Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity

Semana de manifestações culturais: promovendo espaços de transformação

The event “Semana de Manifestações Culturais” (Week of Cultural Manifestations) is held annually by the project of Brazilian Dances and Rhythms of the University UNESP / Rio Claro. The merit of the project is diving in popular culture, going beyond the formal research. The energy that sustains our project comes from music and dance, elements that produce an immediate interaction with others, where learners also teaches, and vice versa. In our activities, we seek to remain true to the traditions, but also we enable new regards and languages, because culture has this aspect of freedom and creation. The Week of Cultural Events arose from the desire and need of the students to disclose, to a wider audience, the work done by the project throughout the year and deepen some discussions. This is attended by inviting guests involved in the subject, as masters of popular culture and researchers. The Week is always open to everyone interested. Each year, the week provides new knowledges and reflections, directly reaching between 100 and 200 people.A Semana de Manifestações Culturais é um evento realizado anualmente pelo Projeto de Extensão de Danças e Ritmos Brasileiros da UNESP/Rio Claro. O mérito do projeto é o mergulho na cultura popular, que ultrapassa a pesquisa formal. A energia que nos mantém vem da música e da dança, elementos que produzem uma imediata interação com o público, onde quem aprende também ensina, e vice-versa. Em nossas atividades, buscamos manter-nos fiéis às tradições, mas também possibilitamos novos olhares e linguagens, pois a cultura possui este aspecto de liberdade e recriação. A Semana de Manifestações Culturais surgiu do desejo e necessidade dos alunos em divulgar, para um público mais amplo, o trabalho realizado pelo projeto ao longo do ano e aprofundar algumas discussões, com a presença de convidados mais envolvidos no assunto, como mestres da cultura popular e pesquisadores do tema. A Semana é sempre aberta a todas as pessoas interessadas. A cada ano, a Semana proporciona novos conhecimentos e reflexões, atingindo diretamente entre 100 e 200 pessoas

Universal Dependencies 2.3

Universal Dependencies is a project that seeks to develop cross-linguistically consistent treebank annotation for many languages, with the goal of facilitating multilingual parser development, cross-lingual learning, and parsing research from a language typology perspective. The annotation scheme is based on (universal) Stanford dependencies (de Marneffe et al., 2006, 2008, 2014), Google universal part-of-speech tags (Petrov et al., 2012), and the Interset interlingua for morphosyntactic tagsets (Zeman, 2008)

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field