Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide

DNA-binding transcription factors (TFs) remain challenging to target with molecular probes. Many TFs function in part through interaction with Mediator, a 26-subunit complex that controls RNA polymerase II activity genome-wide. We sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterize a stapled peptide, with functional mimics of both p53 activation domains, that blocks p53-Mediator binding and selectively inhibits p53-dependent transcription in human cells; importantly, this &ldquo;bivalent&rdquo; peptide has negligible impact, genome-wide, on non-p53 target genes. Our proof-of-concept strategy circumvents the TF entirely and targets the TF-Mediator interface instead, with desired functional outcomes (i.e., selective inhibition of p53 activation). Furthermore, these results demonstrate that TF activation domains represent viable starting points for Mediator-targeting molecular probes, as an alternative to large compound libraries. Different TFs bind Mediator through different subunits, suggesting this strategy could be broadly applied to selectively alter gene expression programs. &nbsp;</p

Cross-Lineage Influenza B and Heterologous Influenza A Antibody Responses in Vaccinated Mice: Immunologic Interactions and B/Yamagata Dominance

The annually reformulated trivalent inactivated influenza vaccine (TIV) includes both influenza A/subtypes (H3N2 and H1N1) but only one of two influenza B/lineages (Yamagata or Victoria). In a recent series of clinical trials to evaluate prime-boost response across influenza B/lineages, influenza-naïve infants and toddlers originally primed with two doses of 2008–09 B/Yamagata-containing TIV were assessed after two doses of B/Victoria-containing TIV administered in the subsequent 2009–10 and 2010–11 seasons. In these children, the Victoria-containing vaccines strongly recalled antibody to the initiating B/Yamagata antigen but induced only low B/Victoria antibody responses. To further evaluate this unexpected pattern of cross-lineage vaccine responses, we conducted additional immunogenicity assessment in mice. In the current study, mice were primed with two doses of 2008–09 Yamagata-containing TIV and subsequently boosted with two doses of 2010–11 Victoria-containing TIV (Group-Yam/Vic). With the same vaccines, we also assessed the reverse order of two-dose Victoria followed by two-dose Yamagata immunization (Group-Vic/Yam). The Group-Yam/Vic mice showed strong homologous responses to Yamagata antigen. However, as previously reported in children, subsequent doses of Victoria antigen substantially boosted Yamagata but induced only low antibody response to the immunizing Victoria component. The reverse order of Group-Vic/Yam mice also showed low homologous responses to Victoria but subsequent heterologous immunization with even a single dose of Yamagata antigen induced substantial boost response to both lineages. For influenza A/H3N2, homologous responses were comparably robust for the differing TIV variants and even a single follow-up dose of the heterologous strain, regardless of vaccine sequence, substantially boosted antibody to both strains. For H1N1, two doses of 2008–09 seasonal antigen significantly blunted response to two doses of the 2010–11 pandemic H1N1 antigen. Immunologic interactions between influenza viruses considered antigenically distant and in particular the cross-lineage influenza B and dominant Yamagata boost responses we have observed in both human and animal studies warrant further evaluation

Adolescent pregnancies and girls' sexual and reproductive rights in the amazon basin of Ecuador: an analysis of providers' and policy makers' discourses

<p>Abstract</p> <p>Background</p> <p>Adolescent pregnancies are a common phenomenon that can have both positive and negative consequences. The rights framework allows us to explore adolescent pregnancies not just as isolated events, but in relation to girls' sexual and reproductive freedom and their entitlement to a system of health protection that includes both health services and the so called social determinants of health. The aim of this study was to explore policy makers' and service providers' discourses concerning adolescent pregnancies, and discuss the consequences that those discourses have for the exercise of girls' sexual and reproductive rights' in the province of Orellana, located in the amazon basin of Ecuador.</p> <p>Methods</p> <p>We held six focus-group discussions and eleven in-depth interviews with 41 Orellana's service providers and policy makers. Interviews were transcribed and analyzed using discourse analysis, specifically looking for interpretative repertoires.</p> <p>Results</p> <p>Four interpretative repertoires emerged from the interviews. The first repertoire identified was "sex is not for fun" and reflected a moralistic construction of girls' sexual and reproductive health that emphasized abstinence, and sent contradictory messages regarding contraceptive use. The second repertoire -"gendered sexuality and parenthood"-constructed women as sexually uninterested and responsible mothers, while men were constructed as sexually driven and unreliable. The third repertoire was "professionalizing adolescent pregnancies" and lead to patronizing attitudes towards adolescents and disregard of the importance of non-medical expertise. The final repertoire -"idealization of traditional family"-constructed family as the proper space for the raising of adolescents while at the same time acknowledging that sexual abuse and violence within families was common.</p> <p>Conclusions</p> <p>Providers' and policy makers' repertoires determined the areas that the array of sexual and reproductive health services should include, leaving out the ones more prone to cause conflict and opposition, such as gender equality, abortion provision and welfare services for pregnant adolescents. Moralistic attitudes and sexism were present - even if divergences were also found-, limiting services' capability to promote girls' sexual and reproductive health and rights.</p

Caracterização da queixa escolar no Centro de Psicologia Aplicada da Universidade Federal de Juiz de Fora

A queixa escolar vem se constituindo, historicamente, como um dos motivos mais frequentes de encaminhamentos de crianças para os serviços-escola de Psicologia, traduzindo, pela sua complexidade, um desafio para a formação e práticas no âmbito da psicologia escolar/educacional. Diante da necessidade de aperfeiçoar o atendimento à clientela e o processo de triagem, o presente estudo objetivou analisar os prontuários referentes à queixa escolar de pacientes atendidos no Centro de Psicologia Aplicada da Universidade Federal de Juiz de Fora, Minas Gerais, Brasil, num total de 1.590 documentos, no período de 1996 a 2009. Os resultados quanto à clientela evidenciaram a prevalência de meninos na faixa entre 9 e 13 anos de idade, com predomínio de encaminhamentos oriundos de escolas de periférias da cidade. Quanto à queixa, constatou-se expressiva coocorrência de problemas comportamentais e de aprendizagem. Os dados permitem uma reflexão crítica acerca da queixa escolar e de alguns fatores contextuais, bem como a necessidade de aperfeiçoamento da ficha de triagem

Phytoplankton across Tropical and Subtropical Regions of the Atlantic, Indian and Pacific Oceans

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