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International audience; The environmental accumulation of polycyclic aromatic hydrocarbons (PAHs) is of great concern due to potential carcinogenic and mutagenic risks, as well as their resistance to remediation. While many fungi have been reported to break down PAHs in environments, the details of gene-based metabolic pathways are not yet comprehensively understood. Specifically, the genome-scale transcriptional responses of fungal PAH degradation have rarely been reported. In this study, we report the genomic and transcriptomic basis of PAH bioremediation by a potent fungal degrader, Dentipellis sp. KUC8613. The genome size of this fungus was 36.71 Mbp long encoding 14,320 putative protein-coding genes. The strain efficiently removed more than 90% of 100 mg/l concentration of PAHs within 10 days. The genomic and transcriptomic analysis of this white rot fungus highlights that the strain primarily utilized non-ligninolytic enzymes to remove various PAHs, rather than typical ligninolytic enzymes known for playing important roles in PAH degradation. PAH removal by non-ligninolytic enzymes was initiated by both different PAH-specific and common upregulation of P450s, followed by downstream PAH-transforming enzymes such as epoxide hydrolases, dehydrogenases, FAD-dependent monooxygenases, dioxygenases, and glycosyl- or glutathione transferases. Among the various PAHs, phenanthrene induced a more dynamic transcriptomic response possibly due to its greater cytotoxicity, leading to highly upregulated genes involved in the translocation of PAHs, a defense system against reactive oxygen species, and ATP synthesis. Our genomic and transcriptomic data provide a foundation of understanding regarding the mycoremediation of PAHs and the application of this strain for polluted environments.

Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small interfering RNAs (siRNAs), and long noncoding RNAs (lncRNAs), regulate target gene expression and can be used as tools for understanding biological processes and identifying new therapeutic targets. Currently, ncRNA molecules for research and therapeutic use are limited to ncRNA mimics made by chemical synthesis. We have recently established a high-yield and cost-effective method of producing bioengineered or biologic ncRNA agents (BERAs) through bacterial fermentation, which is based on a stable tRNA/pre-miR-34a carrier (~ 180 nt) that accommodates target small RNAs. Nevertheless, it remains a challenge to heterogeneously express longer ncRNAs (e.g., > 260 nt), and it is unknown if single BERA may carry multiple small RNAs. To address this issue, we hypothesized that an additional human pre-miR-34a could be attached to the tRNA/pre-miR-34a scaffold to offer a new tRNA/pre-miR-34a/pre-miR-34a carrier (~ 296 nt) for the accommodation of multiple small RNAs. We thus designed ten different combinatorial BERAs (CO-BERAs) that include different combinations of miRNAs, siRNAs, and antagomirs. Our data showed that all target CO-BERAs were successfully expressed in Escherichia coli at high levels, greater than 40% in total bacterial RNAs. Furthermore, recombinant CO-BERAs were purified to a high degree of homogeneity by fast protein liquid chromatography methods. In addition, CO-BERAs exhibited strong anti-proliferative activities against a variety of human non-small cell lung cancer cell lines. These results support the production of long ncRNA molecules carrying different warhead small RNAs for multi-targeting which may open avenues for developing new biologic RNAs as experimental, diagnostic, and therapeutic tools.

Objective Fetal brain diffusion tensor imaging (DTI) offers quantitative analysis of the developing brain. The objective was to 1) quantify DTI measures across gestation in a cohort of fetuses without brain abnormalities using full retrospective correction for fetal head motion 2) compare results obtained in utero to those in preterm infants. Materials and methods Motion-corrected DTI analysis was performed on data sets obtained at 1.5T from 32 fetuses scanned between 21.29 and 37.57 (median 31.86) weeks. Results were compared to 32 preterm infants scanned at 3T between 27.43 and 37.14 (median 33.07) weeks. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were quantified by region of interest measurements and tractography was performed. Results Fetal DTI was successful in 84% of fetuses for whom there was sufficient data for DTI estimation, and at least one tract could be obtained in 25 cases. Fetal FA values increased and ADC values decreased with age at scan (PLIC FA: p = 0.001; R2 = 0.469; slope = 0.011; splenium FA: p

Moiré superlattices enable the generation of new quantum phenomena in two-dimensional heterostructures, in which the interactions between the atomically thin layers qualitatively change the electronic band structure of the superlattice. For example, mini-Dirac points, tunable Mott insulator states and the Hofstadter butterfly pattern can emerge in different types of graphene/boron nitride moiré superlattices, whereas correlated insulating states and superconductivity have been reported in twisted bilayer graphene moiré superlattices1-12. In addition to their pronounced effects on single-particle states, moiré superlattices have recently been predicted to host excited states such as moiré exciton bands13-15. Here we report the observation of moiré superlattice exciton states in tungsten diselenide/tungsten disulfide (WSe2/WS2) heterostructures in which the layers are closely aligned. These moiré exciton states manifest as multiple emergent peaks around the original WSe2 A exciton resonance in the absorption spectra, and they exhibit gate dependences that are distinct from that of the A exciton in WSe2 monolayers and in WSe2/WS2 heterostructures with large twist angles. These phenomena can be described by a theoretical model in which the periodic moiré potential is much stronger than the exciton kinetic energy and generates multiple flat exciton minibands. The moiré exciton bands provide an attractive platform from which to explore and control excited states of matter, such as topological excitons and a correlated exciton Hubbard model, in transition-metal dichalcogenides.

Mobile health, or 'mHealth', is the application of mobile devices, their components and related technologies to healthcare. It is already improving patients' access to treatment and advice. Now, in combination with internet-connected diagnostic devices, it offers novel ways to diagnose, track and control infectious diseases and to improve the efficiency of the health system. Here we examine the promise of these technologies and discuss the challenges in realizing their potential to increase patients' access to testing, aid in their treatment and improve the capability of public health authorities to monitor outbreaks, implement response strategies and assess the impact of interventions across the world.

