Biasing reaction pathways with mechanical force

During the course of chemical reactions, reactant molecules need to surmount an energy barrier to allow their transformation into products. The energy needed for this process is usually provided by heat, light, pressure or electrical potential, which act either by changing the distribution of the reactants on their ground-state potential energy surface or by moving them onto an excited-state potential energy surface and thereby facilitate movement over the energy barrier. A fundamentally different way of initiating or accelerating a reaction is the use of force to deform reacting molecules along a specific direction of the reaction coordinate. Mechanical force has indeed been shown to activate covalent bonds in polymers, but the usual result is chain scission. Here we show that mechanically sensitive chemical groups make it possible to harness the mechanical forces generated when exposing polymer solutions to ultrasound, and that this allows us to accelerate rearrangement reactions and bias reaction pathways to yield products not obtainable from purely thermal or light-induced reactions. We find that when placed within long polymer strands, the trans and cis isomers of a 1,2-disubstituted benzocyclobutene undergo an ultrasound-induced electrocyclic ring opening in a formally conrotatory and formally disrotatory process, respectively, that yield identical products. This contrasts with reaction initiation by light or heat alone, in which case the isomers follow mutually exclusive pathways to different products. Mechanical forces associated with ultrasound can thus clearly alter the shape of potential energy surfaces so that otherwise forbidden or slow processes proceed under mild conditions, with the directionally specific nature of mechanical forces providing a reaction control that is fundamentally different from that achieved by adjusting chemical or physical parameters. Because rearrangement in our system occurs before chain scission, the effect we describe might allow the development of materials that are activated by mechanical stress fields.     

The sources of sodium escaping from Io revealed by spectral high definition imaging

On Jupiter's moon Io, volcanic plumes and evaporating lava flows provide hot gases to form an atmosphere that is subsequently ionized. Some of Io's plasma is captured by the planet's strong magnetic field to form a co-rotating torus at Io's distance; the remaining ions and electrons form Io's ionosphere. The torus and ionosphere are also depleted by three time-variable processes that produce a banana-shaped cloud orbiting with Io, a giant nebula extending out to about 500 Jupiter radii, and a jet close to Io. No spatial constraints exist for the sources of the first two; they have been inferred only from modelling the patterns seen in the trace gas sodium observed far from Io. Here we report observations that reveal a spatially confined stream that ejects sodium only from the wake of the Io-torus interaction, together with a visually distinct, spherically symmetrical outflow region arising from atmospheric sputtering. The spatial extent of the ionospheric wake that feeds the stream is more than twice that observed by the Galileo spacecraft and modelled successfully. This implies considerable variability, and therefore the need for additional modelling of volcanically-driven, episodic states of the great jovian nebula.     

Increased forest ecosystem carbon and nitrogen storage from nitrogen rich bedrock

Nitrogen (N) limits the productivity of many ecosystems worldwide, thereby restricting the ability of terrestrial ecosystems to offset the effects of rising atmospheric CO(2) emissions naturally. Understanding input pathways of bioavailable N is therefore paramount for predicting carbon (C) storage on land, particularly in temperate and boreal forests. Paradigms of nutrient cycling and limitation posit that new N enters terrestrial ecosystems solely from the atmosphere. Here we show that bedrock comprises a hitherto overlooked source of ecologically available N to forests. We report that the N content of soils and forest foliage on N-rich metasedimentary rocks (350-950?mg?N?kg(-1)) is elevated by more than 50% compared with similar temperate forest sites underlain by N-poor igneous parent material (30-70?mg?N?kg(-1)). Natural abundance N isotopes attribute this difference to rock-derived N: (15)N/(14)N values for rock, soils and plants are indistinguishable in sites underlain by N-rich lithology, in marked contrast to sites on N-poor substrates. Furthermore, forests associated with N-rich parent material contain on average 42% more carbon in above-ground tree biomass and 60% more carbon in the upper 30?cm of the soil than similar sites underlain by N-poor rocks. Our results raise the possibility that bedrock N input may represent an important and overlooked component of ecosystem N and C cycling elsewhere.     

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.     

Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site

Common fragile sites have long been identified by cytogeneticists as chromosomal regions prone to breakage upon replication stress. They are increasingly recognized to be preferential targets for oncogene-induced DNA damage in pre-neoplastic lesions and hotspots for chromosomal rearrangements in various cancers. Common fragile site instability was attributed to the fact that they contain sequences prone to form secondary structures that may impair replication fork movement, possibly leading to fork collapse resulting in DNA breaks. Here we show, in contrast to this view, that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kilobases, which forces forks coming from flanking regions to cover long distances in order to complete replication. We also show that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability we observed. Thus, we propose that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates.