Modest Attenuation of HIV-1 Vpu Alleles Derived from Elite Controller Plasma

In the absence of antiretroviral therapy, infection with human immunodeficiency virus type 1 (HIV-1) can typically not be controlled by the infected host and results in the development of acquired immunodeficiency. In rare cases, however, patients spontaneously control HIV-1 replication. Mechanisms by which such elite controllers (ECs) achieve control of HIV-1 replication include particularly efficient immune responses as well as reduced fitness of the specific virus strains. To address whether polymorphisms in the accessory HIV-1 protein Vpu are associated with EC status we functionally analyzed a panel of plasma-derived vpu alleles from 15 EC and 16 chronic progressor (CP) patients. Antagonism of the HIV particle release restriction by the intrinsic immunity factor CD317/tetherin was well conserved among EC and CP Vpu alleles, underscoring the selective advantage of this Vpu function in HIV-1 infected individuals. In contrast, interference with CD317/tetherin induced NF-κB activation was little conserved in both groups. EC Vpus more frequently displayed reduced ability to downregulate cell surface levels of CD4 and MHC class I (MHC-I) molecules as well as of the NK cell ligand NTB-A. Polymorphisms potentially associated with high affinity interactions of the inhibitory killer immunoglobulin-like receptor (KIR) KIR2DL2 were significantly enriched among EC Vpus but did not account for these functional differences. Together these results suggest that in a subgroup of EC patients, some Vpu functions are modestly reduced, possibly as a result of host selection

O Valor Percebido pelo Consumidor Brasileiro de Tênis para Corrida de Rua

The market related to the street races presents strong growth in Brazilian sports retail. In this market, running shoes stand out as one of the main products for this practice, being directly related health and runner performance. As creation of value for the consumer is an important measure to obtain competitive advantage, the aim of this study is empirically evaluate the Customer Perceived Value - CVP about running shoes. The research that has a quantitative approach, with application of an electronic questionnaire to 401 street runners. The data were analyzed by the Structural Equation Modeling (SEM) technique using the Partial Least Squares (PLS) method with software SmartPLS 3.0. The results shows that the functional value of the product, emotional value and economic value are important and significant variables of CVP, wich doesn't occur with social value. This study presents a contribution to marketing literature searching for the understanding of Customer Perceived Value - CVP of running shoes.O mercado relacionado às corridas de rua apresenta forte crescimento no varejo esportivo brasileiro. Nesse mercado, se destaca o tênis de corrida como um dos principais produtos para essa prática, estando diretamente relacionado à saúde e desempenho do corredor. Como a criação de valor para o consumidor é uma importante medida para obtenção de vantagem competitiva o objetivo deste artigo é avaliar empiricamente o Valor Percebido pelo Consumidor (CPV) de tênis para corrida. A pesquisa possui uma abordagem quantitativa utilizando dados de um questionário eletrônico, sendo a amostra composta por 401 corredores de rua. Os dados foram analisados por meio da técnica de Modelagem de Equações Estruturais utilizando o método Partial Least Squares (PLS), com a utilização do software SmartPLS 3.0. Os resultados demonstram que o valor funcional do produto, valor emocional e valor econômico são importantes e significantes variáveis do CPV, o que não ocorre com o valor social. Assim, este estudo apresenta uma contribuição à literatura de marketing ao procurar compreender a construção do Valor Percebido pelo Consumidor - CVP de tênis para corrida de rua.  

Estigma e discriminação vividos na escola por crianças e jovens órfãos por Aids

The restriction of human rights is one of the most poignant features of the AIDS epidemics. Children and youngsters infected or otherwise affected by AIDS are particularly vulnerable to stigma in educational environments. The purpose of this article is to analyze episodes of stigma and discrimination related to HIV/AIDS at school. Integrated to a demographic study, an in-depth analysis was made of seven interviews conducted with pedagogical coordinators from six public and private schools of early childhood and fundamental education in the city of São Paulo. The majority of episodes of stigma experienced by children and youngsters within schools took place in circumstances of dating/sexuality, conflict with schoolmates, learning difficulties, disclosure of orphanhood by AIDS, and interaction between teachers and pupils with HIV, with the most frequently mentioned causes being: being HIV-positive, coming from a "dysfunctional family", and inequality in gender roles, age, and social class. Homophobia and racism were pointed out as stigma reinforcements. Descriptions were made of institutional responses to the AIDS stigma and of practices of prevention against STDs/AIDS. The episodes indicate the extent to which the stigma and discrimination related to HIV/AIDS can aggravate the social inequality already present within the sphere of education, obstructing the youngsters' rights to education, to family life, to leisure, to privacy, to secrecy/confidentiality, and to a love life. Such episodes also reveal the lack of prevention programs in the schools visited, and the difficulty of dealing with other forms of stigma (such as racism and the stigma of poverty).A restrição de direitos humanos é uma das características mais marcantes da epidemia da Aids. Crianças e jovens infectados ou afetados pela Aids são particularmente vulneráveis a sofrer estigma em ambientes educacionais. O objetivo deste artigo foi analisar episódios de estigma e discriminação relacionados ao HIV/Aids na escola. Integradas a um estudo de base populacional, foram analisadas sete entrevistas em profundidade com coordenadores pedagógicos de seis escolas públicas e privadas, de ensino infantil e fundamental, na cidade de São Paulo. A maioria dos episódios de estigma vividos por crianças e jovens no âmbito escolar ocorreu em circunstâncias de namoro/sexualidade, conflito com colegas, dificuldade de aprendizagem, revelação da orfandade por Aids, interação entre professores e alunos com HIV, sendo as causas mais frequentemente atribuídas: ter HIV, ser proveniente de "família desestruturada", desigualdade nos papéis de gênero, idade e classe social. Homofobia e racismo foram indicados como reforçadores do estigma. Foram descritas respostas institucionais ao estigma da Aids e práticas de atividades de prevenção às DST/Aids. Os episódios indicam o quanto o estigma e a discriminação relacionados ao HIV/Aids podem aprofundar uma desigualdade social já instalada no âmbito da educação, constituindo obstáculos ao direito à educação, à convivência familiar, ao lazer, à privacidade, ao sigilo/confidencialidade e à vida afetiva dos jovens. Por outro lado, tais episódios também expressam a ausência de programas de prevenção nas escolas visitadas e a dificuldade de abordar outras modalidades de estigma (tais como racismo e estigma da pobreza)

