Global S&T Development Trend Analysis Platform of Resources and Environment
Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)(1). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.
Ultrahot giant exoplanets receive thousands of times Earth'
Absorption lines of iron in the dayside atmosphere of an ultrahot giant exoplanet disappear after travelling across the nightside, showing that the iron has condensed during its travel.
Most magmatism occurring on Earth is conventionally attributed to passive mantle upwelling at mid-ocean ridges, to slab devolatilization at subduction zones, or to mantle plumes. However, the widespread Cenozoic intraplate volcanism in northeast China(1-3) and the young petit-spot volcanoes(4-7) offshore of the Japan Trench cannot readily be associated with any of these mechanisms. In addition, the mantle beneath these types of volcanism is characterized by zones of anomalously low seismic velocity above and below the transition zone(8-12) (a mantle level located at depths between 410 and 660 kilometres). A comprehensive interpretation of these phenomena is lacking. Here we show that most (or possibly all) of the intraplate and petit-spot volcanism and low-velocity zones around the Japanese subduction zone can be explained by the Cenozoic interaction of the subducting Pacific slab with a hydrous mantle transition zone. Numerical modelling indicates that 0.2 to 0.3 weight per cent of water dissolved in mantle minerals that are driven out from the transition zone in response to subduction and retreat of a tectonic plate is sufficient to reproduce the observations. This suggests that a critical amount of water may have accumulated in the transition zone around this subduction zone, as well as in others of the Tethyan tectonic belt(13) that are characterized by intraplate or petit-spot volcanism and low-velocity zones in the underlying mantle.
The widespread intraplate volcanism in northeast China and the unusual '
Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.
This Review examines inflammatory bowel disease in the context of human genetics studies that help to identify pathways that regulate homeostasis of the mucosal immune system and discusses future prospects for disease-subtype classification and therapeutic intervention.
Self-organized criticality is an elegant explanation of how complex structures emerge and persist throughout nature(1), and why such structures often exhibit similar scale-invariant properties(2-9). Although self-organized criticality is sometimes captured by simple models that feature a critical point as an attractor for the dynamics(10-15), the connection to real-world systems is exceptionally hard to test quantitatively(16-21). Here we observe three key signatures of self-organized criticality in the dynamics of a driven-dissipative gas of ultracold potassium atoms: self-organization to a stationary state that is largely independent of the initial conditions
A driven-dissipative gas of ultracold potassium atoms is used to demonstrate three key signatures of self-organized criticality, and provides a system in which the phenomenon can be experimentally tested.
