A structural basis for the selection of dominant alpha beta T cell receptors in antiviral immunity

We have examined the basis for immunodominant or public TCR usage in an antiviral CTL response. Residues encoded by each of the highly selected genetic elements of an immunodominant clonotype recognizing Epstein-Barr virus were critical to the antigen specificity of the receptor. Upon recognizing antigen the immunodominant TCR undergoes extensive conformational changes in the complementarity determining regions (CDRs), including the disruption of the canonical structures of the germline-encoded CDR1alpha and CDR2alpha loops to produce an enhanced fit with the HLA-peptide complex. TCR ligation induces conformational changes in the TCRalpha constant domain thought to form part of the docking site for CD3epsilon. These findings indicate that TCR immunodominance is associated with structural properties conferring receptor specificity and suggest a novel structural link between TCR ligation and intracellular signaling.

The role of melanocortin-1 receptor polymorphism in skin cancer risk phenotypes

We have examined melanocortin-1 receptor (MC1R) variant allele frequencies in the general population and in a collection of adolescent dizygotic and monozygotic twins to determine statistical associations of pigmentation phenotypes with increased skin cancer risk. This included hair and skin color, freckling, mole count and sun exposed skin reflectance. Nine variants were studied and designated as either strong R (OR = 63; 95% CI 32-140) or weak r (OR = 5; 95% CI 3-11) red hair alleles. Penetrance of each MC1R variant allele was consistent with an allelic model where effects were multiplicative for red hair but additive for skin reflectance. To assess the interaction of the brown eye color gene BEY2/OCA2 on the phenotypic effects of variant MC1R alleles we imputed OCA2 genotype in the twin collection. A modifying effect of OCA2 on MC1R variant alleles was seen on constitutive skin color, freckling and mole count. In order to study the individual effects of these variants on pigmentation phenotype we have established a series of human primary melanocyte strains genotyped for the MC1R receptor. These include strains which are MC1R wild-type consensus, variant heterozygotes, and homozygotes for strong R alleles Arg151Cys and Arg160Trp. Ultrastructural analysis demonstrated that only consensus strains contained stage III and IV melanosomes in their terminal dendrites whereas Arg151Cys and Arg160Trp homozygous strains contained only immature stage I and II melanosomes. Such genetic association studies combined with the functional analysis of MC1R variant alleles in melanocytic cells should provide a link in understanding the association between pigmentary phototypes and skin cancer risk.

Stereological and other methods applied to rock joint size estimation - Does Crofton's theorem apply?

A number of authors concerned with the analysis of rock jointing have used the idea that the joint areal or diametral distribution can be linked to the trace length distribution through a theorem attributed to Crofton. This brief paper seeks to demonstrate why Crofton's theorem need not be used to link moments of the trace length distribution captured by scan line or areal mapping to the moments of the diametral distribution of joints represented as disks and that it is incorrect to do so. The valid relationships for areal or scan line mapping between all the moments of the trace length distribution and those of the joint size distribution for joints modeled as disks are recalled and compared with those that might be applied were Crofton's theorem assumed to apply. For areal mapping, the relationship is fortuitously correct but incorrect for scan line mapping.

Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis

Background The mechanisms responsible for disturbed iron homoeostasis in hereditary haemochromatosis are poorly understood. However, results of some studies indicate a link between hepcidin, a liver-derived peptide, and intestinal iron absorption, suggesting that this molecule could play a part in hepatic iron overload. To investigate this possible association, we studied the hepatic expression of the gene for hepcidin (HAMP) and a gene important in iron transport (IREG1) in patients with haemochromatosis, in normal controls, and in Hfe-knockout mice. Methods We extracted total RNA from the liver tissue of 27 patients with HFE-associated haemochromatosis, seven transplant donors (controls), and Hfe-knockout mice. HAMP and IREG1 mRNA concentrations were examined by ribonuclease protection assays and expressed relative to the housekeeping gene GAPD. Findings There was a significant decrease in HAMP expression in untreated patients compared with controls (5.4-fold, 95% CI 3.3-7.5; p

The paternity of the price-quality 'value map'

In the literature on firm strategy and product differentiation, consumer price-quality trade-offs are sometimes represented using consumer 'value maps'. These involve the geometric representation of indifferent price and quality combinations as points along curves that are concave to the 'quality' axis. In this paper, it is shown that the value map for price-quality tradeoffs may be derived from a Hicksian compensated demand curve for product quality. The paper provides the theoretical link between analytical methods employed in the existing literature on firm strategy and competitive advantage with the broader body of economic analysis.