The electric-field-induced quantum phase transition from topological to conventional insulator has been proposed as the basis of a topological field effect transistor1-4. In this scheme, 'on' is the ballistic flow of charge and spin along dissipationless edges of a two-dimensional quantum spin Hall insulator5-9, and 'off' is produced by applying an electric field that converts the exotic insulator to a conventional insulator with no conductive channels. Such a topological transistor is promising for low-energy logic circuits4, which would necessitate electric-field-switched materials with conventional and topological bandgaps much greater than the thermal energy at room temperature, substantially greater than proposed so far6-8. Topological Dirac semimetals are promising systems in which to look for topological field-effect switching, as they lie at the boundary between conventional and topological phases3,10-16. Here we use scanning tunnelling microscopy and spectroscopy and angle-resolved photoelectron spectroscopy to show that mono- and bilayer films of the topological Dirac semimetal3,17 Na3Bi are two-dimensional topological insulators with bulk bandgaps greater than 300millielectronvolts owing to quantum confinement in the absence of electric field. On application of electric field by doping with potassium or by close approach of the scanning tunnelling microscope tip, the Stark effect completely closes the bandgap and re-opens it as a conventional gap of 90millielectronvolts. The large bandgaps in both the conventional and quantum spin Hall phases, much greater than the thermal energy at room temperature (25millielectronvolts), suggest that ultrathin Na3Bi is suitable for room-temperature topological transistor operation.

High-performance coatings that durably and fully repel liquids are of interest for fundamental research and practical applications. Such coatings should allow for droplet beading, roll off and bouncing, which is difficult to achieve for ultralow surface tension liquids. Here we report a bottom-up approach to prepare super-repellent coatings using a mixture of fluorosilanes and cyanoacrylate. On application to surfaces, the coatings assemble into thin films of locally multi-re-entrant hierarchical structures with very low surface energies. The resulting materials are super-repellent to solvents, acids and bases, polymer solutions and ultralow surface tension liquids, characterized by ultrahigh liquid contact angles (>150°) and negligible roll-off angles (~0°). Furthermore, the coatings are transparent, durable and demonstrate universal liquid bouncing, tailored responsiveness and anti-freezing properties, and are thus a promising alternative to existing synthetic super-repellent coatings.

Marine social-ecological conditions in the Arctic are rapidly changing. With many transboundary issues, such as shifting ranges of fisheries, biodiversity loss, sea ice retreat, economic development and pollution, greater pan-Arctic assessment and co-management are necessary. We adapted the Ocean Health Index (OHI) to compile pan-Arctic data and evaluate ocean health for nine regions above the Arctic Circle to assess the extent to which pan-Arctic assessment is possible and identify broad social-ecological trends. While the quality and availability of data varied, we assessed and scored nine OHI goals, including the pressures and resilience measures acting upon them. Our results show the Arctic is sustainably delivering a range of benefits to people, but with room for improvement in all goals, particularly tourism, fisheries, and protected places. Successful management of biological resources and short-term positive impacts on biodiversity in response to climate change underlie these high goal scores. The OHI assesses the past and near-term future but does not account for medium- and long-term future risks associated with climate change, highlighting the need for ongoing monitoring, dynamic management, and strong action to mitigate its anticipated effects. A general increase in and standardisation of monitoring is urgently needed in the Arctic. Unified assessments, such as this one, can support national comparisons, data quality assessments, and discussions on the targeting of limited monitoring capabilities at the most pressing and urgent transboundary management challenges, which is a priority for achieving successful Arctic stewardship.

Here we summarize recent progress in machine learning for the chemical sciences. We outline machine-learning techniques that are suitable for addressing research questions in this domain, as well as future directions for the field. We envisage a future in which the design, synthesis, characterization and application of molecules and materials is accelerated by artificial intelligence.

The classical portrayal of poor health in tropical countries is one of infections and parasites, contrasting with wealthy Western countries, where unhealthy diet and behaviours cause non-communicable diseases (NCDs) such as heart disease and cancer. Using international mortality data, we show that most NCDs cause more deaths at every age in low- and middle-income tropical countries than in high-income Western countries. Causes of NCDs in low- and middle-income countries include poor nutrition and living environment, infections, insufficient taxation and regulation of tobacco and alcohol, and under-resourced and inaccessible healthcare. We identify a comprehensive set of actions across health, social, economic and environmental sectors that could confront NCDs in low- and middle-income tropical countries and reduce global health inequalities.

We present two narratives on the future of Antarctica and the Southern Ocean, from the perspective of an observer looking back from 2070. In the first scenario, greenhouse gas emissions remained unchecked, the climate continued to warm, and the policy response was ineffective; this had large ramifications in Antarctica and the Southern Ocean, with worldwide impacts. In the second scenario, ambitious action was taken to limit greenhouse gas emissions and to establish policies that reduced anthropogenic pressure on the environment, slowing the rate of change in Antarctica. Choices made in the next decade will determine what trajectory is realized.

The onset of the North Atlantic Deep Water formation is thought to have coincided with Antarctic ice-sheet growth about 34 million years ago (Ma). However, this timing is debated, in part due to questions over the geochemical signature of the ancient Northern Component Water (NCW) formed in the deep North Atlantic. Here we present detailed geochemical records from North Atlantic sediment cores located close to sites of deep-water formation. We find that prior to 36 Ma, the northwestern Atlantic was stratified, with nutrient-rich, low-salinity bottom waters. This restricted basin transitioned into a conduit for NCW that began flowing southwards approximately one million years before the initial Antarctic glaciation. The probable trigger was tectonic adjustments in subarctic seas that enabled an increased exchange across the Greenland–Scotland Ridge. The increasing surface salinity and density strengthened the production of NCW. The late Eocene deep-water mass differed in its carbon isotopic signature from modern values as a result of the leakage of fossil carbon from the Arctic Ocean. Export of this nutrient-laden water provided a transient pulse of CO2 to the Earth system, which perhaps caused short-term warming, whereas the long-term effect of enhanced NCW formation was a greater northward heat transport that cooled Antarctica.

