Mutations within a furin consensus sequence block proteolytic release of ectodysplasin-A and cause X-linked hypohidrotic ectodermal dysplasia

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a heritable disorder of the ED-1 gene disrupting the morphogenesis of ectodermal structures. The ED-1 gene product, ectodysplasin-A (EDA), is a tumor necrosis factor (TNF) family member and is synthesized as a membrane-anchored precursor protein with the TNF core motif located in the C-terminal domain. The stalk region of EDA contains the sequence -Arg-Val-Arg-Arg156-Asn-Lys-Arg159-, representing overlapping consensus cleavage sites (Arg-X-Lys/Arg-Arg↓) for the proprotein convertase furin. Missense mutations in four of the five basic residues within this sequence account for ≈20% of all known XLHED cases, with mutations occurring most frequently at Arg156, which is shared by the two consensus furin sites. These analyses suggest that cleavage at the furin site(s) in the stalk region is required for the EDA-mediated cell-to-cell signaling that regulates the morphogenesis of ectodermal appendages. Here we show that the 50-kDa EDA parent molecule is cleaved at -Arg156Asn-Lys-Arg159↓- to release the soluble C-terminal fragment containing the TNF core domain. This cleavage appears to be catalyzed by furin, as release of the TNF domain was blocked either by expression of the furin inhibitor α1-PDX or by expression of EDA in furin-deficient LoVo cells. These results demonstrate that mutation of a functional furin cleavage site in a developmental signaling molecule is a basis for human disease (XLHED) and raise the possibility that furin cleavage may regulate the ability of EDA to act as a juxtacrine or paracrine factor.

As razões do direito: um estudo da razão pública a partir do modelo liberal-igualitário de John Rawls

Em 1993, John Rawls, notável filósofo e professor da distinta Harvard University, publicou seu Political Liberalism, um livro em que pela primeira vez sintetiza sistematicamente o conceito de razão pública, uma ideia chave de sua teoria da justiça como equidade (justice as fairness). Segundo Rawls, a razão pública consiste fundamentalmente no modo e conteúdo adequados ao debate e à fundamentação de escolhas essenciais de justiça no espaço público de uma democracia constitucional. Nesse sentido, Rawls advoga que o único meio razoável de justificação da coerção estatal reside no reconhecimento e/ou obtenção de consensos (overlapping consensus) em relação às escolhas essenciais de uma sociedade democrática, o que só é possível se atores públicos e privados se despojarem de suas respectivas doutrinas filosóficas ou morais abrangentes ao debater e decidir tais questões essenciais de justiça. A presente dissertação tem por objetivo analisar a proposta de razão pública de Rawls, dentro do contexto de sua teoria da justiça como equidade, propondo-se a verificar se o pensamento rawlsiano procede no contexto jurídico-filosófico da pós-modernidade e se a sua teoria pode ser concretamente aplicada aos ordenamentos jurídicos contemporâneos, em especial no que tange ao conteúdo e pleno exercício da liberdade religiosa pelos cidadãos de um estado constitucional democrático.

Regulação financeira sistêmica no Brasil: desafios e propostas de aprimoramento institucional

