Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8(+) T cell response.

Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8(+) T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3133-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2(+) TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2(+) TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs

Drug repurposing of quinine as antiviral against dengue virus infection

10.1016/j.virusres.2018.07.018Virus Research255171-178complete

Carrier Screening is a Deficient Strategy for Determining Sperm Donor Eligibility and Reducing Risk of Disease in Recipient Children

Aims: DNA-based carrier screening is a standard component of donor eligibility protocols practiced by U.S. sperm banks. Applicants who test positive for carrying a recessive disease mutation are typically disqualified. The aim of our study was to examine the utility of a range of screening panels adopted by the industry and the effectiveness of the screening paradigm in reducing a future child's risk of inheriting disease. Methods: A cohort of 27 donor applicants, who tested negative on an initial cystic fibrosis carrier test, was further screened with three expanded commercial carrier testing panels. These results were then compared to a systematic analysis of the applicants' DNA using next-generation sequencing (NGS) data. Results: The carrier panels detected serious pediatric disease mutations in one, four, or six donor applicants. Because each panel screens distinct regions of the genome, no single donor was uniformly identified as carrier positive by all three panels. In contrast, systematic NGS analysis identified all donors as carriers of one or more mutations associated with severe monogenic pediatric disease. These included 30 variants classified as “pathogenic” based on clinical observation and 66 with a high likelihood of causing gene dysfunction. Conclusion: Despite tremendous advances in variant identification, understanding, and analysis, the vast majority of disease-causing mutation combinations remain undetected by commercial carrier screening panels, which cover a narrow, and often distinct, subset of genes and mutations. The biological reality is that all donors and recipients carry serious recessive disease mutations. This challenges the utility of any screening protocol that anchors donor eligibility to carrier status. A more effective approach to reducing recessive disease risk would consider joint comprehensive analysis of both donor and recipient disease mutations. This type of high-resolution recessive disease risk analysis is now available and affordable, but industry practice must be modified to incorporate its use

Adaptação e avaliação de uma intervenção cognitivo-comportamental para meninos vítimas de violência sexual

Objetivou-se adaptar e avaliar um modelo de intervenção cognitivo-comportamental para meninos vítimas de Violência Sexual (VS), derivado de um modelo avaliado com meninas. A dissertação é composta por um artigo teórico sobre VS contra meninos, um capítulo que descreve o processo de adaptação do modelo, um relato de experiência sobre a produção e utilização de um documentário sobre VS contra meninos utilizado na aplicação do modelo adaptado e um artigo com os resultados dessa aplicação. Três meninos vítimas de VS com idades entre oito e 16 anos foram avaliados antes e após a intervenção por meio de instrumentos psicológicos quanto a sintomas comumente presentes em vítimas de VS. A aplicação do modelo adaptado foi avaliada por três juízes independentes por meio de seis indicadores. As avaliações sintomatológicas dos participantes e a da aplicação do modelo adaptado se constituem como evidências iniciais sobre sua ação terapêutica.This work aimed to adapt and assess a cognitive-behavioral intervention model for boys who are victims of sexual violence that was derived from a model that evaluated girls. The master thesis consists of a theoretical article about sexual violence against boys; a chapter describing the process of adapting the model; a report on the experience of producing and using the documentary about sexual violence against boys while applying the adapted model; and an article with the results from this application. Three boys between the ages of eight and 16 who had been victims of sexual violence were evaluated, through psychological instruments before and after the intervention, in terms of symptoms common to sexual violence victims. Three independent judges evaluated the application of the adapted model through six indicators. The evaluations of the participants’ symptoms as well as of the adapted model’s application provide initial proof of therapeutic effectiveness