Expressão dos genes da via mTORC1 e seu envolvimento nas Neoplasias Mieloproliferativas

As Neoplasias Mieloproliferativas (NMPs) se caracterizam por apresentarem acúmulo de eritrócitos, leucócitos e plaquetas morfologicamente normais e seus precursores. Nos últimos anos vários estudos buscaram conhecer os mecanismos celulares e moleculares envolvidos na fisiopatologia e evolução dessas desordens, com o intuito de encontrar marcadores de diagnóstico, prognóstico e terapias eficazes. A mutação pontual no gene que codifica a enzima Janus Kinase 2 (JAK2 V617F), presente em aproximadamente 90% dos pacientes com PV e em 50% dos pacientes com TE e MF, foi o principal achado genético anormal associado a essas doenças. Essa mutação resulta na ativação constitutiva da enzima JAK2 e na desregulação da proliferação celular e resistência à apoptose. Nosso grupo de pesquisa descreveu em PV, TE e MF a expressão alterada de genes reguladores da apoptose e dados da literatura indicam que a desregulação do ciclo celular contribui para a fisiopatologia das NMPs. Nesse projeto o intuito foi investigar a associação da via de sinalização m-TOR com as alterações do ciclo celular e via JAK/STAT nas NMPs. A via de sinalização m-TOR participa dos processos celulares de sobrevivência e proliferação. A estratégia experimental foi avaliar a expressão de genes e proteínas, reguladores da via m-TOR, em leucócitos de pacientes com NPMC e linhagens celulares JAK2+ tratadas com inibidores de JAK2 e AKT. Para determinar a relação da via m-TOR nas NMPs foi escolhido o gene eIF4E, alterado nessas doenças, para observar sua modulação diante da inibição farmacológica nas linhagens celulares JAK2 positivas. Os resultados desse estudo contribuem para a descrição de novos alvos terapêuticos dependentes e indepentendes da atividade quinase JAK2 e para o melhor conhecimento da participação da via de sinalização m-TOR na fisiopatologia das NMPs.

Social Inequity and Globalization: Understanding Violent and Nonviolent Responses

Globalization generates economic growth that is dominated by the free market dynamics of liberalization, deregulation, and privatization. The benefits of this growth are not distributed equally. The resulting inequities cause poverty, marginalization, exclusion, and instability. People respond to these inequities in both positive/nonviolent and negative/violent ways. This capstone project investigates the reasons for divergent responses to globalization by contrasting the underlying social factors in two case studies: peace communities in Colombia and piracy in Somalia. By measuring the level of vulnerability, considering security in a variety of domains, and examining stress on socio-cultural norms, this project develops a social factors framework for understanding the reasons for negative/violent versus positive/nonviolent responses to globalization.

Asymmetric rivalry within and between strategic groups

Our study examines asymmetric rivalry within and between strategic groups defined according to the size of their members. We hypothesize that, owing to several forms of group-level effects, including switching costs and efficiency, strategic groups comprising large firms expect to experience a large amount of retaliation from firms within their group and accommodation from the group comprising smaller firms. Small firms, on the other hand, expect to experience a small amount of retaliation from the group comprising large firms and no reaction from the other firms in their group. We estimate the effect of group-level strategic interactions on firm performance. Our analysis reveals that the rivalry behavior within and between groups is asymmetric, which supports the dominant-fringe relation between firms, as described in our hypothesis.

Who performs a stronger response to whom? Detecting individual competitive actions and reactions

This study analyzes the degree of competition through individual actions and reactions. Empirical support for this analysis has derived mainly from structural econometric models describing the nature of competition. This analysis extends the existing literature by empirically considering a direct measurement of competition through the analysis of the competitive actions and responses, and describing how firms compete within and between strategic groups. We estimate the firms’ conduct in the Spanish deposits market with 146 firms and 18,888 observations. This is a specially compelling context for the banking industry, in which a deregulation process gives rise to the adoption of aggressive strategies seeking to increase the market shares of deposit accounts; thus, producing a turbulent situation of increasing rivalry. Our results offer a deeper understanding of the firms’ competitive behavior, since we identify different patterns of actions and reactions depending upon the strategic group the firm belongs to.