A presente dissertação versa sobre o estudo da regulação financeira sistêmica brasileira e está dividida em quatro capítulos. No primeiro capítulo, descreve-se a essência das atividades financeiras e narra-se a trajetória histórica que deu ensejo à criação de Bancos Centrais e o surgimento da regulação bancária no mundo. Em seguida, discorre-se sobre o processo de expansão do sistema financeiro e sua internacionalização face à globalização financeira dos mercados. Após a exposição de razões políticas, comportamentais, econômicas e técnicas consideradas determinantes para a consumação da última crise financeira mundial (caso subprime), demonstra-se que uma regulação financeira sistêmica adequada constitui um processo complexo, dinâmico e contínuo de gestão pública com vistas a evitar ou atenuar os efeitos de crises sistêmicas. Nesse sentido, são expostos os motivos por que o Brasil enfrentou bem tal crise, através da apresentação da evolução dos processos regulatórios domésticos nos últimos anos. No segundo capítulo, utilizado o marco político-filosófico de John Rawls, sustenta-se a ideia de que a estabilidade financeira sustentável ao longo do tempo é uma questão de justiça básica que deve influenciar o desenho político-institucional em sociedades democráticas constitucionais. Nesse sentido, afirma-se a possibilidade de geração de um consenso sobreposto, segundo o ideal de razão pública, quanto à necessidade de estabelecimento de instituições, relativamente descoladas dos ciclos político-eleitorais e dotadas de especialização técnica, responsáveis pelo planejamento e acompanhamento público e transparente da sustentabilidade da execução da política monetária e da regulação financeira sistêmica propriamente dita no longo prazo. Adicionalmente, em razão da globalização financeira dos mercados, discorre-se sobre os limites e possibilidades do ideal de razão pública nos organismos financeiros internacionais (redes globais de governo), instituídos para definir padrões de regulação financeira sistêmica, e são feitos comentários acerca da existência de um Direito Administrativo Global. No terceiro capítulo, defende-se a ideia de razão prática regulatória como a diretriz adequada de atuação sustentável do Estado na economia com foco em resultados, a fim de estimular o progresso nos processos regulatórios, mediante o uso do better regulation como paradigma de análise de custos e benefícios. Após, expõe-se a noção de juridicidade administrativa como a mais compatível com a Constituição, além de defender-se a legitimidade democrática e o poder normativo das agências reguladoras financeiras. Por fim, com fundamento nas características do desenho institucional da estrutura regulatória brasileira, são formuladas propostas de aprimoramento institucional. No último capítulo, são feitos comentários sobre as vantagens, limites e riscos de judicialização dos processos regulatórios financeiros em democracias constitucionais, o que motiva a construção de parâmetros institucionais e materiais de atuação judicial, posteriormente analisados em precedentes importantes julgados no Brasil nos últimos anos.

La despenalización del aborto en una sociedad liberal : el caso colombiano

El presente artículo pretende exponer un debate de filosofía política sobre un problema moral álgido: el aborto. Partiendo de la base de que en todas las democracias occidentales una cuestión central en esta discusión tiene que ver con quién es, en último término, el que debe o puede decidir sobre la legalidad del mismo, lo que aquí se analiza es el problema de diseño y legitimidad constitucional con que se responde en una democracia liberal a esta controversia. Reconociendo que no son pocas las ocasiones en que este controvertido debate moral ha dividido profundamente a la sociedad, el presente artículo tiene como objetivo específico explicar brevemente cuál fue el mecanismo utilizado para lograr la “despenalización” del aborto en Colombia, para luego analizar la justicia del procedimiento, las pretensiones de quienes promovieron la acción de constitucionalidad y, así mismo, la decisión de la Corte Constitucional a la luz del modelo de justicia de John Rawls, especialmente a la luz del concepto de consenso traslapado. Lo anterior, con el propósito de defender la postura de que, al menos en el modelo jurídico-político colombiano, existen serios reparos frente a quienes consideran que la Corte Constitucional es el órgano democráticamente competente para cerrar el debate respecto al aborto.

Multiculturalismo y consenso: una aproximación desde el liberalismo político de John Rawls

La presente tesis gravita en torno a la siguiente pregunta: ¿cómo puede ser el liberalismo político una alternativa frente a los desafíos del multiculturalismo? La respuesta se presenta a partir de tres capítulos: en el primero se especifica la estructura y contenido del liberalismo político; en el segundo se caracterizan los desafíos del multiculturalismo en Francia, a partir del asunto del velo islámico y las consideraciones de los actores involucrados; en el tercero se analizan los argumentos y opiniones sobre el asunto del velo en Francia, con base en las categorías específicas del liberalismo político, especialmente el consenso traslapado. Se concluye que las posibilidades de consenso dependen del apego que tengan los ciudadanos hacia ciertos valores propios de una concepción política de la justicia, de la capacidad para apartarse de su forma particular de ver el mundo (doctrina comprensiva) en las discusiones públicas, así como de la voluntad que tengan los individuos para ser razonables y respetar las directivas de indagación en las discusiones políticas.

Similar T-cell immune responses induced by group M consensus env immunogens with wild-type or minimum consensus variable regions.

