Discrete devaluations and multiple equilibria in a first generation model of currency crises

The first generation models of currency crises have often been criticized because they predict that, in the absence of very large triggering shocks, currency attacks should be predictable and lead to small devaluations. This paper shows that these features of first generation models are not robust to the inclusion of private information. In particular, this paper analyzes a generalization of the Krugman-Flood-Garber (KFG) model, which relaxes the assumption that all consumers are perfectly informed about the level of fundamentals. In this environment, the KFG equilibrium of zero devaluation is only one of many possible equilibria. In all the other equilibria, the lack of perfect information delays the attack on the currency past the point at which the shadow exchange rate equals the peg, giving rise to unpredictable and discrete devaluations.

Development of a Selective Peptide Macrocycle Inhibitor of Coagulation Factor XII toward the Generation of a Safe Antithrombotic Therapy.

Inhibition of coagulation factor XII (FXII) activity represents an attractive approach for the treatment and prevention of thrombotic diseases. The few existing FXII inhibitors suffer from low selectivity. Using phage display combined to rational design, we developed a potent inhibitor of FXII with more than 100-fold selectivity over related proteases. The highly selective peptide macrocycle is a promising candidate for the control of FXII activity in antithrombotic therapy and a valuable tool in hematology research.

Ontology Mapping Evolution

Introdução Hoje em dia, o conceito de ontologia (Especificação explícita de uma conceptualização [Gruber, 1993]) é um conceito chave em sistemas baseados em conhecimento em geral e na Web Semântica em particular. Entretanto, os agentes de software nem sempre concordam com a mesma conceptualização, justificando assim a existência de diversas ontologias, mesmo que tratando o mesmo domínio de discurso. Para resolver/minimizar o problema de interoperabilidade entre estes agentes, o mapeamento de ontologias provou ser uma boa solução. O mapeamento de ontologias é o processo onde são especificadas relações semânticas entre entidades da ontologia origem e destino ao nível conceptual, e que por sua vez podem ser utilizados para transformar instâncias baseadas na ontologia origem em instâncias baseadas na ontologia destino. Motivação Num ambiente dinâmico como a Web Semântica, os agentes alteram não só os seus dados mas também a sua estrutura e semântica (ontologias). Este processo, denominado evolução de ontologias, pode ser definido como uma adaptação temporal da ontologia através de alterações que surgem no domínio ou nos objectivos da própria ontologia, e da gestão consistente dessas alterações [Stojanovic, 2004], podendo por vezes deixar o documento de mapeamento inconsistente. Em ambientes heterogéneos onde a interoperabilidade entre sistemas depende do documento de mapeamento, este deve reflectir as alterações efectuadas nas ontologias, existindo neste caso duas soluções: (i) gerar um novo documento de mapeamento (processo exigente em termos de tempo e recursos computacionais) ou (ii) adaptar o documento de mapeamento, corrigindo relações semânticas inválidas e criar novas relações se forem necessárias (processo menos existente em termos de tempo e recursos computacionais, mas muito dependente da informação sobre as alterações efectuadas). O principal objectivo deste trabalho é a análise, especificação e desenvolvimento do processo de evolução do documento de mapeamento de forma a reflectir as alterações efectuadas durante o processo de evolução de ontologias. Contexto Este trabalho foi desenvolvido no contexto do MAFRA Toolkit1. O MAFRA (MApping FRAmework) Toolkit é uma aplicação desenvolvida no GECAD2 que permite a especificação declarativa de relações semânticas entre entidades de uma ontologia origem e outra de destino, utilizando os seguintes componentes principais: Concept Bridge – Representa uma relação semântica entre um conceito de origem e um de destino; Property Bridge – Representa uma relação semântica entre uma ou mais propriedades de origem e uma ou mais propriedades de destino; Service – São aplicados às Semantic Bridges (Property e Concept Bridges) definindo como as instâncias origem devem ser transformadas em instâncias de destino. Estes conceitos estão especificados na ontologia SBO (Semantic Bridge Ontology) [Silva, 2004]. No contexto deste trabalho, um documento de mapeamento é uma instanciação do SBO, contendo relações semânticas entre entidades da ontologia de origem e da ontologia de destino. Processo de evolução do mapeamento O processo de evolução de mapeamento é o processo onde as entidades do documento de mapeamento são adaptadas, reflectindo eventuais alterações nas ontologias mapeadas, tentando o quanto possível preservar a semântica das relações semântica especificadas. Se as ontologias origem e/ou destino sofrerem alterações, algumas relações semânticas podem tornar-se inválidas, ou novas relações serão necessárias, sendo por isso este processo composto por dois sub-processos: (i) correcção de relações semânticas e (ii) processamento de novas entidades das ontologias. O processamento de novas entidades das ontologias requer a descoberta e cálculo de semelhanças entre entidades e a especificação de relações de acordo com a ontologia/linguagem SBO. Estas fases (“similarity measure” e “semantic bridging”) são implementadas no MAFRA Toolkit, sendo o processo (semi-) automático de mapeamento de ontologias descrito em [Silva, 2004]. O processo de correcção de entidades SBO inválidas requer um bom conhecimento da ontologia/linguagem SBO, das suas entidades e relações, e de todas as suas restrições, i.e. da sua estrutura e semântica. Este procedimento consiste em (i) identificar as entidades SBO inválidas, (ii) a causa da sua invalidez e (iii) corrigi-las da melhor forma possível. Nesta fase foi utilizada informação vinda do processo de evolução das ontologias com o objectivo de melhorar a qualidade de todo o processo. Conclusões Para além do processo de evolução do mapeamento desenvolvido, um dos pontos mais importantes deste trabalho foi a aquisição de um conhecimento mais profundo sobre ontologias, processo de evolução de ontologias, mapeamento etc., expansão dos horizontes de conhecimento, adquirindo ainda mais a consciência da complexidade do problema em questão, o que permite antever e perspectivar novos desafios para o futuro.

