Lemmingherrera4049

The metabolic requirements of hematopoietic stem cells (HSCs) change with their cell cycle activity. However, the underlying role of mitochondria remains ill-defined. Here we found that, after mitochondrial activation with replication, HSCs irreversibly remodel the mitochondrial network and that this network is not repaired after HSC re-entry into quiescence, contrary to hematopoietic progenitors. HSCs keep and accumulate dysfunctional mitochondria through asymmetric segregation during active division. Mechanistically, mitochondria aggregate and depolarize after stress because of loss of activity of the mitochondrial fission regulator Drp1 onto mitochondria. Genetic and pharmacological studies indicate that inactivation of Drp1 causes loss of HSC regenerative potential while maintaining HSC quiescence. Molecularly, HSCs carrying dysfunctional mitochondria can re-enter quiescence but fail to synchronize the transcriptional control of core cell cycle and metabolic components in subsequent division. Thus, loss of fidelity of mitochondrial morphology and segregation is one type of HSC divisional memory and drives HSC attrition. Identification of clinically relevant drivers of breast cancers in intact mammary epithelium is critical for understanding tumorigenesis yet has proven challenging. Here, we show that intra-amniotic lentiviral injection can efficiently transduce progenitor cells of the adult mammary gland and use that as a platform to functionally screen over 500 genetic lesions for functional roles in tumor formation. Targeted progenitors establish long-term clones of both luminal and myoepithelial lineages in adult animals, and via lineage tracing with stable barcodes, we found that each mouse mammary gland is generated from a defined number of ∼120 early progenitor cells that expand uniformly with equal growth potential. We then designed an in vivo screen to test genetic interactions in breast cancer and identified candidates that drove not only tumor formation but also molecular subtypes. Thus, this methodology enables rapid and high-throughput cancer driver discovery in mammary epithelium. BACKGROUND Identifying modifiable risk factors is essential to reduce the prevalence adolescent depression. Self-report data suggest that physical activity and sedentary behaviour might be associated with depressive symptoms in adolescents. We examined associations between depressive symptoms and objectively measured physical activity and sedentary behaviour in adolescents. METHODS From a population-based cohort of adolescents whose mothers were invited to participate in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, we included participants with at least one accelerometer recording and a Clinical Interview Schedule-Revised (CIS-R) depression score at age 17·8 years (reported as age 18 years hereafter). Amounts of time spent in sedentary behaviour and physical activity (light or moderate-to-vigorous) were measured with accelerometers at around 12 years, 14 years, and 16 years of age. Total physical activity was also recorded as count per minute (CPM), with raw accelerometer counts averageour displaces light activity throughout adolescence, and is associated with a greater risk of depressive symptoms at 18 years of age. Increasing light activity and decreasing sedentary behaviour during adolescence could be an important target for public health interventions aimed at reducing the prevalence of depression. FUNDING Details of funding are provided in the Acknowledgments. Ebola virus disease is a severe health problem in Africa. Vaccines that display the Zaire ebolavirus glycoprotein spike complex are a prime component for the effort to combat it. The VH3-15/Vλ1-40-based class of antibodies was recently discovered to be a common response in individuals who received the Ebola virus vaccines. Givinostat mw These antibodies display attractive properties, and thus likely contribute to the efficacy of the vaccines. Here, we use cryo-EM to elucidate how three VH3-15/Vλ1-40 antibodies from different individuals target the virus and found a convergent mechanism against a partially conserved site on the spike complex. Our study rationalizes the selection of the VH3-15/Vλ1-40 germline genes for specifically targeting this site and highlights Ebolavirus species-specific sequence divergences that may restrict breadth of VH3-15/Vλ1-40-based humoral response. The results from this study could help develop improved immunization schemes and further enable the design of immunogens that would be efficacious against a broader set of Ebolavirus species. The trinuclear ruthenium amine ruthenium red (RuR) inhibits diverse ion channels, including K2P potassium channels, TRPs, the calcium uniporter, CALHMs, ryanodine receptors, and Piezos. Despite this extraordinary array, there is limited information for how RuR engages targets. Here, using X-ray crystallographic and electrophysiological studies of an RuR-sensitive K2P, K2P2.1 (TREK-1) I110D, we show that RuR acts by binding an acidic residue pair comprising the "Keystone inhibitor site" under the K2P CAP domain archway above the channel pore. We further establish that Ru360, a dinuclear ruthenium amine not known to affect K2Ps, inhibits RuR-sensitive K2Ps using the same mechanism. Structural knowledge enabled a generalizable design strategy for creating K2P RuR "super-responders" having nanomolar sensitivity. Together, the data define a "finger in the dam" inhibition mechanism acting at a novel K2P inhibitor binding site. These findings highlight the polysite nature of K2P pharmacology and provide a new framework for K2P inhibitor development. Autophagy is a protective cellular mechanism in response to stress conditions. However, whether autophagy is required for maintenance of the alveolar epithelium is unknown. Here, we report that the loss of autophagy-related 5 (Atg5) in AT2 cells worsened bleomycin-induced lung injury. Mechanistically, during bleomycin injury, autophagy downregulated lipid metabolism but upregulated glucose metabolism in AT2 cells for alveolar repair. Chemical blockade of fatty acid synthesis promoted organoid growth of AT2 cells and counteracted the effects of autophagy loss on bleomycin injury. However, genetic loss of glucose transporter 1, interference with glycolysis, or interference with the pentose phosphate pathway reduced the proliferation of AT2 cells. Inhibition of glucose metabolism exacerbated the effects of bleomycin injury. Failure of autophagy generated additional hydrogen peroxide, which reduced AT2 cell proliferation. These data highlight an essential role for autophagy in reprogramming the metabolism of alveolar progenitor cells to meet energy needs for alveolar epithelial regeneration.