A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy-inducing peptide, Tat-Beclin 1, derived from the autophagy protein Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed "autosis," has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxia-ischemia in vivo. A chemical screen of ∼5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na

SUMMARY Elucidating the mechanism of reprogramming is confounded by heterogeneity due to the low efficiency and differential kinetics of obtaining induced pluripotent stem cells (iPSCs) from somatic cells. Therefore, we increased the efficiency with a combination of epigenomic modifiers and signaling molecules and profiled the transcriptomes of individual reprogramming cells. Contrary to the established temporal order, somatic gene inactivation and upregulation of cell cycle, epithelial, and early pluripotency genes can be triggered independently such that any combination of these events can occur in single cells. Sustained co-expression of Epcam, Nanog, and Sox2 with other genes is required to progress toward iPSCs. Ehf, Phlda2, and translation initiation factor Eif4a1 play functional roles in robust iPSC generation. Using regulatory network analysis, we identify a critical role for signaling inhibition by 2i in repressing somatic expression and synergy between the epigenomic modifiers ascorbic acid and a Dot1L inhibitor for pluripotency gene activation.

Abstract:The wireless motility capsule (WMC) is an ambulatory noninvasive and nonradioactive diagnostic sensor that continuously samples intraluminal pH, temperature, and pressure as it moves through the gastrointestinal (GI) tract. This review summarizes the data obtained in clinical trials with the WMC and discusses its role in clinical practice. The United States Food and Drug Administration has approved the SmartPill GI monitoring system for the evaluation of gastric emptying time in patients with suspected gastroparesis, the evaluation of colonic transit time in patients with suspected chronic constipation, and for the characterization of pressure profiles from the antrum and duodenum. Clinical studies have shown that WMC-measured GI transit times can distinguish patients with motility abnormalities similarly to conventional testing. However, the WMC offers the advantage of providing a full GI-tract profile, enabling the detection of multiregional GI transit abnormalities in patients with suspected upper or lower GI dysmotility. The WMC also characterizes pressure profiles of the GI tract and impaired pressure profile limits are reported for the antrum and duodenum. In comparison with manometry, interpretations of pressure measurements obtained by the WMC are limited by an inability to detect a peristaltic pressure wave front, and further investigation is required to develop clinical applications. Clinical studies with the WMC indicated that it should be considered for the evaluation of regional and whole gut transit time in patients with suspected upper or lower dysmotility, particularly if there are concerns about multiregional dysmotility.

The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity.DOI: http://dx.doi.org/10.7554/eLife.05920.001