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

RhoA GTPase inhibition organizes contraction during epithelial morphogenesis

During morphogenesis, contraction of the actomyosin cytoskeleton within individual cells drives cell shape changes that fold tissues. Coordination of cytoskeletal contractility is mediated by regulating RhoA GTPase activity. Guanine nucleotide exchange factors (GEFs) activate and GTPase-activating proteins (GAPs) inhibit RhoA activity. Most studies of tissue folding, including apical constriction, have focused on how RhoA is activated by GEFs to promote cell contractility, with little investigation as to how GAPs may be important. Here, we identify a critical role for a RhoA GAP, Cumberland GAP (C-GAP), which coordinates with a RhoA GEF, RhoGEF2, to organize spatiotemporal contractility during Drosophila melanogaster apical constriction. C-GAP spatially restricts RhoA pathway activity to a central position in the apical cortex. RhoGEF2 pulses precede myosin, and C-GAP is required for pulsation, suggesting that contractile pulses result from RhoA activity cycling. Finally, C-GAP expression level influences the transition from reversible to irreversible cell shape change, which defines the onset of tissue shape change. Our data demonstrate that RhoA activity cycling and modulating the ratio of RhoGEF2 to C-GAP are required for tissue folding.American Cancer Society (125792-RSG-14-039-01-CSM

Reggie-1/flotillin-2 promotes secretion of the long-range signalling forms of Wingless and Hedgehog in Drosophila

The lipid-modified morphogens Wnt and Hedgehog diffuse poorly in isolation yet can spread over long distances in vivo, predicting existence of two distinct forms of these mophogens. The first is poorly mobile and activates short-range target genes. The second is specifically packed for efficient spreading to induce long-range targets. Subcellular mechanisms involved in the discriminative secretion of these two forms remain elusive. Wnt and Hedgehog can associate with membrane microdomains, but the function of this association was unknown. Here we show that a major protein component of membrane microdomains, reggie-1/flotillin-2, plays important roles in secretion and spreading of Wnt and Hedgehog in Drosophila. Reggie-1 loss-of-function results in reduced spreading of the morphogens, while its overexpression stimulates secretion of Wnt and Hedgehog and expands their diffusion. The resulting changes in the morphogen gradients differently affect the short- and long-range targets. In its action reggie-1 appears specific for Wnt and Hedgehog. These data suggest that reggie-1 is an important component of the Wnt and Hedgehog secretion pathway dedicated to formation of the mobile pool of these morphogens

A MILI-independent piRNA biogenesis pathway empowers partial germline reprogramming.

In mice, the pathway involving PIWI and PIWI-interacting RNA (PIWI-piRNA) is essential to re-establish transposon silencing during male-germline reprogramming. The cytoplasmic PIWI protein MILI mediates piRNA-guided transposon RNA cleavage as well as piRNA amplification. MIWI2's binding to piRNA and its nuclear localization are proposed to be dependent upon MILI function. Here, we demonstrate the existence of a piRNA biogenesis pathway that sustains partial MIWI2 function and reprogramming activity in the absence of MILI

Circadian variation in acute myocardial infarct size assessed by cardiovascular magnetic resonance in reperfused STEMI patients.

Clinical studies using serum cardiac biomarkers to investigate a circadian variation in acute myocardial infarct (MI) size in ST-segment elevation myocardial infarction (STEMI) patients reperfused by primary percutaneous coronary intervention (PPCI) have produced mixed results. We aimed to investigate this phenomenon using acute MI size measured by cardiovascular magnetic resonance (CMR).This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.Published (Open Access