The RNA-guided CRISPR-Cas9 nuclease from Streptococcus pyogenes (SpCas9) has been widely repurposed for genome editing. High-fidelity (SpCas9-HF1) and enhanced specificity (eSpCas9(1.1)) variants exhibit substantially reduced off-target cleavage in human cells, but the mechanism of target discrimination and the potential to further improve fidelity were unknown. Using single-molecule Forster resonance energy transfer (smFRET) experiments, we show that both SpCas9-HF1 and eSpCas9(1.1) are trapped in an inactive state when bound to mismatched targets. We find that a non-catalytic domain within Cas9, REC3, recognizes target mismatches and governs the HNH nuclease to regulate overall catalytic competence. Exploiting this observation, we identified residues within REC3 involved in mismatch sensing and designed a new hyper-accurate Cas9 variant (HypaCas9) that retains robust on-target activity in human cells. These results offer a more comprehensive model to rationalize and modify the balance between target recognition and nuclease activation for precision genome editing.

Mapping of the longitudinal relaxation time (T1) and extracellular volume (ECV) offers a means of identifying pathological changes in myocardial tissue, including diffuse changes that may be invisible to existing T1-weighted methods. This technique has recently shown strong clinical utility for pathologies such as Anderson- Fabry disease and amyloidosis and has generated clinical interest as a possible means of detecting small changes in diffuse fibrosis; however, scatter in T1 and ECV estimates offers challenges for detecting these changes, and bias limits comparisons between sites and vendors. There are several technical and physiological pitfalls that influence the accuracy (bias) and precision (repeatability) of T1 and ECV mapping methods. The goal of this review is to describe the most significant of these, and detail current solutions, in order to aid scientists and clinicians to maximise the utility of T1 mapping in their clinical or research setting. A detailed summary of technical and physiological factors, issues relating to contrast agents, and specific disease-related issues is provided, along with some considerations on the future directions of the field. Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions. Available from: https://www.researchgate.net/publication/317548806_Towards_accurate_and_precise_T1_and_extracellular_volume_mapping_in_the_myocardium_a_guide_to_current_pitfalls_and_their_solutions [accessed Jun 13, 2017].

Objectives: Our objectives involved identifying whether repeated averaging in basal and mid left ventricular myocardial levels improves precision and correlation with collagen volume fraction for 11 heartbeat MOLLI T1 mapping versus assessment at a single ventricular level. Materials and methods: For assessment of T1 mapping precision, a cohort of 15 healthy volunteers underwent two CMR scans on separate days using an 11 heartbeat MOLLI with a 5(3)3 beat scheme to measure native T1 and a 4(1)3(1)2 beat post-contrast scheme to measure post-contrast T1, allowing calculation of partition coefficient and ECV. To assess correlation of T1 mapping with collagen volume fraction, a separate cohort of ten aortic stenosis patients scheduled to undergo surgery underwent one CMR scan with this 11 heartbeat MOLLI scheme, followed by intraoperative tru-cut myocardial biopsy. Six models of myocardial diffuse fibrosis assessment were established with incremental inclusion of imaging by averaging of the basal and mid-myocardial left ventricular levels, and each model was assessed for precision and correlation with collagen volume fraction. Results: A model using 11 heart beat MOLLI imaging of two basal and two mid ventricular level averaged T1 maps provided improved precision (Intraclass correlation 0.93 vs 0.84) and correlation with histology (R2 = 0.83 vs 0.36) for diffuse fibrosis compared to a single mid-ventricular level alone. ECV was more precise and correlated better than native T1 mapping. Conclusion: T1 mapping sequences with repeated averaging could be considered for applications of 11 heartbeat MOLLI, especially when small changes in native T1/ECV might affect clinical management.

Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumour growth, and ERF loss rescues TMPRSS2-ERG-positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.

The Zayandeh-Rud River basin, Iran, is projected to face spatiotemporally heterogeneous temperature increase and precipitation reduction that will decrease water supply by mid-century. With projected increase (0.70–1.03 °C) in spring temperature and reduction (6– 55%) in winter precipitation, the upper Zayandeh-Rud sub-basin, the main source of renewable water supply, will likely become warmer and drier. In the lower sub-basin, 1.1–1.5 °C increase in temperature and 11–31% decrease in annual precipitation are likely. A system dynamics model was used to analyze adaptation strategies taking into account feedbacks between water resources development and biophysical and socioeconomic sub-systems. Results suggest that infrastructural improvements, rigorous water demand management (e.g., replacing high water demand crops such as rice, corn, and alfalfa), and ecosystem-based regulatory prioritization, complemented by supply augmentation can temporarily alleviate water stress in a basin that is essentially governed by the Limits to Growth archetype

Deviation between thermodynamic and experimental voltages is one of the key issues in Li-ion conversion-type electrode materials; the factor that affects this phenomenon has not been understood well in spite of its importance. In this work, we combine first principles calculations and electrochemical experiments with characterization tools to probe the conversion reaction voltage of transition metal difluorides MF2 (M = Fe, Ni, and Cu). We find that the conversion reaction voltage is heavily dependent on the size of the metal nanoparticles generated. The surface energy of metal nanoparticles appears to penalize the reaction energy, which results in a lower voltage compared to the thermodynamic voltage of a bulk-phase reaction. Furthermore, we develop a reversible CuF2 electrode coated with NiO. Electron energy loss spectroscopy (EELS) elemental maps demonstrate that the lithiation process mostly occurs in the area of high NiO content. This suggests that NiO can be considered a suitable artificial solid electrolyte interphase that prevents direct contact between Cu nanoparticles and the electrolyte. Thus, it alleviates Cu dissolution into the electrolyte and improves the reversibility of CuF2.