ATP activates ataxia-telangiectasia mutated (ATM) in vitro - Importance of autophosphorylation

Ataxia-telangiectasia Mutated (ATM), mutated in the human disorder ataxia-telangiectasia, is rapidly activated by DNA double strand breaks. The mechanism of activation remains unresolved, and it is uncertain whether autophosphorylation contributes to activation. We describe an in vitro immunoprecipitation system demonstrating activation of ATM kinase from unirradiated extracts by preincubation with ATP. Activation is both time- and ATP concentration-dependent, other nucleotides fail to activate ATM, and DNA is not required. ATP activation is specific for ATM since it is not observed with kinase-dead ATM, it requires Mn2+, and it is inhibited by wortmannin. Exposure of activated ATM to phosphatase abrogates activity, and repeat cycles of ATP and phosphatase treatment reveal a requirement for autophosphorylation in the activation process. Phosphopeptide mapping revealed similarities between the patterns of autophosphorylation for irradiated and ATP-treated ATM. Caffeine inhibited ATM kinase activity for substrates but did not interfere with ATM autophosphorylation. ATP failed to activate either A-T and rad3-related protein (ATR) or DNA-dependent protein kinase under these conditions, supporting the specificity for ATM. These data demonstrate that ATP can specifically induce activation of ATM by a mechanism involving autophosphorylation. The relationship of this activation to DNA damage activation remains unclear but represents a useful model for understanding in vivo activation.

Matrix metalloproteinase-2 and-9 involvement in canine tumors

Matrix metalloproteinases (MMPs) are a family of enzymes implicated in the degradation and remodeling of extracellular matrix and in vascularization. They are also involved in pathologic processes such as tumor invasion and metastasis in experimental cancer models and in human malignancies. We used gelatin zymography and inummohistochemistry to determine whether MMP-2 and MMP-9 are present in canine tumors and normal tissues and whether MMP production correlates with clinicopathologic parameters of prognostic importance. High levels of pro-MMP-9, pro-MMP-2, and active MMP-2 were detected in most canine tumors. Significantly higher MMP levels were measured in canine tumors than in nontumors, malignancies had higher MMP levels than benign tumors, and sarcomas had higher active MMP-2 than carcinomas. Cartilaginous tumors produced higher MMP levels than did nonsarcomatous malignancies, benign tumors, and normal tissues, and significantly greater MMP-2 than osteosarcomas and fibrosarcomas. Pro-MMP-9 production correlated with the histologic grade of osteosarcomas. The 62-kd form of active MMP-2 was detected only in high-grade, p53-positive, metastatic malignancies. Zymography proved to be a sensitive and quantitative technique for the assessment of MMP presence but has the limitation of requiring fresh tissue; inummohistochemistry is qualitative and comparatively insensitive but could be of value in archival studies. MMP presence was shown in a range of canine tumors, and their link to tumor type and grade was demonstrated for the first time. This study will allow a substantially improved evaluation of veterinary cancer patients and provides baseline information necessary for the design of clinical trials targeting MMPs.

The relationship of adult attachment dimensions to depression and agoraphobia

We examined the unique relations between the five dimensions of the Attachment Style Questionnaire (ASQ; Feeney, Noller, & Hanrahan, 1994) and depression and agoraphobic behavior (i.e., avoidance of situations where high anxiety is experienced). In addition, we examined mediation models in an attempt to clarify the link between adult attachment and these two dimensions of psychopathology. In testing these models, we administered the ASQ, General Self-Efficacy Scale, Agoraphobic Catastrophic Cognitions Questionnaire, Beck Depression Inventory, and the Mobility Inventory for Agoraphobia (a measure of the degree to which situations are avoided that are typically anxiety provoking for people with agoraphobia) to 122 participants (44 with agoraphobia, 25 with a current major depressive disorder, and 53 with no current psychopathology). The results showed that the insecure attachment dimensions of need for approval, preoccupation with relationships, and relationships as secondary were uniquely associated with depression and that general self-efficacy partly mediated the relationship between need for approval and depression. In contrast, only preoccupation with relationships was uniquely associated with agoraphobic behavior, and catastrophic cognitions about bodily sensations partly mediated this association.