Consensus HIV-1 genes can decrease the genetic distances between candidate immunogens and field virus strains. To ensure the functionality and optimal presentation of immunologic epitopes, we generated two group-M consensus env genes that contain variable regions either from a wild-type B/C recombinant virus isolate (CON6) or minimal consensus elements (CON-S) in the V1, V2, V4, and V5 regions. C57BL/6 and BALB/c mice were primed twice with CON6, CON-S, and subtype control (92UG37_A and HXB2/Bal_B) DNA and boosted with recombinant vaccinia virus (rVV). Mean antibody titers against 92UG37_A, 89.6_B, 96ZM651_C, CON6, and CON-S Env protein were determined. Both CON6 and CON-S induced higher mean antibody titers against several of the proteins, as compared with the subtype controls. However, no significant differences were found in mean antibody titers in animals immunized with CON6 or CON-S. Cellular immune responses were measured by using five complete Env overlapping peptide sets: subtype A (92UG37_A), subtype B (MN_B, 89.6_B and SF162_B), and subtype C (Chn19_C). The intensity of the induced cellular responses was measured by using pooled Env peptides; T-cell epitopes were identified by using matrix peptide pools and individual peptides. No significant differences in T-cell immune-response intensities were noted between CON6 and CON-S immunized BALB/c and C57BL/6 mice. In BALB/c mice, 10 and eight nonoverlapping T-cell epitopes were identified in CON6 and CON-S, whereas eight epitopes were identified in 92UG37_A and HXB2/BAL_B. In C57BL/6 mice, nine and six nonoverlapping T-cell epitopes were identified after immunization with CON6 and CON-S, respectively, whereas only four and three were identified in 92UG37_A and HXB2/BAL_B, respectively. When combined together from both mouse strains, 18 epitopes were identified. The group M artificial consensus env genes, CON6 and CON-S, were equally immunogenic in breadth and intensity for inducing humoral and cellular immune responses.

Differential crosstalk between estrogen receptor (ER) alpha and ER beta and the thyroid hormone receptor isoforms results in flexible regulation of the consensus ERE

Crosstalk between nuclear receptors is important for conversion of external and internal stimuli to a physiologically meaningful response by cells. Previous studies from this laboratory have demonstrated crosstalk between the estrogen (ER) and thyroid hormone receptors (TR) on two estrogen responsive physiological promoters, the preproenkephalin and oxytocin receptor gene promoter. Since ERa and ERb are isoforms possessing overlapping and distinct transactivation properties, we hypothesized that the interaction of ERa and b with the various TR isoforms would not be equivalent. To explore this hypothesis, the consensus estrogen response element (ERE)derived from the Xenopus vitellogenin gene is used to investigate the differences in interaction between ERa and b isoforms and the different TR isoforms in fibroblast cells. Both the ER isoforms transactivate from the consensus ERE, though ERa transactivates to a greater extent than ERb. Although neither of the TRb isoforms have an effect on ERa transactivation from the consensus ERE, the liganded TRa1 inhibits the ERa transactivation from the consensus ERE. In contrast, the liganded TRa1 facilitates ERb-mediated transactivation. The crosstalk between the TRb isoforms with the ERa isoform, on the consensus ERE, is different from that with the ERb isoform. The use of a TRa1 mutant, which is unable to bind DNA, abolishes the ability of the TRa1 isoform to interact with either of the ER isoforms. These differences in nuclear receptor crosstalk reveal an important functional difference between isoforms, which provides a novel mechanism for neuroendocrine integration.

Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes

Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.

Clinical education for nephrology nurse practitioner candidates in Australia : a consensus statement

Objectives: To develop recommendations for the clinical education required to prepare Australian Nurse Practitioner candidates for advanced and extended practice in nephrology settings. Methods: Using the Delphi research technique a consensus statement was developed over a nine month period. All endorsed and candidate Nephrology Nurse Practitioners (NNP) were invited to participate as the expert panel. The Delphi research technique uses a systematic and iterative process. The expert panel were asked to generate a list of items which were then circulated to all NNPs. They were asked to determine their degree of agreement or disagreement with each statement using a 5-point Likert scale There was opportunity for free-text comments to be provided if desired. Results from each round were collated; the document was refined and circulated to the experts for a subsequent round. Consensus was demonstrated after three Delphi rounds. Results: The consensus statement comprises four components explaining the role and membership of the mentorship team, the setting and location of NNP clinical education, learning strategies to support the NNP, and outcomes of NNP clinical education. Demographic questions in the final survey revealed information about the qualifications, years of experience, and practice location of Australian NNPs. Conclusions: The consensus statement is not prescriptive but it will inform NNP candidates, university course providers and mentors about the expected extended nephrology specific clinical education that will enable the NNP to provide advanced nursing care for patients regardless of the stage of chronic kidney disease (CKD) and the practice setting.