Composition of electricity generation portfolios, pivotal dynamics and market prices

We use a simulation model to study how the diversification of electricity generation portfoliosinfluences wholesale prices. We find that technological diversification generally leads to lower market prices but that the relationship is mediated by the supply to demand ratio. In each demand case there is a threshold where pivotal dynamics change. Pivotal dynamics pre- and post-threshold are the cause of non-linearities in the influence of diversification on market prices. The findings are robust to our choice of behavioural parameters and match close-form solutions where those are available.

Generation of the primary hair follicle pattern.

Hair follicles are spaced apart from one another at regular intervals through the skin. Although follicles are predominantly epidermal structures, classical tissue recombination experiments indicated that the underlying dermis defines their location during development. Although many molecules involved in hair follicle formation have been identified, the molecular interactions that determine the emergent property of pattern formation have remained elusive. We have used embryonic skin cultures to dissect signaling responses and patterning outcomes as the skin spatially organizes itself. We find that ectodysplasin receptor (Edar)-bone morphogenetic protein (BMP) signaling and transcriptional interactions are central to generation of the primary hair follicle pattern, with restriction of responsiveness, rather than localization of an inducing ligand, being the key driver in this process. The crux of this patterning mechanism is rapid Edar-positive feedback in the epidermis coupled with induction of dermal BMP4/7. The BMPs in turn repress epidermal Edar and hence follicle fate. Edar activation also induces connective tissue growth factor, an inhibitor of BMP signaling, allowing BMP action only at a distance from their site of synthesis. Consistent with this model, transgenic hyperactivation of Edar signaling leads to widespread overproduction of hair follicles. This Edar-BMP activation-inhibition mechanism appears to operate alongside a labile prepattern, suggesting that Edar-mediated stabilization of beta-catenin active foci is a key event in determining definitive follicle locations.

SwissParam: a fast force field generation tool for small organic molecules.

The drug discovery process has been deeply transformed recently by the use of computational ligand-based or structure-based methods, helping the lead compounds identification and optimization, and finally the delivery of new drug candidates more quickly and at lower cost. Structure-based computational methods for drug discovery mainly involve ligand-protein docking and rapid binding free energy estimation, both of which require force field parameterization for many drug candidates. Here, we present a fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field. Output files can be used with CHARMM or GROMACS. The topologies and parameters generated by SwissParam are used by the docking software EADock2 and EADock DSS to describe the small molecules to be docked, whereas the protein is described by the CHARMM force field, and allow them to reach success rates ranging from 56 to 78%. We have also developed a rapid binding free energy estimation approach, using SwissParam for ligands and CHARMM22/27 for proteins, which requires only a short minimization to reproduce the experimental binding free energy of 214 ligand-protein complexes involving 62 different proteins, with a standard error of 2.0 kcal mol(-1), and a correlation coefficient of 0.74. Together, these results demonstrate the relevance of using SwissParam topologies and parameters to describe small organic molecules in computer-aided drug design applications, together with a CHARMM22/27 description of the target protein. SwissParam is available free of charge for academic users at www.swissparam.ch.

