Inhibitors of the small membrane (M) protein viroporin prevent Zika virus infection.

Flaviviruses, including Zika virus (ZIKV), are a significant global health concern, yet no licensed antivirals exist to treat disease. The small Membrane (M) protein plays well-defined roles during viral egress and remains within virion membranes following release and maturation. However, it is unclear whether M plays a functional role in this setting. Here, we show that M forms oligomeric membrane-permeabilising channels in vitro, with increased activity at acidic pH and sensitivity to the prototypic channel-blocker, rimantadine. Accordingly, rimantadine blocked an early stage of ZIKV cell culture infection. Structure-based channel models, comprising hexameric arrangements of two trans-membrane domain protomers were shown to comprise more stable assemblages than other oligomers using molecular dynamics (MD) simulations. Models contained a predicted lumenal rimantadine binding site, as well as a second druggable target region on the membrane-exposed periphery. In silico screening enriched for repurposed drugs/compounds predicted to bind to either one site or the other. Hits displayed superior potency in vitro and in cell culture compared with rimantadine, with efficacy demonstrably linked to virion-resident channels. Finally, rimantadine effectively blocked ZIKV viraemia in preclinical models, supporting that M constitutes a physiologically relevant target. This could be explored by repurposing rimantadine, or development of new M-targeted-therapies.

Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages.

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.

PD-1 Limits IL-2 Production and Thymic Regulatory T Cell Development.

Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been studied extensively in peripheral T cell responses to foreign Ags, self-Ags, and neoantigens. Notably, these proteins are first expressed during T cell development in the thymus. Reports suggest that PD-1 limits regulatory T cell (Treg) development, but the mechanism by which PD-1 exerts this function remains unknown. The present study expands the evaluation of murine PD-1 and its ligands in the thymus, demonstrating that some of the highest expressers of PD-1 and programmed death-ligand 1 are agonist selected cells. Surprisingly, we reveal a selective role for PD-1 in regulating the developmental niche only for Tregs because other agonist selected cell populations, such as NK T cells, remain unchanged. We also ruled out PD-1 as a regulator of proliferation or cell death of agonist selected Tregs and further demonstrated that PD-1-deficient Tregs have reduced TCR signaling. Unexpectedly, the data suggest that PD-1-deficient thymocytes produce elevated levels of IL-2, a Treg niche-limiting cytokine. Collectively, these data suggest a novel role for PD-1 in regulating IL-2 production and the concurrent agonist selection of murine thymic Tregs. This observation has implications for the use of checkpoint blockade in the context of cancer and infection.

Mediating integration: latino immigrant organizations in greater Boston / Mediadores do processo de integração: organizações de imigrantes latinos na Grande Boston

In recent years scholars have debated the role of immigrant organizations in the processes of integration, political incorporation, and transnational activities (for example, Huntington 2004; Portes and Rumbault 2006; Bloemraad 2006; Portes, Escolar and Walton 2006). The current research adds to this discussion through a case study of selected immigrant organizations from Greater Boston’s largest Latino immigrant communities. Through qualitative interviews with leaders of immigrant organizations we found that connections and alliances matter for integration. Immigrant-led organizations are unique because of their leadership and proximity to the community. Even groups focused on cultural, religious, and transnational activities serve as informal mediators in the integration process. They provide practical information, support, and connections to mainstream society. Our findings inform how local governments can leverage the position of immigrant organiizations to build social and human capital in marginalized communities. Working with these informal networks allows the government to increase the efficiency and quality of its outreach to immigrants.(AU)

Nos últimos anos, estudiosos têm debatido o papel das organizações de imigrantes no processo de integração, incorporação política e transnacional (por exemplo, Huntington 2004; Portes e Rumbaut 2006; Bloemraad 2006; Portes, Escobar e Walton 2006). Este projeto acrescenta a esta discussão através de um estudo de caso focado num grupo de organizações das maiores comunidades imigrantes latinas da Grande Boston. Através de entrevistas qualitativas com líderes destas organizações; descobrimos que conexões e alianças são fundamentais no processo integração. Organizações de imigrantes têm caracteres únicos devido à sua liderança e proximidade com a comunidade. Mesmo os grupos focados em atividades culturais, religiosas e atividades transnacionais servem como mediadores informais no processo de integração. Eles fornecem informações práticas, apoio e ligações a sociedade mainstream. Os resultados da pesquisa em questão informam como governos locais podem alavancar o trabalho das organizações de imigrantes para construir capital social e humano nas comunidades marginalizadas. Trabalhar com essas redes informais permite ao governo aumentar a eficiência e a qualidade da sua atuação junto à populações imigrantes.(AU)