Due to their low-temperature processing properties and inherent mechanical flexibility, conjugated polymer field-effect transistors (FETs) are promising candidates for enabling flexible electronic circuits and displays. Much progress has been made on materials performance; however, there remain significant concerns about operational and environmental stability, particularly in the context of applications that require a very high level of threshold voltage stability, such as active-matrix addressing of organic light-emitting diode displays. Here, we investigate the physical mechanisms behind operational and environmental degradation of high-mobility, p-type polymer FETs and demonstrate an effective route to improve device stability. We show that water incorporated in nanometre-sized voids within the polymer microstructure is the key factor in charge trapping and device degradation. By inserting molecular additives that displace water from these voids, it is possible to increase the stability as well as uniformity to a high level sufficient for demanding industrial applications.\ud \ud

Type III-A CRISPR-Cas systems are prokaryotic RNA-guided adaptive immune systems that use a protein-RNA complex, Csm, for transcription-dependent immunity against foreign DNA. Csm can cleave RNA and single-stranded DNA (ssDNA), but whether it targets one or both nucleic acids during transcription elongation is unknown. Here, we show that binding of a Thermus thermophilus (T. thermophilus) Csm (TthCsm) to a nascent transcript in a transcription elongation complex (TEC) promotes tethering but not direct contact of TthCsm with RNA polymerase (RNAP). Biochemical experiments show that both TthCsm and Staphylococcus epidermidis (S. epidermidis) Csm (SepCsm) cleave RNA transcripts, but not ssDNA, at the transcription bubble. Taken together, these results suggest that Type III systems primarily target transcripts, instead of unwound ssDNA in TECs, for immunity against double-stranded DNA (dsDNA) phages and plasmids. This reveals similarities between Csm and eukaryotic RNA interference, which also uses RNA-guided RNA targeting to silence actively transcribed genes., Type III CRISPR-Cas systems are able to target transcriptionally active DNA sequences in phages and plasmids. Here, the authors reveal the mechanism of the target nucleic acid preference of Type III-A CRISPR-Cas complexes at the transcription bubble by a combination of structural and biochemical approaches.

The ability to link soil microbial diversity to soil processes requires technologies that differentiate active microbes from extracellular DNA and dormant cells. Here, we use BONCAT (bioorthogonal non-canonical amino acid tagging) to measure translationally active cells in soils. We compare the active population of two soil depths from Oak Ridge (Tennessee, USA) and find that a maximum of 25–70% of the extractable cells are active. Analysis of 16S rRNA sequences from BONCAT-positive cells recovered by fluorescence-activated cell sorting (FACS) reveals that the phylogenetic composition of the active fraction is distinct from the total population of extractable cells. Some members of the community are found to be active at both depths independently of their abundance rank, suggesting that the incubation conditions favor the activity of similar organisms. We conclude that BONCAT-FACS is effective for interrogating the active fraction of soil microbiomes in situ and provides a new approach for uncovering the links between soil processes and specific microbial groups., Standard DNA-based analyses of microbial communities cannot distinguish between active microbes and dead or dormant cells. Here, Couradeau et al. use BONCAT (bioorthogonal non-canonical amino acid tagging), flow cytometry, and 16S rRNA gene amplicon sequencing to identify active microbial cells in soils.

The recent discovery of magnetism in atomically thin layers of van der Waals crystals has created great opportunities for exploring light-matter interactions and magneto-optical phenomena in the two-dimensional limit. Optical and magneto-optical experiments have provided insights into these topics, revealing strong magnetic circular dichroism and giant Kerr signals in atomically thin ferromagnetic insulators. However, the nature of the giant magneto-optical responses and their microscopic mechanism remain unclear. Here, by performing first-principles GW and Bethe-Salpeter equation calculations, we show that excitonic effects dominate the optical and magneto-optical responses in the prototypical two-dimensional ferromagnetic insulator, CrI$_3$. We simulate the Kerr and Faraday effects in realistic experimental setups, and based on which we predict the sensitive frequency- and substrate-dependence of magneto-optical responses. These findings provide physical understanding of the phenomena as well as potential design principles for engineering magneto-optical and optoelectronic devices using two-dimensional magnets., To appear in Nature Communications

Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.

Despite the importance of studying the instability of delithiated cathode materials, it remains difficult to underpin the degradation mechanism of lithium-rich cathode materials due to the complication of combined chemical and structural evolutions. Herein, we use state-of-the-art electron microscopy tools, in conjunction with synchrotron X-ray techniques and first-principle calculations to study a 4d-element-containing compound, Li2Ru0.5Mn0.5O3. We find surprisingly, after cycling, ruthenium segregates out as metallic nanoclusters on the reconstructed surface. Our calculations show that the unexpected ruthenium metal segregation is due to its thermodynamic insolubility in the oxygen deprived surface. This insolubility can disrupt the reconstructed surface, which explains the formation of a porous structure in this material. This work reveals the importance of studying the thermodynamic stability of the reconstructed film on the cathode materials and offers a theoretical guidance for choosing manganese substituting elements in lithium-rich as well as stoichiometric layer-layer compounds for stabilizing the cathode surface., The authors show that after cycling the model cathode material Li2Ru0.5Mn0.5O3 undergoes ruthenium segregation and even exsolution at the reconstructed oxide surface, which triggers a progressive degradation process. The insights enable new dimensions in choosing dopants for stabilized cathode surface.