Potential for early involvement of CYP isoforms in aspects of human cadmium toxicity

This paper investigates the possible link between non-workplace cadmium (Cd) exposure, cytochrome P450 expression and hypertension. We present results of our investigation into the relationships between liver and kidney Cd burdens and the abundance of the CYP isoform 4A11. Our data show associations between non-workplace Cd exposure and changes in the abundance of hepatic and renal cortical CYP4A11. In liver the levels of immunochemically detectable CYP4A11 were positively correlated with tissue Cd content while in contrast CYP4A11 abundance was inversely correlated with kidney Cd burden. These differences are most likely related to the different Cd burden of the tissues. These observations suggest the potential for involvement of Cd as a mediator of CYP4A11 expression in kidney cortex and indicate that elevations in kidney Cd content may be involved in hypertension via alteration of the expression of this particular isoform. Potential mechanisms by which Cd may alter CYP4A11 expression are discussed briefly. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

A trag??dia da regi??o serrana do Rio de Janeiro em 2011: procurando respostas

O estudo de caso trata do desastre natural ocorrido na regi??o serrana do Rio de Janeiro nos dias 11 e 12 de janeiro de 2011, considerado a maior cat??strofe clim??tica e geot??cnica do pa??s, causado por fortes chuvas que provocaram enchentes e deslizamentos em sete munic??pios. O caso tem por finalidade despertar a discuss??o sobre as vari??veis e atores que influenciaram o processo de gest??o da crise, contextualizando o desastre no cen??rio da regi??o e reconstituindo, especialmente, o processo de resposta imediata dada ?? trag??dia pelos ??rg??os envolvidos. O estudo pode ser utilizado em cursos que abordem, entre outros, os seguintes t??picos: gest??o de crise e gest??o de riscos, negocia????o, comunica????o e planejamento estrat??gico

Passando do limite no ambiente de trabalho

Fernanda ?? servidora p??blica. Ap??s ter feito doutorado no exterior, retornou ao Brasil ??vida por aplicar seus novos conhecimentos em a????es desenvolvidas pelo minist??rio de origem. Contudo, seu novo superior imediato mostrou-se refrat??rio ?? servidora, demonstrando oposi????o sistem??tica e injustificada ??s suas ideias e ridicularizando-a em diversas oportunidades diante de seus pares e subordinados. As atribui????es de Fernanda foram paulatinamente retiradas, culminando na perda de seu cargo comissionado. A servidora tentou reagir, acionou o Departamento de Recursos Humanos do minist??rio e outros ??rg??os, mas nada adiantou. Fernanda, ao final, tomou uma atitude desesperada. O caso trata de ass??dio moral e de como tal situa????o se desenvolve dentro de um ??rg??o p??blico, sem que outros servidores e as unidades do ??rg??o se envolvam na quest??o. Ao final da narrativa, h?? quest??es para discuss??o que focam o ass??dio moral e seus desdobramentos

Necessidades de informa????o e compet??ncias informacionais no setor p??blico: um estudo de caso

O texto apresenta parte do referencial te??rico de pesquisa de doutorado, que buscou estabelecer rela????es te??ricas e pr??ticas entre as necessidades de informa????o de uma determinada atividade e as compet??ncias informacionais desenvolvidas para atend??-las. A premissa da pesquisa foi que a atividade estudada, a supervis??o indireta de institui????es financeiras, era intensiva em informa????o e poderia ser estudada como atividade informacional, a partir do uso de par??metros informacionais. Os par??metros utilizados nos modelos te??ricos foram o ciclo e a tecnologia da informa????o e os contextos de comunica????o da informa????o. A pesquisa emp??rica se iniciou com a identifica????o dos fatores cr??ticos de sucesso da atividade, visando a posterior mapeamento das necessidades de informa????o e das compet??ncias dos profissionais supervisores. Os resultados obtidos e sua an??lise permitiram relacionar os fatores cr??ticos de sucesso da atividade ??s necessidades de informa????o dos profissionais de supervis??o indireta e ??s suas compet??ncias informacionais.

Elites estatais e reforma do estado na nova rep??blica: o projeto Enap e a forma????o da carreira de gestor governamental no Brasil

