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Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain poorly understood. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and non-apoptotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking impaired lysosomal acidification, mitochondrial malfunction and inflammation in vivo.

To mount a protective response to infection while preventing hyperinflammation, gene expression in innate immune cells must be tightly regulated. Despite the importance of pre-mRNA splicing in shaping the proteome, its role in balancing immune outcomes remains understudied. Transcriptomic analysis of murine macrophage cell lines identified Serine/Arginine Rich Splicing factor 6 (SRSF6) as a gatekeeper of mitochondrial homeostasis. SRSF6-dependent orchestration of mitochondrial health is directed in large part by alternative splicing of the pro-apoptosis pore-forming protein BAX. Loss of SRSF6 promotes accumulation of BAX-κ, a variant that sensitizes macrophages to undergo cell death and triggers upregulation of interferon stimulated genes through cGAS sensing of cytosolic mitochondrial DNA. Upon pathogen sensing, macrophages regulate SRSF6 expression to control the liberation of immunogenic mtDNA and adjust the threshold for entry into programmed cell death. This work defines BAX alternative splicing by SRSF6 as a critical node not only in mitochondrial homeostasis but also in the macrophage’s response to pathogens.

China's establishment of a Central National Security Commission (CNSC) in late 2013 was a potentially transformative event in the evolution of China's national security decision-making structure. Yet, as of mid-2017, few details about this organization and its activities have been released, leading to continuing questions about its likely role and functions in the Chinese system. Based on an analysis of numerous authoritative but under-utilized Chinese sources, this article addresses the rationale, prospects and implications of the CNSC. It argues that the organization is both a fulfilment of a long-held desire by many in China for a centralized, permanent national security deliberation forum and also a reflection of the unique challenges facing China in the 21st century. Contrary to existing analyses, which argue that the CNSC is likely to be focused primarily on domestic security tasks, the article contends that it is more likely to play a major role in both internal and external security affairs. Moreover, the article argues that if certain obstacles can be addressed, the CNSC may have broad implications in areas ranging from China's crisis response capability to the role played by the Chinese Communist Party general secretary in the national security decision-making process. The conclusion recaps the findings and suggests avenues for further research. 中国在 2013 年底设立的中央国家安全委员会 (简称为国安委) 成为了中国国家安全决策结构演变的潜在的改革性的时刻. 但是, 截至 2015 年后期, 中国公布了较少关于国安委的结构和行动的信息, 而引起了对于它在中国体系的作用和职能的持续问题. 这片文章采用了各种不常利用的权威性的研究资料而进行了对于国安委的意图, 前途, 和影响力的探索. 本篇文章认为国安委的成立不仅实现了建立一个固定的国家安全决策机构长期持有的期望, 也是中国在 21 世纪面临的独特挑战的反映。 现有研究分析认为国安委的主要任务集中在国内安全事务, 但本文章却认为组织更有可能发挥内部以及外部安全事务的重大作用. 此外, 文章认为, 如果某些障碍能取得解决, 国安委即可影响到各种各样的安全领域, 包括了中国的危机应对能力以及中共总书记在国家安全决策过程中的角色等领域. 结论重述结果和提出了进一步研究的领域。

A very good friend and one of the best H&N radiologists on the planet went online and purchased a package of faux ribbons of the highest order. If I'm brightly festooned, I must be sought after and of the highest value.

Three guests of disparate Southern backgrounds, DJ and producer Questlove, talk show host Dr. Phil, and journalist Charlayne Hunter-Gault, find astonishing tales of bondage in their family histories.

In an interview, Phillip C. Stone, president of Bridgewater College, talked about his career. Every organization seems to be a people organization no matter what you make or what service you perform. Management ultimately seems to come down to how you work with people, how you inspire people, and how you manage people. Certainly that is something that you have across the board in any industry. He thinks that first of all, colleges had to get leaner because of declining appropriations for public universities and the difficulties of getting and managing appropriate resources for the small universities. So he thinks that there has been a real focus on economies of scale, efficiencies, doing more consolidation of things, outsourcing, looking at all kinds of ways to work efficiently and use resources better -- that has certainly been one change. He believes a couple of things to be very important in managing and leading this organization.