A synthetic route to racemic helicenes via a vinylacetylene mediated gas phase chemistry involving elementary reactions with aryl radicals is presented. In contrast to traditional synthetic routes involving solution chemistry and ionic reaction intermediates, the gas phase synthesis involves a targeted ring annulation involving free radical intermediates. Exploiting the simplest helicene as a benchmark, we show that the gas phase reaction of the 4-phenanthrenyl radical ([C14H9]•) with vinylacetylene (C4H4) yields [4]-helicene (C18H12) along with atomic hydrogen via a low-barrier mechanism through a resonance-stabilized free radical intermediate (C18H13). This pathway may represent a versatile mechanism to build up even more complex polycyclic aromatic hydrocarbons such as [5]- and [6]-helicene via stepwise ring annulation through bimolecular gas phase reactions in circumstellar envelopes of carbon-rich stars, whereas secondary reactions involving hydrogen atom assisted isomerization of thermodynamically less stable isomers of [4]-helicene might be important in combustion flames as well., Helicenes represent key building blocks leading eventually to carbonaceous nanostructures. Here, exploiting [4]-helicene as a benchmark, the authors present a synthetic route to racemic helicenes via a vinylacetylene mediated gas phase chemistry with aryl radicals involving ring annulation.

著者人数: 13名, Accepted: 2019-01-22, 資料番号: SA1180260000

Rapid bulk assembly of nanoparticles into microstructures is challenging, but highly desirable for applications in controlled release, catalysis, and sensing. We report a method to form hollow microstructures via a two-stage nematic nucleation process, generating size-tunable closed-cell foams, spherical shells, and tubular networks composed of closely packed nanoparticles. Mesogen-modified nanoparticles are dispersed in liquid crystal above the nematic-isotropic transition temperature (TNI). On cooling through TNI, nanoparticles first segregate into shrinking isotropic domains where they locally depress the transition temperature. On further cooling, nematic domains nucleate inside the nanoparticle-rich isotropic domains, driving formation of hollow nanoparticle assemblies. Structural differentiation is controlled by nanoparticle density and cooling rate. Cahn-Hilliard simulations of phase separation in liquid crystal demonstrate qualitatively that partitioning of nanoparticles into isolated domains is strongly affected by cooling rate, supporting experimental observations that cooling rate controls aggregate size. Microscopy suggests the number and size of internal voids is controlled by second-stage nucleation., Synthetic routes to hollow microstructures typically require templates or long processing times. Here, the authors discover a two-stage nematic nucleation mechanism that allows them to assemble liquid crystal-dispersed nanoparticles into various hollow microstructures, on the order of seconds.

Exploring robust catalysts for water oxidation in acidic electrolyte is challenging due to the limited material choice. Iridium (Ir) is the only active element with a high resistance to the acid corrosion during water electrolysis. However, Ir is rare, and its large-scale application could only be possible if the intrinsic activity of Ir could be greatly enhanced. Here, a pseudo-cubic SrCo0.9Ir0.1O3-δ perovskite, containing corner-shared IrO6 octahedrons, is designed. The Ir in the SrCo0.9Ir0.1O3-δ catalyst shows an extremely high intrinsic activity as reflected from its high turnover frequency, which is more than two orders of magnitude higher than that of IrO2. During the electrochemical cycling, a surface reconstruction, with Sr and Co leaching, over SrCo0.9Ir0.1O3-δ occurs. Such reconstructed surface region, likely contains a high amount of structural domains with corner-shared and under-coordinated IrOx octahedrons, is responsible for the observed high activity., While water splitting could provide a green means to store energy, there are few materials that can sustain high water oxidation half-reaction rates in acidic electrolytes. Here, authors design a perovskite oxide that generates high performance under-coordinated iridium sites during electrocatalysis.

Land-use change pushes biodiversity into human-modified landscapes, where native ecosystems are surrounded by anthropic land covers (ALCs). Yet, the ability of species to use these emerging covers remains poorly understood. We quantified the use of ALCs by primates worldwide, and analyzed species’ attributes that predict such use. Most species use secondary forests and tree plantations, while only few use human settlements. ALCs are used for foraging by at least 86 species with an important conservation outcome: those that tolerate heavily modified ALCs are 26% more likely to have stable or increasing populations than the global average for all primates. There is no phylogenetic signal in ALCs use. Compared to all primates on Earth, species using ALCs are less often threatened with extinction, but more often diurnal, medium or large-bodied, not strictly arboreal, and habitat generalists. These findings provide valuable quantitative information for improving management practices for primate conservation worldwide., Primates utilise human-modified landscapes, and how they do so can provide key conservation insights. This study shows that primates using anthropic lands are less often threatened with extinction, but more often diurnal, not strictly arboreal, with medium or large body sizes, and habitat generalists.

The field-effect transistor kickstarted the digital revolution that propelled our society into the information age. One member of the now large family of field-effect devices is the thin-film transistor (TFT), best known for its enabling role in modern flat-panel displays. TFTs can be used in all sorts of innovative applications because of the broad variety of materials they can be made from, which give them diverse electrical and mechanical characteristics. To successfully utilize TFT technologies in a variety of rapidly emerging applications, such as flexible, stretchable and transparent large-area microelectronics, there are a number of metrics that matter.

In supercapacitors based on ionic liquid electrolytes, small amounts of absorbed water could potentially reduce the electrochemical window of electrolytes and cause performance degradation. The same would take place if ionic liquids are used as solvents for electrocatalysis involving the dissolved molecular species. In this work, we carry out molecular dynamics simulations, with gold and carbon electrodes in typical ionic liquids, hydrophobic and hydrophilic, to study electrosorption of water. We investigate the effects of hydrophobicity/hydrophilicity of ionic liquids and electrodes on interfacial distribution of ions and electrosorbed water. Results reveal that using hydrophilic ionic liquids would help to keep water molecules away from the negatively charged electrodes, even at large electrode polarizations. This conclusion is supported by electrochemical cyclic voltammetry measurements on gold and carbon electrodes in contact with humid ionic liquids. Thereby, our findings suggest potential mechanisms for protection of electrodes from water electrosorption., Ionic liquid electrolytes can impart increased operational voltage and energy density in supercapacitors, but water may diminish performance. Here the authors show that the hydrophilicity/hydrophobicity of ionic liquids can influence electrosorption of water and ultimately the supercapacitor performance.

After DNA replication, chromosomal processes including DNA repair and transcription take place in the context of sister chromatids. While cell cycle regulation can guide these processes globally, mechanisms to distinguish pre- and post-replicative states locally remain unknown. Here we reveal that new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the human TONSL–MMS22L homologous recombination complex. We identify the TONSL ankyrin repeat domain (ARD) as a reader of histone H4 tails unmethylated at K20 (H4K20me0), which are specific to new histones incorporated during DNA replication and mark post-replicative chromatin until the G2/M phase of the cell cycle. Accordingly, TONSL–MMS22L binds new histones H3–H4 both before and after incorporation into nucleosomes, remaining on replicated chromatin until late G2/M. H4K20me0 recognition is required for TONSL–MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions. Consequently, TONSL ARD mutants are toxic, compromising genome stability, cell viability and resistance to replication stress. Together, these data reveal a histone-reader-based mechanism for recognizing the post-replicative state, offering a new angle to understand DNA repair with the potential for targeted cancer therapy.

Christopher Golden and colleagues calculate that declining numbers of marine fish will spell more malnutrition in many developing nations.

Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Such toxins have not been identified previously in human pathogenic fungi. Here we identify the first, to our knowledge, fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signalling pathway and activates epithelial immunity. Membrane permeabilization is enhanced by a positive charge at the carboxy terminus of the peptide, which triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name 'Candidalysin' for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans.

International audience; Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans. Host range breaches are limited by incompatibilities between avian virus components and the human host. Barriers include receptor preference, virion stability and poor activity of the avian virus RNA-dependent RNA polymerase in human cells. Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown. We show that a species-specific difference in host protein ANP32A accounts for the suboptimal function of avian virus polymerase in mammalian cells. Avian ANP32A possesses an additional 33 amino acids between the leucine-rich repeats and carboxy-terminal low-complexity acidic region domains. In mammalian cells, avian ANP32A rescued the suboptimal function of avian virus polymerase to levels similar to mammalian-adapted polymerase. Deletion of the avian-specific sequence from chicken ANP32A abrogated this activity, whereas its insertion into human ANP32A, or closely related ANP32B, supported avian virus polymerase function. Substitutions, such as PB2(E627K), were rapidly selected upon infection of humans with avian H5N1 or H7N9 influenza viruses, adapting the viral polymerase for the shorter mammalian ANP32A. Thus ANP32A represents an essential host partner co-opted to support influenza virus replication and is a candidate host target for novel antivirals.

Pectin-rich biomasses, such as citrus peel and sugar beet pulp, hold promise as inexpensive feedstocks for microbial fermentations as enzymatic hydrolysis of their component polysaccharides can be accomplished inexpensively to yield high concentrations of fermentable sugars and d-galacturonic acid (d-galUA). In this study, we tackle a number of challenges associated with engineering a microbial strain to convert pectin-rich hydrolysates into commodity and specialty chemicals. First, we engineer d-galUA utilization into yeast, Saccharomyces cerevisiae. Second, we identify that the mechanism of d-galUA uptake into yeast is mediated by hexose transporters and that consumption of d-galUA is inhibited by d-glucose. Third, we enable co-utilization of d-galUA and d-glucose by identifying and expressing a heterologous transporter, GatA, from Aspergillus niger. Last, we demonstrate the use of this transporter for production of the platform chemical, meso-galactaric acid, directly from industrial Navel orange peel waste., Pectin-rich agricultural byproducts are ideal feedstocks for biobased chemicals production. Here, the authors engineer the yeast, S. cerevisiae, in several steps to co-utilize d-galacturonic acid and d-glucose and demonstrate the potential of producing meso-galactaric acid from industrial orange peel.

Known giant virus diversity is currently skewed towards viruses isolated from aquatic environments and cultivated in the laboratory. Here, we employ cultivation-independent metagenomics and mini-metagenomics on soils from the Harvard Forest, leading to the discovery of 16 novel giant viruses, chiefly recovered by mini-metagenomics. The candidate viruses greatly expand phylogenetic diversity of known giant viruses and either represented novel lineages or are affiliated with klosneuviruses, Cafeteria roenbergensis virus or tupanviruses. One assembled genome with a size of 2.4 Mb represents the largest currently known viral genome in the Mimiviridae, and others encode up to 80% orphan genes. In addition, we find more than 240 major capsid proteins encoded on unbinned metagenome fragments, further indicating that giant viruses are underexplored in soil ecosystems. The fact that most of these novel viruses evaded detection in bulk metagenomes suggests that mini-metagenomics could be a valuable approach to unearth viral giants., Current knowledge of giant virus diversity is largely based on samples from aquatic environments. Here the authors employ cultivation-independent metagenomics and mini-metagenomics on forest soil and identify 16 novel giant virus genomes, some of which representing novel lineages, including the so far largest genome in Mimiviridae.

