Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.     

Overcoming lability of extremely long alkane carbon-carbon bonds through dispersion forces

Steric effects in chemistry are a consequence of the space required to accommodate the atoms and groups within a molecule, and are often thought to be dominated by repulsive forces arising from overlapping electron densities (Pauli repulsion). An appreciation of attractive interactions such as van der Waals forces (which include London dispersion forces) is necessary to understand chemical bonding and reactivity fully. This is evident from, for example, the strongly debated origin of the higher stability of branched alkanes relative to linear alkanes and the possibility of constructing hydrocarbons with extraordinarily long C-C single bonds through steric crowding. Although empirical bond distance/bond strength relationships have been established for C-C bonds (longer C-C bonds have smaller bond dissociation energies), these have no present theoretical basis. Nevertheless, these empirical considerations are fundamental to structural and energetic evaluations in chemistry, as summarized by Pauling as early as 1960 and confirmed more recently. Here we report the preparation of hydrocarbons with extremely long C-C bonds (up to 1.704??), the longest such bonds observed so far in alkanes. The prepared compounds are unexpectedly stable--noticeable decomposition occurs only above 200?°C. We prepared the alkanes by coupling nanometre-sized, diamond-like, highly rigid structures known as diamondoids. The extraordinary stability of the coupling products is due to overall attractive dispersion interactions between the intramolecular H???H contact surfaces, as is evident from density functional theory computations with and without inclusion of dispersion corrections.     

A disinhibitory microcircuit for associative fear learning in the auditory cortex

Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits.     

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules.     

Aerobic bacterial pyrite oxidation and acid rock drainage during the Great Oxidation Event

The enrichment of redox-sensitive trace metals in ancient marine sedimentary rocks has been used to determine the timing of the oxidation of the Earth's land surface. Chromium (Cr) is among the emerging proxies for tracking the effects of atmospheric oxygenation on continental weathering; this is because its supply to the oceans is dominated by terrestrial processes that can be recorded in the Cr isotope composition of Precambrian iron formations. However, the factors controlling past and present seawater Cr isotope composition are poorly understood. Here we provide an independent and complementary record of marine Cr supply, in the form of Cr concentrations and authigenic enrichment in iron-rich sedimentary rocks. Our data suggest that Cr was largely immobile on land until around 2.48?Gyr ago, but within the 160?Myr that followed--and synchronous with independent evidence for oxygenation associated with the Great Oxidation Event (see, for example, refs 4-6)--marked excursions in Cr content and Cr/Ti ratios indicate that Cr was solubilized at a scale unrivalled in history. As Cr isotope fractionations at that time were muted, Cr must have been mobilized predominantly in reduced, Cr(III), form. We demonstrate that only the oxidation of an abundant and previously stable crustal pyrite reservoir by aerobic-respiring, chemolithoautotrophic bacteria could have generated the degree of acidity required to solubilize Cr(III) from ultramafic source rocks and residual soils. This profound shift in weathering regimes beginning at 2.48?Gyr ago constitutes the earliest known geochemical evidence for acidophilic aerobes and the resulting acid rock drainage, and accounts for independent evidence of an increased supply of dissolved sulphate and sulphide-hosted trace elements to the oceans around that time. Our model adds to amassing evidence that the Archaean-Palaeoproterozoic boundary was marked by a substantial shift in terrestrial geochemistry and biology.     

The role of dyking and fault control in the rapid onset of eruption at Chaitén volcano, Chile

Rhyolite is the most viscous of liquid magmas, so it was surprising that on 2?May 2008 at Chaitén Volcano, located in Chile's southern Andean volcanic zone, rhyolitic magma migrated from more than 5?km depth in less than 4?hours (ref.?1) and erupted explosively with only two days of detected precursory seismic activity. The last major rhyolite eruption before that at Chaitén was the largest volcanic eruption in the twentieth century, at Novarupta volcano, Alaska, in 1912. Because of the historically rare and explosive nature of rhyolite eruptions and because of the surprisingly short warning before the eruption of the Chaitén volcano, any information about the workings of the magmatic system at Chaitén, and rhyolitic systems in general, is important from both the scientific and hazard perspectives. Here we present surface deformation data related to the Chaitén eruption based on radar interferometry observations from the Japan Aerospace Exploration Agency (JAXA) DAICHI (ALOS) satellite. The data on this explosive rhyolite eruption indicate that the rapid ascent of rhyolite occurred through dyking and that melt segregation and magma storage were controlled by existing faults.     

Experimental infection of bats with Geomyces destructans causes white-nose syndrome

White-nose syndrome (WNS) has caused recent catastrophic declines among multiple species of bats in eastern North America. The disease's name derives from a visually apparent white growth of the newly discovered fungus Geomyces destructans on the skin (including the muzzle) of hibernating bats. Colonization of skin by this fungus is associated with characteristic cutaneous lesions that are the only consistent pathological finding related to WNS. However, the role of G. destructans in WNS remains controversial because evidence to implicate the fungus as the primary cause of this disease is lacking. The debate is fuelled, in part, by the assumption that fungal infections in mammals are most commonly associated with immune system dysfunction. Additionally, the recent discovery that G. destructans commonly colonizes the skin of bats of Europe, where no unusual bat mortality events have been reported, has generated further speculation that the fungus is an opportunistic pathogen and that other unidentified factors are the primary cause of WNS. Here we demonstrate that exposure of healthy little brown bats (Myotis lucifugus) to pure cultures of G. destructans causes WNS. Live G. destructans was subsequently cultured from diseased bats, successfully fulfilling established criteria for the determination of G. destructans as a primary pathogen. We also confirmed that WNS can be transmitted from infected bats to healthy bats through direct contact. Our results provide the first direct evidence that G. destructans is the causal agent of WNS and that the recent emergence of WNS in North America may represent translocation of the fungus to a region with a naive population of animals. Demonstration of causality is an instrumental step in elucidating the pathogenesis and epidemiology of WNS and in guiding management actions to preserve bat populations against the novel threat posed by this devastating infectious disease.