Revisiting the Measurement of Anomie

Sociologists coined the term "anomie" to describe societies that are characterized by disintegration and deregulation. Extending beyond conceptualizations of anomie that conflate the measurements of anomie as 'a state of society' and as a 'state of mind', we disentangle these conceptualizations and develop an analysis and measure of this phenomenon focusing on anomie as a perception of the 'state of society'. We propose that anomie encompasses two dimensions: a perceived breakdown in social fabric (i.e., disintegration as lack of trust and erosion of moral standards) and a perceived breakdown in leadership (i.e., deregulation as lack of legitimacy and effectiveness of leadership). Across six studies we present evidence for the validity of the new measure, the Perception of Anomie Scale (PAS). Studies 1a and 1b provide evidence for the proposed factor structure and internal consistency of PAS. Studies 2a-c provide evidence of convergent and discriminant validity. Finally, assessing PAS in 28 countries, we show that PAS correlates with national indicators of societal functioning and that PAS predicts national identification and well-being (Studies 3a & 3b). The broader implications of the anomie construct for the study of group processes are discussed.

The EU essential facilities doctrine. Research Papers in Law, 6/2006

Introduction. The essential facilities doctrine may be seen as the ‘extra weight’ which is put onto the balance, in order to give precedence to the maintenance of competition over the complete contractual freedom of undertakings controlling an important and unique facility. The main purpose of the doctrine is to impose upon such ‘dominant’ undertakings the duty to negotiate and/or give access to the facility, against a reasonable fee, to other undertakings, which cannot pursue their own activity (and therefore will perish) without access to such a facility. This very simple description of the content of the doctrine underlines its limitations: through the imposition of a duty to negotiate or contractual obligations, the rule tends to compensate for the weaknesses of the competitive structure of a market, which are due to the existence of some essential facility. In other words, the doctrine does not by itself provide a definitive solution to the lack of competition, but tends to contractually maintain or even create some competition.1 The doctrine of essential facilities originates in the US antitrust case law of the Circuit and District Courts, but has never been officially acknowledged by the Supreme Court. It has been further developed and hotly debated by scholars in the US, both from a legal and from an economic viewpoint. In the EU, the essential facilities doctrine was openly introduced by the Commission during the early 1990s, but has received only limited and indirect support by the Court of First Instance (the CFI) and the European Court of Justice (the ECJ). It also indirectly inspired the legislation concerning the deregulation of traditional ‘natural’ monopolies. The judicial origin of the doctrine, combined with the hesitant application by the appeal courts, both in the US and the EU, cast uncertainty not only on the precise scope of the doctrine, but also on the issue of its very existence. These questions receive a particular light within the EU context, where the doctrine is called upon to play a different role from its US counterpart. In order to address the above issues, we will first pretend that an EU essential facility doctrine does indeed exist and we shall try to identify the scope and content thereof, through its main applications (Section 1). Subsequently, we will try to answer the question whether such a doctrine should exist at all in the EU (Section 2).

Legal Aspects in Establishing the Internal Market for services. Research Papers in Law, 6/2007

Introduction. The internal market for services is one of the objectives set by the founding fathers of the EC back in 1957. It is only in the last ten-fifteen years, however, that this aspect of the internal market has seriously attracted the attention of the EC legislature and judiciary.1 With the exception of some sector-specific directives dating back in the late ‘80s, it is only with the deregulation of network industries, the development of electronic communications and the spread of financial services, in the ‘90s that substantial bits of legislation got adopted in the field of services. Similarly, the European Court of Justice (ECJ, the Court) left the principles established in Van Binsbergen back in 1973, hibernate for a long time before fully applying them in Säger and constantly thereafter.2 Ever since, the Court’s case law in this field has grown so important that it has become the compulsory starting point for any study concerning the (horizontal) regulation of the internal market in services. The limits inherent to negative integration and to the casuistic approach pursued by judiciary decisions have prompted the need for a general legislative text to be adopted for services in the internal market. This text, however, hotly debated both at the political and at the legal level, has ended up in little more than a complex restatement of the Court’s case law. It may be, however, that this ‘little more’ is not that little. In view of the ever expanding application of the Treaty rules on services, promoted by the ECJ (para. 1),3 the Directive certainly appears to be a limited regulatory attempt (para. 2). This, however, does not mean that the Directive is a toothless, or useless regulatory instrument (conclusion: para. 3).

