Search

In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit., Molecular heterogeneity of acute myeloid leukaemia (AML) across patients is a major challenge for prognosis and therapy. Here, the authors show that NPM1 mutated AML is a heterogeneous class, consisting of two subtypes which exhibit distinct molecular characteristics, differentiation state, patient survival and drug response.

Power system reliability is sensitive to climate-driven variations in both energy demand and water availability, yet the combined effect of these impacts is rarely evaluated. Here we show that combined climate change impacts on loads and hydropower generation may have a transformative effect on the nature and seasonality of power shortfall risk in the U.S. Pacific Northwest. Under climate change, potential shortfall events occur more readily, but are significantly less severe in nature. A seasonal reversal in shortfall risk occurs: winter shortfalls are eradicated due to reduced building heating demands, while summer shortfalls multiply as increased peak loads for day-time cooling coincide with impaired hydropower generation. Many of these summer shortfalls go unregistered when climate change impacts on loads and hydropower dispatch are analyzed in isolation—highlighting an important role of compound events., Climate change will affect both the demand for electrical power and the generating capabilities of hydropower plants. Here the authors investigated the combined impact of these effects in the US Pacific Northwest by considering the dynamics of the regional power grid, where they reveal a profound impact of climate change on power shortfall risk by the year 2035.

The hallmark of many bacterial infections is pain. The underlying mechanisms of pain during live pathogen invasion are not well understood. Here, we elucidate key molecular mechanisms of pain produced during live methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that spontaneous pain is dependent on the virulence determinant agr and bacterial pore-forming toxins (PFTs). The cation channel, TRPV1, mediated heat hyperalgesia as a distinct pain modality. Three classes of PFTs—alpha-hemolysin (Hla), phenol-soluble modulins (PSMs), and the leukocidin HlgAB—directly induced neuronal firing and produced spontaneous pain. From these mechanisms, we hypothesized that pores formed in neurons would allow entry of the membrane-impermeable sodium channel blocker QX-314 into nociceptors to silence pain during infection. QX-314 induced immediate and long-lasting blockade of pain caused by MRSA infection, significantly more than lidocaine or ibuprofen, two widely used clinical analgesic treatments., Bacterial infection can cause pain but the underlying mechanism is unclear. This study shows pain induced in mice by methicillin-resistant Staphylococcus aureus infection is mediated by bacterial pore-forming toxins, and a sodium channel blocker QX-314 can alleviate infection-associated pain.

Entangling a single spin to the polarization of a single incoming photon, generated by an external source, would open new paradigms in quantum optics such as delayed-photon entanglement, deterministic logic gates or fault-tolerant quantum computing. These perspectives rely on the possibility that a single spin induces a macroscopic rotation of a photon polarization. Such polarization rotations induced by single spins were recently observed, yet limited to a few 10−3 degrees due to poor spin–photon coupling. Here we report the enhancement by three orders of magnitude of the spin–photon interaction, using a cavity quantum electrodynamics device. A single hole spin in a semiconductor quantum dot is deterministically coupled to a micropillar cavity. The cavity-enhanced coupling between the incoming photons and the solid-state spin results in a polarization rotation by ±6° when the spin is optically initialized in the up or down state. These results open the way towards a spin-based quantum network., The recently observed rotation of a photon's polarization by interaction with a single solid state spin has potential implications in quantum computing. Here, Arnold et al. demonstrate enhanced spin–photon coupling and polarization rotation via a coupled quantum dot/micropillar cavity system.

We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6α-epoxy-cholesterol and histamine. Dendrogenin A was not detected in cancer cell lines and was fivefold lower in human breast tumours compared with normal tissues, suggesting a deregulation of dendrogenin A metabolism during carcinogenesis. We established that dendrogenin A is a selective inhibitor of cholesterol epoxide hydrolase and it triggered tumour re-differentiation and growth control in mice and improved animal survival. The properties of dendrogenin A and its decreased level in tumours suggest a physiological function in maintaining cell integrity and differentiation. The discovery of dendrogenin A reveals a new metabolic pathway at the crossroads of cholesterol and histamine metabolism and the existence of steroidal alkaloids in mammals., It has been hypothesized that the steroidal alkaloid dendrogenin A (DDA) is a natural metabolite. de Medina et al. show that DDA is produced in mammalian tissues from 5,6α-epoxy-cholesterol and histamine metabolism, and that the compound displays cell differentiation and anti-tumour activities.