A glutathione precursor, N-acetyl-cysteine, modulates mismatch negativity generation in schizophrenia patients

Schizophrenia patients exhibit deficits in low-level processing, including pitch discrimination. This deficiency manifests in auditory evoked potentials (AEPs) as an impaired mismatch negativity (MMN), an electrophysiological response to infrequent target stimuli interspersed among frequent standard stimuli that typically peaks ~100ms post-stimulus onset. NMDA receptor antagonists have been shown to block MMN generation in both animals and humans, and NMDA dysfunction has been linked to the underlying pathophysiology of schizophrenia. A parallel line of evidence indicates that glutathione (GSH) regulation is perturbed in schizophrenia patients at the gene, protein and functional levels (Tosic et al., 2006). This GSH dysregulation leads to NMDA receptors' hypofunction through interaction with their redox site (Steullet et al., 2006). The present study aimed to modulate GSH levels in schizophrenia patients and assessed the effects of such a modulation on MMN generation mechanisms. N-acetyl-cysteine (NAC), a GSH precursor, was administered to schizophrenia patients, using a double-blind cross-over protocol. One group received NAC (2g/day) for 60 days and then placebo for another 60 days, and vice-versa for the second group. AEPs from patients were recorded at the onset of the protocol, at the point of cross-over, and at the end of the study. Participants were instructed to manually respond to target stimuli (2kHz pure tones occurring 20% of the time among 1kHz pure tones). Analyses of AEPs recorded at protocol onset indicated that patients (n=11) were significantly impaired in generating the MMN relative to age-matched controls (n=11). Specifically, the global field power (GFP), an index of AEP magnitude, was measured over the 70- 155ms post-stimulus interval and submitted to an analysis of variance (ANOVA). There was a significant interaction between population and stimulus frequency, indicating impaired MMN generation in patients at protocol onset. Analyses of AEPs recorded during administration of NAC (n=7) versus placebo (n=7) revealed the efficacy of this GSH precursor in modulating MMN generation mechanisms. ANOVA of GFP over the 70- 155ms post-stimulus interval, using stimulus frequency and treatment as within-participants variables, revealed a significant interaction and indicated that NAC can ameliorate MMN generation. We discuss these results in terms of potential therapeutic strategies for schizophrenia.

The Gene Ontology: enhancements for 2011.

The Gene Ontology (GO) (http://www.geneontology.org) is a community bioinformatics resource that represents gene product function through the use of structured, controlled vocabularies. The number of GO annotations of gene products has increased due to curation efforts among GO Consortium (GOC) groups, including focused literature-based annotation and ortholog-based functional inference. The GO ontologies continue to expand and improve as a result of targeted ontology development, including the introduction of computable logical definitions and development of new tools for the streamlined addition of terms to the ontology. The GOC continues to support its user community through the use of e-mail lists, social media and web-based resources.

Complete Ontology- Three level Integration

This file contains the complete ontology (OntoProcEDUOC_OKI_Final.owl). At loading time to edit, the OKI ontology corresponding to the implementation level (OntoOKI_DEFINITIVA.owl)must be imported.

Generation of short-term murine natural killer cell clones to analyze Ly49 gene expression.

Natural killer (NK) cellsexpress receptors specific for class I major histocompatibility complex (MHC) molecules. In the mouse, the class I specific receptors identified to date belong to the polymorphic Ly49 receptor family. Engagement of Ly49 receptors with their respective MHC ligands results in negative regulation of NK cell effector functions, consistent with a critical role of these receptors in "missing self" recognition. The Ly49 receptors analyzed so far are clonally distributed such that multiple distinct Ly49 receptors can be expressed by individual NK cells (for review see refs. 1-3). The finding that most NK cells that express the Ly49A receptor do so from a single Ly49A allele (whereby expression can occur from the maternal or the paternal chromosome) may thus reflect a putative receptor distribution process that restricts the number of Ly49 receptors expressed in a single NK cell (3-5).