La disoccupazione giovanile in tempo di crisi: un monito all’Europa (continentale) per rifondare il diritto del lavoro? = Youth Unemployment in Recessionary Times: a Caveat to (Continental) Europe to Reconstruct its Labour Law. WP C.S.D.L.E. "Massimo D'Antona" .INT - 91/2012

The current debate taking place in continental Europe on the need to reform labour law to reduce the duality between labour market insiders and outsiders, thus giving new employment opportunities to young people seems to be, at its best, a consequence of the crisis, or at its worst, an excuse. The considerable emphasis placed on the power of legislation to reduce youth unemployment prevents real labour market problems from being clearly identified, thus reducing the scope to adopt more effective measures. Action is certainly required to help young people during the current crisis, yet interventions should not be exclusively directed towards increased flexibility and deregulation. This paper questions the “thaumaturgic power” wrongly attributed to legislative interventions and put forward a more holistic approach to solve the problem of youth employment, by focusing on the education systems, school-to-work transition and industrial relations. As a comparative analysis demonstrates, in order to effectively tackle the issue of youth employment, it is not enough to reform labour law. High quality education systems, apprenticeship schemes, efficient placement and employment services, cooperative industrial relations and flexible wage determination mechanisms are the key to success when it comes to youth employment, not only in times of recession.

Étude de la migration des populations de lymphocytes B du sang de patients infectés par le virus d’immunodéficience humaine (VIH)

La dérégulation du compartiment de cellules B est une conséquence importante de l’infection par le virus de l’immunodéficience humaine (VIH-1). On observe notamment une diminution des nombres de lymphocytes B sanguins ainsi qu’une variation des fréquences relatives des différentes populations de lymphocytes B chez les individus infectés par rapport aux contrôles sains. Notre laboratoire a précédemment démontré l’implication des cellules dendritiques dans la dérégulation des lymphocytes B via la roduction excessive de BLyS/BAFF, un stimulateur des cellules B. De plus, lors l’études menées chez la souris transgénique présentant une maladie semblable au SIDA, et chez la souris BLyS/BAFF transgénique, l’infection au VIH-1 fut associée à une expansion de la zone marginale (MZ) de la rate. De façon intéressante, nous observons chez les contrôleurs élites une diminution de la population B ‘mature’ de la MZ. Il s’agit du seul changement important chez les contrôleurs élites et reflète possiblement un recrutement de ces cellules vers la périphérie ainsi qu’une implication dans des mécanismes de contrôle de l’infection. Pour tenter d’expliquer et de mieux comprendre ces variations dans les fréquences des populations B, nous avons analysé les axes chimiotactiques CXCL13-CXCR5, CXCL12-CXCR4/CXCR7, CCL20-CCR6 et CCL25-CCR9. L’étude longitudinale de cohortes de patients avec différents types de progression clinique ou de contrôle de l’infection démontre une modulation des niveaux plasmatiques de la majorité des chimiokines analysées chez les progresseurs rapides et classiques. Au contraire, les contrôleurs élites conservent des niveaux normaux de chimiokines, démontrant leur capacité à maintenir l’homéostasie. La migration des populations de cellules B semble être modulée selon la progression ou le contrôle de l’infection. Les contrôleurs élites présentent une diminution de la population B ‘mature’ de la MZ et une augmentation de la fréquence d’expression du récepteur CXCR7 associé à la MZ chez la souris, suggérant un rôle important des cellules de la MZ dans le contrôle de l’infection au VIH-1. De façon générale, les résultats dans cette étude viennent enrichir nos connaissances du compartiment de cellules B dans le contexte de l’infection au VIH-1 et pourront contribuer à élaborer des stratégies préventives et thérapeutiques contre ce virus.

Rôle des cellules endothéliales dans l’immunité innée précoce induite lors d’infections par des coronavirus murins