Os objetos desta pesquisa s??o: 1) a atua????o das elites burocr??ticas do Poder Executivo Federal no processo de transi????o pol??tica no Brasil, nos anos 1980; 2) as frentes de reforma na Nova Rep??blica, nas ??reas social, econ??mica e administrativa e 3) as tentativas de renova????o da gest??o p??blica representadas pela cria????o da Escola Nacional de Administra????o P??blica (ENAP) e da Carreira de Gestor Governamental (EPPGG). Esse era um contexto de reinstitucionaliza????o da fun????o diretiva do Estado e de deslocamento das fronteiras entre o burocr??tico e o pol??tico no setor p??blico brasileiro. A hip??tese central aqui defendida ?? de que a ENAP e a Carreira de Gestor Governamental eram duas op????es inovadoras frente ao dilema sobre quais seriam os pap??is cab??veis a pol??ticos e administradores na nova ordem democr??tica, mas tamb??m eram op????es sem enraizamento nos pactos e agendas de prioridades que viabilizaram a mudan??a de regime no pa??s. A Escola e a Carreira estavam em disson??ncia com as principais tend??ncias de recomposi????o das elites estatais na transi????o a partir do regime militar e sofreram bloqueios em raz??o disso, mas a pesquisa procurou desconstruir algumas narrativas sobre esses conflitos interburocr??ticos, que associam as resist??ncias impostas ?? ENAP e ?? Carreira pelos grupos de funcion??rios da Fazenda e Planejamento a interesses meramente corporativistas. Com um trajeto pelos estudos sobre as burocracias dos regimes militares e sobre as transi????es no Brasil e na Am??rica Latina, buscou-se aqui uma melhor identifica????o dos grupos integrantes das ???tecnoburocracias??? e de suas contribui????es para a moderniza????o administrativa e econ??mica do pa??s, na segunda metade do s??culo XX. Buscou-se revelar algumas conflu??ncias entre as ideias de tecnocratiza????o e profissionaliza????o das altas fun????es p??blicas e seus elos com as aspira????es pela reconstru????o do Estado sob bases mais democr??ticas, mostrando que, nos anos 1980, as propostas da SEDAP n??o eram os ??nicos projetos de moderniza????o em curso, tampouco os grupos que a elas se opuseram representavam interesses univocamente antidemocr??ticos.

Pais adolescentes : vivência e significação

Foram investigadas mudanças ocorridas na vida de pais adolescentes e identificados os significados da paternidade e da maternidade para esses jovens. Oito participantes com idades de 16 a 21 anos foram entrevistados com base em roteiro focalizando: mudanças decorrentes da paternidade; significados da paternidade e da maternidade; práticas parentais. Entre as mudanças referidas destacaram-se a perda de liberdade e a inserção no mercado de trabalho. Para eles ser pai significa, principalmente, trabalhar para prover as necessidades da criança e também educar, dar carinho e atenção. A mãe é aquela que cuida e dá carinho, sacrifica-se e é a figura mais importante na vida da criança. As práticas parentais mais mencionadas estavam relacionadas com lazer e brincadeiras. Os dados indicaram a permanência de forte vínculo com os modelos tradicionais de parentalidade, embora tenham mostrado também a emergência de relações afetivas significativas entre pais e filhos.

O diagnóstico da linguagem e a linguagem do diagnóstico : uma perspectiva pragmática

A teoria dos atos de fala, de John Austin, apresenta a linguagem a partir de uma perspectiva pragmática, ou seja, quando os signos têm um compromisso com a produção de realidades, de mundo e de sujeitos. A linguagem possui – nessa perspectiva – força de criação. Em sintonia com os estudos da pragmática da linguagem, defenderemos a ideia que uma classificação não é mera descrição neutra acerca dos fatos, e Ian Hacking será a ponte entre a linguagem (enquanto fonte de produção de mundo) e as classificações (como produtoras de sujeitos). Para esse autor, as classificações tanto transformam quanto são transformadas. Elas, de diversas formas, interagem entre si, com os sujeitos, com as instituições, com os saberes, enfim, com tudo aquilo a que faz referência. A partir de uma revisão, análise e composição bibliográfica, o trabalho se dedicará a produzir um elo entre a problemática da linguagem-ato, tal como postulada por John Austin, e o caráter produtor de realidade das classificações. Dentre as classificações, daremos importância particular ao diagnóstico (enquanto uma espécie de estudo de caso na teoria dos enunciados) e seus efeitos pragmáticos, a partir dos elementos que lhe dão força de eficácia e existência em nosso mundo contemporâneo, tendo em vista o aumento do número e da proliferação de categorias nosológicas no corpo social. Trataremos, em particular, as classificações da medicina psiquiátrica. Abordaremos, por um lado, as condições que contribuem na emergência e na potência de um diagnóstico e, por outro, seus efeitos. Dentre os efeitos que daremos importância, encontramos a formação de novos sujeitos e modos de vida. Sendo assim, tanto as condições de eficácia de um enunciado quanto seus efeitos são estendidos à noção de diagnóstico enquanto uma classificação numa condição sociohistórica particular.