although all radiographers were able to fulfill the duties demanded after the training period, some radiographers could not enter or complete the program because they were unable to work with dead bodies.Our study presents the advantages of integrating radiographers into the medicolegal team and proposes how to train the forensic radiographers. In addition, the duties and responsibilities of these new specialists are defined.

Caractéristiques de la clientèle des structures à bas seuil d'accès pour toxicomanes mettant à disposition du matériel d'injection stérile en Suisse [Characteristics of attenders of low threshold syringe-exchange centers providing sterile syringes in Switzerland].

BACKGROUND: The objectives of the present study were to evaluate Aids prevention in drug users attending low threshold centres providing sterile injection equipment in Switzerland, to identify the characteristics of these users, and to monitor the progress of indicators of drug-related harm. METHODS: This paper presents results from a cross-sectional survey carried out in 1994. RESULTS: The mean age of attenders was 28 years, and women represented 27% of the sample. 75% of attenders used a combination of hard drugs (heroin and cocaine). Mean duration of heroin consumption was 8 years, and of cocaine 7 years; 76% of attenders had a fixed abode, but only 34% had stable employment; 45% were being treated with methadone; 9% had shared their injection material in the last 6 months; 24% always used condoms in the case of a stable relationship, and 71% in casual relationships. In a cluster analysis constructed on the basis of multiple correspondence analysis, two distinct profiles of users emerge: highly marginalised users with a high level of consumption (21%); irregular users, better integrated socially, of which the majority are under methadone treatment (79%). CONCLUSION: Theses centres play a major role in Aids prevention. Nevertheless, efforts to improve the hygiene conditions of drug injection in Switzerland should be pursued and extended. At the same time, prevention of HIV sexual transmissions should be reinforced.