Les cellules endothéliales (EC) constituent une première barrière physique à la dissémination de virus pléiotropiques circulant par voie hématogène mais leur contribution à la défense innée anti-virale est peu connue. Des dysfonctions des EC de la barrière hémato-encéphalique (BMEC) et des sinusoïdes hépatiques (LSEC) ont été rapportées dans des neuropathologies et des hépatites aiguës ou chroniques d’origine virale, suggérant que des atteintes à leur intégrité contribuent à la pathogenèse. Les sérotypes de coronavirus de l’hépatite murine (MHV), se différenciant par leur capacité à induire des hépatites et des maladies neurologiques de sévérité variable et/ou leur tropisme pour les EC, représentent des modèles viraux privilégiés pour déterminer les conséquences de l’infection des EC sur la pathogenèse virale. Lors d’infection par voie hématogène, le sérotype MHV3, le plus virulent des MHV, induit une hépatite fulminante, caractérisée par une réponse inflammatoire sévère, et des lésions neurologiques secondaires alors que le sérotype moins virulent, MHV-A59, induit une hépatite modérée sans atteintes secondaires du système nerveux central (SNC). Par ailleurs, le sérotype MHV3, à la différence du MHV-A59, démontre une capacité à stimuler la production de cytokines par la voie TLR2. Les variants atténués du MHV3, les virus 51.6-MHV3 et YAC-MHV3, sont caractérisés par un faible tropisme pour les LSEC et induisent respectivement une hépatite modérée et subclinique. Compte tenu de l’importance des LSEC dans le maintien de la tolérance hépatique et de l’élimination des pathogènes circulants, il a été postulé que la sévérité de l’hépatite et de la réponse inflammatoire lors d’infections par les MHV est associée à la réplication virale et à l’altération des propriétés tolérogéniques et vasculaires des LSEC. Les désordres inflammatoires hépatiques pourraient résulter d’une activation différentielle du TLR2, plutôt que des autres TLR et des hélicases, selon les sérotypes. D’autre part, compte tenu du rôle des BMEC dans la prévention des infections du SNC, il a été postulé que l’invasion cérébrale secondaire par les coronavirus est reliée à l’infection des BMEC et le bris subséquent de la barrière hémato-encéphalique (BHE). À l’aide d’infections in vivo et in vitro par les différents sérotypes MHV, chez des souris ou des cultures de BMEC et de LSEC, nous avons démontré, d’une part, que l’infection in vitro des LSEC par le sétotype MHV3, à la différence des variants 51.6- et YAC-MHV3, altérait la production du facteur vasodilatant NO et renversait leur phénotype tolérogénique en favorisant la production de cytokines et de chimiokines inflammatoires. Ces dysfonctions se traduisaient in vivo par une réponse inflammatoire incontrôlée et une dérégulation du recrutement intrahépatique de leucocytes, favorisant la réplication virale et les dommages hépatiques. Nous avons aussi démontré, à l’aide de souris TLR2 KO et de LSEC dont l’expression du TLR2 a été abrogée par des siRNA, que la sévérité de l’hépatite et de la réponse inflammatoire induite par le sérotype MHV3, dépendait en partie de l’induction et de l’activation préférentielle du TLR2 par le virus dans le foie. D’autre part, la sévérité de la réplication virale au foie et des désordres dans le recrutement leucocytaire intrahépatique induits par le MHV3, et non par le MHV-A59 et le 51.6-MHV3, corrélaient avec une invasion virale subséquente du SNC, au niveau de la BHE. Nous avons démontré que l’invasion cérébrale du MHV3 était associée à une infection productive des BMEC et l’altération subséquente des protéines de jonctions serrées occludine, VE-cadhérine et ZO-1 se traduisant par une augmentation de la perméabilité de la BHE et l’entrée consécutive du virus dans le cerveau. Dans l’ensemble, les résultats de cette étude mettent en lumière l’importance du maintien de l’intégrité structurale et fonctionnelle des LSEC et des BMEC lors d’infections virales aigües par des MHV afin de limiter les dommages hépatiques associés à l’induction d’une réponse inflammatoire exagérée et de prévenir le passage des virus au cerveau suite à une dissémination par voie hématogène. Ils révèlent en outre un nouveau rôle aggravant pour le TLR2 dans l’évolution de l’hépatite virale aigüe ouvrant la voie à de nouvelles avenues thérapeutiques visant à moduler l’activité inflammatoire du TLR2.

The Future of Model Germany: Challenges to the Corporatist System of Business Labor Relations. CES Germany & Europe Working Papers, No. 07.4, 12 December 1996

Germany's economic and social system faces immense economic, social, and political demands. These may be encapsulated in challenges like "new management concepts and labor policies," "deregulation of the infrastructure sector," "globalization," and "reunification." The paper analyzes these challenges and changes to the corporatist system of industrial relations--a cornerstone in .Model Germany's specific economic success and social consensus until now.

The European and Southeast Asian Single Aviation Markets. EU Centre, Background Brief No. 15, July 2015

Civil aviation in Europe is one major area where landmark changes have taken place since the late 1980s – the liberalization and deregulation of the sector by member states in three “packages” in the 1980s has transformed an economic sector historically characterized by heavy protectionism, collusion and strong state intervention. Today, the European Union’s (EU) aviation sector contributes to 2.4% of European GDP and supports 5.1 million jobs. The Association of Southeast Asian Nations (ASEAN) has also eagerly taken steps to integrate its aviation markets as part of the ASEAN Economic Community (AEC) in 2015. This background brief chronicles the changes made in the aviation sector in Europe through regional integration and examines how these changes have affected policymaking in member states, the airline industry and consumers. The brief also examines ASEAN’s own effort in the integration of its own aviation sector and, taking into account the EU’s strong interest in cooperating with ASEAN on transport and civil aviation policy, whether the changes in the EU are applicable in the ASEAN context.