Refining animal models in fracture research: Seeking consensus in optimising both animal welfare and scientific validity for appropriate biomedical use

Background In an attempt to establish some consensus on the proper use and design of experimental animal models in musculoskeletal research, AOVET (the veterinary specialty group of the AO Foundation) in concert with the AO Research Institute (ARI), and the European Academy for the Study of Scientific and Technological Advance, convened a group of musculoskeletal researchers, veterinarians, legal experts, and ethicists to discuss, in a frank and open forum, the use of animals in musculoskeletal research. Methods The group narrowed the field to fracture research. The consensus opinion resulting from this workshop can be summarized as follows: Results & Conclusion Anaesthesia and pain management protocols for research animals should follow standard protocols applied in clinical work for the species involved. This will improve morbidity and mortality outcomes. A database should be established to facilitate selection of anaesthesia and pain management protocols for specific experimental surgical procedures and adopted as an International Standard (IS) according to animal species selected. A list of 10 golden rules and requirements for conduction of animal experiments in musculoskeletal research was drawn up comprising 1) Intelligent study designs to receive appropriate answers; 2) Minimal complication rates (5 to max. 10%); 3) Defined end-points for both welfare and scientific outputs analogous to quality assessment (QA) audit of protocols in GLP studies; 4) Sufficient details for materials and methods applied; 5) Potentially confounding variables (genetic background, seasonal, hormonal, size, histological, and biomechanical differences); 6) Post-operative management with emphasis on analgesia and follow-up examinations; 7) Study protocols to satisfy criteria established for a "justified animal study"; 8) Surgical expertise to conduct surgery on animals; 9) Pilot studies as a critical part of model validation and powering of the definitive study design; 10) Criteria for funding agencies to include requirements related to animal experiments as part of the overall scientific proposal review protocols. Such agencies are also encouraged to seriously consider and adopt the recommendations described here when awarding funds for specific projects. Specific new requirements and mandates related both to improving the welfare and scientific rigour of animal-based research models are urgently needed as part of international harmonization of standards.

Helping someone with problem drinking: Mental health first aid guidelines - a Delphi expert consensus study

Background Alcohol is a leading risk factor for avoidable disease burden. Research suggests that a drinker's social network can play an integral role in addressing hazardous (i.e., high-risk) or problem drinking. Often however, social networks do not have adequate mental health literacy (i.e., knowledge about mental health problems, like problem drinking, or how to treat them). This is a concern as the response that a drinker receives from their social network can have a substantial impact on their willingness to seek help. This paper describes the development of mental health first aid guidelines that inform community members on how to help someone who may have, or may be developing, a drinking problem (i.e., alcohol abuse or dependence). Methods A systematic review of the research and lay literature was conducted to develop a 285-item survey containing strategies on how to help someone who may have, or may be developing, a drinking problem. Two panels of experts (consumers/carers and clinicians) individually rated survey items, using a Delphi process. Surveys were completed online or via postal mail. Participants were 99 consumers, carers and clinicians with experience or expertise in problem drinking from Australia, Canada, Ireland, New Zealand, the United Kingdom, and the United States. Items that reached consensus on importance were retained and written into guidelines. Results The overall response rate across all three rounds was 68.7% (67.6% consumers/carers, 69.2% clinicians), with 184 first aid strategies rated as essential or important by ≥80% of panel members. The endorsed guidelines provide guidance on how to: recognize problem drinking; approach someone if there is concern about their drinking; support the person to change their drinking; respond if they are unwilling to change their drinking; facilitate professional help seeking and respond if professional help is refused; and manage an alcohol-related medical emergency. Conclusion The guidelines provide a consensus-based resource for community members seeking to help someone with a drinking problem. Improving community awareness and understanding of how to identify and support someone with a drinking problem may lead to earlier recognition of problem drinking and greater facilitation of professional help seeking.