Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.

Metabolic reprogramming is an important driver of tumor progression; however, the metabolic regulators of tumor cell motility and metastasis are not understood. Here, we show that tumors maintain energy production under nutrient deprivation through the function of HSP90 chaperones compartmentalized in mitochondria. Using cancer cell lines, we found that mitochondrial HSP90 proteins, including tumor necrosis factor receptor-associated protein-1 (TRAP-1), dampen the activation of the nutrient-sensing AMPK and its substrate UNC-51-like kinase (ULK1), preserve cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from inhibition by the autophagy initiator FIP200. In turn, this results in enhanced tumor cell invasion in low nutrients and metastatic dissemination to bone or liver in disease models in mice. Moreover, we found that phosphorylated ULK1 levels were correlated with shortened overall survival in patients with non-small cell lung cancer. These results demonstrate that mitochondrial HSP90 chaperones, including TRAP-1, overcome metabolic stress and promote tumor cell metastasis by limiting the activation of the nutrient sensor AMPK and preventing autophagy.

Metastatic traits appear to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor microRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non-small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a "stemness" transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor-like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer

About 3ieThe International Initiative for Impact Evaluation (3ie) promotes evidence-informed equitable, inclusive and sustainable development. We support the generation and effective use of high-quality evidence to inform decision-making and improve the lives of people living in poverty in low-and middle-income countries. We provide guidance and support to produce, synthesise and quality assure evidence of what works, for whom, how, why and at what cost. 3ie systematic reviews 3ie systematic reviews examine available high-quality evidence on the effects of social and economic development interventions in low-and middle-income countries. These reviews follow scientifically recognised review methods, and are peer reviewed and quality assured according to internationally accepted standards. 3ie is providing leadership in demonstrating rigorous review methodologies, such as using theory-based designs, for combining different types of evidence suited to respond to the complex and dynamic contexts and challenges of development. 3ie also publishes summary reports, based on the full reviews, that are designed for use by policymakers and programme managers.

Abstractobjective To understand factors that influence sustained adoption of water, sanitation and hygiene (WASH) technologies or behaviours.methods Systematic review of the current literature. Articles were gathered from databases of peerreviewed articles and grey literature, and screened for relevance. After exclusion, we created a descriptive map of 148 articles and analysed in-depth 44 articles that had an explicit focus on promoting or evaluating sustained adoption or programme sustainability. Twenty-two of these articles met our definition of measuring sustained adoption.results Definitions of sustained adoption varied widely and were often inadequate, making comparison of sustained adoption across studies difficult. The time frame for measurements of sustained adoption is frequently inadequate for examination of longer-term behaviour change.conclusions Ideally, an evaluation should specify the project period and describe the context surrounding adoption, make measurements at multiple time points, diversify measurement methods and describe and measure a range of factors affecting sustained adoption. Additional consideration needs to be given to developing behaviour change models that emphasise factors related to sustained adoption, and how they differ from those related to initial adoption.

Background There has been an exponential increase in the offering of short-term international field experiences in recent years in response to student demands for global health opportunities. Pre-departure preparation is an essential component to equip trainees with the adequate safety, wellness, and cultural competence needed to engage in a meaningful and mutually beneficial elective. This review seeks to quantify the plethora of pre-departure preparation training available to public health, clinical, and undergraduate trainees across the continuum of education for short-term experiences in low-and middle-income countries (LMICs). Methods We performed a systematic review of Pubmed, Embase, Web of Science, Scopus, and Ovid Global Health in February, 2018. A three-concept search was employed and included “global or international health”; “education or preparation of personnel/students”; and “field programs or travel.” The study teamed used PRISMA reporting guidelines to conduct title and full-text reviews and conduct data extraction and analysis. Results The search returned 2506 unique articles. Of these, 55 met inclusion criteria and were included in the final review. Ninety one percent (91%) of articles focused on pre-departure trainings for medical students and residents. Nine thematic domains for short-term international field experiences emerged; culture, safety, and project-specific knowledge were the most frequently covered domains while mentorship, professionalism, and emotional wellness and culture shock were least common. Approximately half (53.3%) of studies specifically evaluated the pre-departure component of the international experience using a survey or evaluation form. Recommendations emerged from these evaluations including early engagement with international partners, inclusion of self-reflection exercises and site-specific content, and utilization of interactive approaches in learning. Some institutions face barriers to conducting pre-departure preparation such as lack of dedicated faculty, finances, and institutional support. Conclusions Interest in pre-departure training for international experiences is growing but few programs conduct and publish evaluations of these trainings. Pre-departure trainings should be developed in partnership with receiving institutions and faculty and incorporate critical self- reflection throughout the experience. In addition to the experience itself, institutions need to evaluate these curricula to better understand how they influence trainees’ capacity to effectively engage in LMIC settings. Electronic supplementary material The online version of this article (10.1186/s12909-019-1586-y) contains supplementary material, which is available to authorized users.

Background: Signals originated from mitochondria can affect other intracellular compartments. Results: Decreased levels in mitochondrial cyclophilin D promote cell proliferation and cell motility via chemokine/STAT3 signaling. Conclusion: Mitochondria regulate nuclear gene expression. Significance: Interorganelle signaling affects cell proliferation and cell motility.

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