Bok Is Not Pro-Apoptotic But Suppresses Poly ADP-Ribose Polymerase-Dependent Cell Death Pathways and Protects against Excitotoxic and Seizure-Induced Neuronal Injury.

UNLABELLED Bok (Bcl-2-related ovarian killer) is a Bcl-2 family member that, because of its predicted structural homology to Bax and Bak, has been proposed to be a pro-apoptotic protein. In this study, we demonstrate that Bok is highly expressed in neurons of the mouse brain but thatbokwas not required for staurosporine-, proteasome inhibition-, or excitotoxicity-induced apoptosis of cultured cortical neurons. On the contrary, we found thatbok-deficient neurons were more sensitive to oxygen/glucose deprivation-induced injuryin vitroand seizure-induced neuronal injuryin vivo Deletion ofbokalso increased staurosporine-, excitotoxicity-, and oxygen/glucose deprivation-induced cell death inbax-deficient neurons. Single-cell imaging demonstrated thatbok-deficient neurons failed to maintain their neuronal Ca(2+)homeostasis in response to an excitotoxic stimulus; this was accompanied by a prolonged deregulation of mitochondrial bioenergetics.bokdeficiency led to a specific reduction in neuronal Mcl-1 protein levels, and deregulation of both mitochondrial bioenergetics and Ca(2+)homeostasis was rescued by Mcl-1 overexpression. Detailed analysis of cell death pathways demonstrated the activation of poly ADP-ribose polymerase-dependent cell death inbok-deficient neurons. Collectively, our data demonstrate that Bok acts as a neuroprotective factor rather than a pro-death effector during Ca(2+)- and seizure-induced neuronal injuryin vitroandin vivo SIGNIFICANCE STATEMENT Bcl-2 proteins are essential regulators of the mitochondrial apoptosis pathway. The Bcl-2 protein Bok is highly expressed in the CNS. Because of its sequence similarity to Bax and Bak, Bok has long been considered part of the pro-apoptotic Bax-like subfamily, but no studies have yet been performed in neurons to test this hypothesis. Our study provides important new insights into the functional role of Bok during neuronal apoptosis and specifically in the setting of Ca(2+)- and seizure-mediated neuronal injury. We show that Bok controls neuronal Ca(2+)homeostasis and bioenergetics and, contrary to previous assumptions, exerts neuroprotective activitiesin vitroandin vivo Our results demonstrate that Bok cannot be placed unambiguously into the Bax-like Bcl-2 subfamily of pro-apoptotic proteins.

The Legacy of regulatory reform : restoring America's competitiveness.

Mode of access: Internet.

An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis

Despite the well-characterised role of sonic hedgehog (Shh) in promoting interfollicular basal cell proliferation and hair follicle downgrowth, the role of hedgehog signalling during epidermal stem cell fate remains largely uncharacterised. In order to determine whether the three vertebrate hedgehog molecules play a role in regulating epidermal renewal we overexpressed sonic (Shh), desert (Dhh) and Indian (Ihh) hedgehog in the basal cells of mouse skin under the control of the human keratin 14 promoter. We observed no overt epidermal morphogenesis phenotype in response to Ihh overexpression, however Dhh overexpression resulted in a range of embryonic and adult skin manifestations indistinguishable from Shh overexpression. Two distinct novel phenotypes were observed amongst Shh and Dhh transgenics, one exhibiting epidermal progenitor cell hyperplasia with the other displaying a complete loss of epidermal tissue renewal indicating deregulation of stem cell activity. These data suggest that correct temporal regulation of hedgehog activity is a key factor in ensuring epidermal stem cell maintenance. In addition, we observed Shh and Dhh transgenic skin from both phenotypes developed lesions reminiscent of human basal cell carcinoma (BCC), indicating that BCCs can be generated despite the loss of much of the proliferative (basal) compartment. These data suggest the intriguing possibility that BCC can arise outside the stem cell population. Thus the elucidation of Shh (and Dhh) target gene activation in the skin will likely identify those genes responsible for increasing the proliferative potential of epidermal basal cells and the mechanisms involved in regulating epidermal stem cell fate.