P09-11. Reduced replication capacity of NL4-3 chimeric viruses encoding RT-Integrase sequences from HIV-1 elite controllers

Background: Spontaneous control of HIV to 0.05). Viruses derived from HLA-B57+ EC (N = 20) appeared to replicate slower than those from B57+ progressors (N = 8) (p = 0.004). Similar results were observed between B51+ EC (N = 4) and B51+ progressors (N = 10) (p = 0.024), but not between B27+ EC (N = 9) and B27+ progressors (N = 5) (p = 0.437). Conclusion: This study extends previous observations for Gag and demonstrates that Pol variants from EC also display reduced function. The association between fitness and expression of certain HLA that present Pol epitopes suggests that immune-mediated mutations impairing viral fitness may play a key role in spontaneous control of HIV. Results indicate that HLA alleles responsible for such defects in protein function may differ among viral genes. Further identification of HLA-associated changes in HIV may allow design of vaccines targeting the most vulnerable regions of the virus

Variation in HIV-1 Nef function within and among viral subtypes reveals genetically separable antagonism of SERINC3 and SERINC5

HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis

Selective high frequency mechanical actuation driven by the VO2 electronic instability

Micro- and nano-electromechanical resonators are a fundamental building block of modern technology, used in environmental monitoring, robotics, medical tools as well as fundamental science. These devices rely on dedicated electronics to generate their driving signal, resulting in an increased complexity and size. Here, we present a new paradigm to achieve high-frequency mechanical actuation based on the metal-insulator transition of VO$\mathrm{_2}$, where the steep variation of its electronic properties enables to realize high-frequency electrical oscillations. The dual nature of this phase change, which is both electronic and structural, turns the electrical oscillations into an intrinsic actuation mechanism, powered by a small DC voltage and capable to selectively excite the different mechanical modes of a microstructure. Our results pave the way towards the realization of micro- and nano-electro-mechanical systems with autonomous actuation from integrated DC power sources such as solar cells or micro-batteries.Comment: Main text: 6 pages, 4 figures Supplemental Material: 16 pages, 7 section

Augmentation of HIV-specific T cell function by immediate treatment of hyperacute HIV-1 infection

Sustained viremia after acute HIV infection is associated with profound CD4+ T cell loss and exhaustion of HIV-specific CD8+ T cell responses. To determine the impact of combination antiretroviral therapy (cART) on these processes, we examined the evolution of immune responses in acutely infected individuals initiating treatment before peak viremia. Immediate treatment of Fiebig stages I and II infection led to a rapid decline in viral load and diminished magnitude of HIV-specific (tetramer+) CD8+ T cell responses compared to untreated donors. There was a strong positive correlation between cumulative viral antigen exposure before full cART-induced suppression and immune responses measured by MHC class I tetramers, IFN-γ ELISPOT, and CD8+ T cell activation. HIV-specific CD8+ T responses of early treated individuals were characterized by increased CD127 and BCL-2 expression, greater in vitro IFN-γ secretion, and enhanced differentiation into effector memory (Tem) cells. Transcriptional analysis of tetramer+ CD8+ T cells from treated persons revealed reduced expression of genes associated with activation and apoptosis, with concurrent up-regulation of prosurvival genes including BCL-2, AXL, and SRC. Early treatment also resulted in robust HIV-specific CD4+ T cell responses compared to untreated HIV-infected individuals. Our data show that limiting acute viremia results in enhanced functionality of HIV-specific CD4+ and CD8+ T cells, preserving key antiviral properties of these cells

Applications and challenges of marker-assisted selection in the Western Australian Wheat Breeding Program

Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the beta1 subunit inhibit tumor growth and sensitize cells to irradiation or cytotoxic chemotherapy in preclinical breast cancer models and are under clinical investigation. We found that the loss of beta1 integrins attenuated breast tumor growth but markedly enhanced tumor cell dissemination to the lungs. When cultured in three-dimensional ECM scaffolds, antibodies that blocked beta1 integrin function or knockdown of beta1 switched the migratory behavior of human and mouse E-cadherin-positive triple-negative breast cancer (TNBC) cells from collective to single cell movement. This switch involved activation of the transforming growth factor-beta (TGFbeta) signaling network that led to a shift in the balance between miR-200 microRNAs and the transcription factor zinc finger E-box-binding homeobox 2 (ZEB2), resulting in suppressed transcription of the gene encoding E-cadherin. Reducing the abundance of a TGFbeta receptor, restoring the ZEB/miR-200 balance, or increasing the abundance of E-cadherin reestablished cohesion in beta1 integrin-deficient cells and reduced dissemination to the lungs without affecting growth of the primary tumor. These findings reveal that beta1 integrins control a signaling network that promotes an epithelial phenotype and suppresses dissemination and indicate that targeting beta1 integrins may have undesirable effects in TNBC

Children's active play: self-reported motivators, barriers and facilitators

Physical activity has important benefits for children's physical health and mental wellbeing, but many children do not meet recommended levels. Research suggests that active play has the potential to make a valuable contribution to children's overall physical activity, whilst providing additional cognitive, social and emotional benefits. However, relatively little is known about the determinants of UK children's active play. Understanding these factors provides the critical first step in developing interventions to increase children's active play, and therefore overall physical activity. Eleven focus groups were conducted with 77, 10-11 year old children from four primary schools in Bristol, UK. Focus groups examined: (i) factors which motivate children to take part in active play; (ii) factors which limit children's active play and (iii) factors which facilitate children's active play. All focus groups were audio-taped and transcribed verbatim. Data were analysed using a thematic approach. Children were motivated to engage in active play because they perceived it to be enjoyable, to prevent boredom, to have physical and mental health benefits and to provide freedom from adult control, rules and structure. However, children's active play was constrained by a number of factors, including rainy weather and fear of groups of teenagers in their play spaces. Some features of the physical environment facilitated children's active play, including the presence of green spaces and cul-de-sacs in the neighbourhood. Additionally, children's use of mobile phones when playing away from home was reported to help to alleviate parents' safety fears, and therefore assist children's active play. Children express a range of motivational and environmental factors that constrain and facilitate their active play. Consideration of these factors should improve effectiveness of interventions designed to increase active play