Niche-adaptation of a bacterial pathogen hinges on the ability to recognize the complexity of signals from the environment and integrate that information with the regulation of genes critical for infection. Here we report the transcriptome of the attaching and effacing pathogen Citrobacter rodentium during infection of its natural murine host. Pathogen gene expression in vivo was heavily biased towards the virulence factor repertoire and was found to be co-ordinated uniquely in response to the host. Concordantly, we identified the host-specific induction of a metabolic pathway that overlapped with the regulation of virulence. The essential type 3 secretion system and an associated suite of distinct effectors were found to be modulated co-ordinately through a unique mechanism involving metabolism of microbiota-derived 1,2-propanediol, which dictated the ability to colonize the host effectively. This study provides novel insights into how host-specific metabolic adaptation acts as a cue to fine-tune virulence.

Extracellular electron transfer (EET) describes microbial bioelectrochemical processes in which electrons are transferred from the cytosol to the exterior of the cell1. Mineral-respiring bacteria use elaborate haem-based electron transfer mechanisms2-4 but the existence and mechanistic basis of other EETs remain largely unknown. Here we show that the food-borne pathogen Listeria monocytogenes uses a distinctive flavin-based EET mechanism to deliver electrons to iron or an electrode. By performing a forward genetic screen to identify L. monocytogenes mutants with diminished extracellular ferric iron reductase activity, we identified an eight-gene locus that is responsible for EET. This locus encodes a specialized NADH dehydrogenase that segregates EET from aerobic respiration by channelling electrons to a discrete membrane-localized quinone pool. Other proteins facilitate the assembly of an abundant extracellular flavoprotein that, in conjunction with free-molecule flavin shuttles, mediates electron transfer to extracellular acceptors. This system thus establishes a simple electron conduit that is compatible with the single-membranestructure of the Gram-positive cell. Activation of EET supports growth on non-fermentable carbon sources, and an EET mutant exhibited a competitive defect within the mouse gastrointestinal tract. Orthologues of the genes responsible for EET are present in hundreds of species across the Firmicutes phylum, including multiple pathogens and commensal members of the intestinal microbiota, and correlate with EET activity in assayed strains. These findings suggest a greaterprevalence of EET-based growth capabilities and establish a previously underappreciated relevance for electrogenic bacteria across diverse environments, including host-associated microbial communities and infectious disease.

Ethologically relevant stimuli are often multidimensional. In many brain systems, neurons with “pure” tuning to one stimulus dimension are found along with “conjunctive” neurons that encode several dimensions, forming an apparently redundant representation. Here we show using theoretical analysis that a mixed-dimensionality code can efficiently represent a stimulus in different behavioral regimes: encoding by conjunctive cells is more robust when the stimulus changes quickly, whereas on long timescales pure cells represent the stimulus more efficiently with fewer neurons. We tested our predictions experimentally in the bat head-direction system and found that many head-direction cells switched their tuning dynamically from pure to conjunctive representation as a function of angular velocity—confirming our theoretical prediction. More broadly, our results suggest that optimal dimensionality depends on population size and on the time available for decoding—which might explain why mixed-dimensionality representations are common in sensory, motor, and higher cognitive systems across species., Multidimensional stimuli are often represented by neurons encoding only a single dimension and those encoding multiple dimensions. Here, the authors present theoretical and experimental analyses to show that mixed representations are optimal to efficiently encode such stimuli under different behavioral modes.

Machines powered by artificial intelligence increasingly mediate our social, cultural, economic and political interactions. Understanding the behaviour of artificial intelligence systems is essential to our ability to control their actions, reap their benefits and minimize their harms. Here we argue that this necessitates a broad scientific research agenda to study machine behaviour that incorporates and expands upon the discipline of computer science and includes insights from across the sciences. We first outline a set of questions that are fundamental to this emerging field and then explore the technical, legal and institutional constraints on the study of machine behaviour. published

Anharmonic crystal lattice dynamics have been observed in lead halide perovskites on picosecond timescales. Here, we report that the soft nature of the perovskite crystal lattice gives rise to dynamic fluctuations in the electronic properties of excited states. We use linear polarization selective transient absorption spectroscopy to study the charge carrier relaxation dynamics in lead-halide perovskite films and nanocrystals. We find that photo-excited charge carriers maintain an initial polarization anisotropy for several picoseconds, independent of crystallite size and composition, and well beyond the reported timescales of carrier scattering. First-principles calculations find intrinsic anisotropies in the transition dipole moment, which depend on the orientation of light polarization and the polar distortion of the local crystal lattice. Lattice dynamics are imprinted in the optical transitions and anisotropies arise on the time-scales of structural motion. The strong coupling between electronic states and structural dynamics requires a unique interpretation of recombination and transport mechanisms.

The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, caspase-1 activation and IL-1β release. These data indicate that sumoylation of NLRP3 restrains inflammasome activation, and identify SUMO proteases as potential drug targets for the treatment of inflammatory diseases., The NLRP3 inflammasome is an important component of inflammatory responses, but how it is negatively regulated is still unclear. Here the authors show that post-translational modification of NLRP3 by sumoylation suppresses inflammasome activity, and that desumoylation of NLRP3 by the SENP6 and SENP7 proteases promotes NLRP3 activation.

In the original version of this Article, the concentration of boric acid buffer for the SDS clearing solution was given incorrectly as ‘1 M sodium borate’ and should have read ‘0.2 M boric acid’. Also, the composition of PBST incorrectly read ‘1% Triton X-100 (vol/vol) and 0.1% sodium azide (wt/vol)’ and should have read ‘0.1% Triton X-100 (vol/vol) and 0.01% sodium azide (wt/vol)’. Further, the pH of the OPTIClear solution was not stated, and should have read ‘with a pH between 7 to 8 adjusted with hydrochloric acid’. These errors have been corrected in both the PDF and HTML versions of the Article.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling., Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

Ensuring the fitness of the pluripotent cells that will contribute to future development is important both for the integrity of the germline and for proper embryogenesis. Consequently, it is becoming increasingly apparent that pluripotent cells can compare their fitness levels and signal the elimination of those cells that are less fit than their neighbours. In mammals the nature of the pathways that communicate fitness remain largely unknown. Here we identify that in the early mouse embryo and upon exit from naive pluripotency, the confrontation of cells with different fitness levels leads to an inhibition of mTOR signalling in the less fit cell type, causing its elimination. We show that during this process, p53 acts upstream of mTOR and is required to repress its activity. Finally, we demonstrate that during normal development around 35% of cells are eliminated by this pathway, highlighting the importance of this mechanism for embryonic development.

Understanding the unique contributions of frontoparietal networks (FPN) in cognition is challenging because they overlap spatially and are co-activated by diverse tasks. Characterizing these networks therefore involves studying their activation across many different cognitive tasks, which previously was only possible with meta-analyses. Here, we use neuroadaptive Bayesian optimization, an approach combining real-time analysis of functional neuroimaging data with machine-learning, to discover cognitive tasks that segregate ventral and dorsal FPN activity. We identify and subsequently refine two cognitive tasks, Deductive Reasoning and Tower of London, which maximally dissociate the dorsal from ventral FPN. We subsequently investigate these two FPNs in the context of a wider range of FPNs and demonstrate the importance of studying the whole activity profile across tasks to uniquely differentiate any FPN. Our findings deviate from previous meta-analyses and hypothesized functional labels for these FPNs. Taken together the results form the starting point for a neurobiologically-derived cognitive taxonomy., The unique contributions of different frontoparietal networks (FPNs) in cognition remains unclear. Here, authors use neuroadaptive Bayesian optimization to identify cognitive tasks that segregate dorsal and ventral FPNs and reveal complex many-to-many mappings between cognitive tasks and FPNs.

Recordings of magnetic fields, thought to be crucial to our solar system’s rapid accretion, are potentially retained in unaltered nanometric low-Ni kamacite (~ metallic Fe) grains encased within dusty olivine crystals, found in the chondrules of unequilibrated chondrites. However, most of these kamacite grains are magnetically non-uniform, so their ability to retain four-billion-year-old magnetic recordings cannot be estimated by previous theories, which assume only uniform magnetization. Here, we demonstrate that non-uniformly magnetized nanometric kamacite grains are stable over solar system timescales and likely the primary carrier of remanence in dusty olivine. By performing in-situ temperature-dependent nanometric magnetic measurements using off-axis electron holography, we demonstrate the thermal stability of multi-vortex kamacite grains from the chondritic Bishunpur meteorite. Combined with numerical micromagnetic modeling, we determine the stability of the magnetization of these grains. Our study shows that dusty olivine kamacite grains are capable of retaining magnetic recordings from the accreting solar system., Magnetic fields are thought to have been influential in the formation of our solar system. Here, the authors observe thermomagnetically stable, non-uniformly magnetized kamacite grains within chondritic meteorites, and calculate the grains to retain recordings of these magnetic fields.

The importance of organic aerosol particles in the environment has been long established, influencing cloud formation and lifetime, absorbing and scattering sunlight, affecting atmospheric composition and impacting on human health. Conventionally, ambient organic particles were considered to exist as liquids. Recent observations in field measurements and studies in the laboratory suggest that they may instead exist as highly viscous semi-solids or amorphous glassy solids under certain conditions, with important implications for atmospheric chemistry, climate and air quality. This review explores our understanding of aerosol particle phase, particularly as identified by measurements of the viscosity of organic particles, and the atmospheric implications of phase state., The phase state of organic particles in the atmosphere has important consequences for the impact of aerosols on climate, visibility, air quality and health. Here, the authors review the evidence for the formation of amorphous glassy particles and the methods for determining aerosol particle viscosity.

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches., This work has been sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III and Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR). Sílvia Bonàs was FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. This study also makes use of data generated by the UK10K Consortium, derived from samples from UK10K COHORT IMPUTATION (EGAS00001000713). A full list of the investigators who contributed to the generation of the data is available in www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We acknowledge PRACE for awarding us to access MareNostrum supercomputer, based in Spain at Barcelona. The technical support group, particularly Pablo Ródenas and Jorge Rodríguez, from the Barcelona Supercomputing Center is gratefully acknowledged. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667191. Mercè Planas-Fèlix is funded by the Obra Social Fundación la Caixa fellowship under the Severo Ochoa 2013 program. Work from Irene Miguel-Escalada, Ignasi Moran, Goutham Atla, and Jorge Ferrer was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, the Wellcome Trust (WT101033), Ministerio de Economía y Competitividad (BFU2014-54284-R) and Horizon 2020 (667191). Irene Miguel-Escalada has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement No 658145. We acknowledge Prof. Giulio Cossu (Institute of Inflammation and Repair, University of Manchester) for providing the muscle myoblast cell line. We also acknowledge the InterAct and SIGMA Type 2 Diabetes Consortia for access to the data to replicate the rs146662075 variant. A full list of the investigators of the SIGMA Type 2 Diabetes and the InterAct consortia is provided in Supplementary Notes 3 and 4. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). This research has been conducted using the UK Biobank Resource (application number 16803). We also acknowledge Bianca C. Porneala, MS for his technical assistance in the collection and curation of the genotype and phenotype data from Partners Biobank. We also thank Marcin von Grotthuss for their support for uploading the summary statistics data to the Type 2 Diabetes Genetic Portal (AMP-T2D portal). Finally, we thank all the Computational Genomics group at the BSC for their helpful discussions and valuable comments on the manuscript.