Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities.
Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4',6'-O-acetal and 4'-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4'-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.
The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.
Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.
Binary expression systems have revolutionised genetic research by enabling delivery of loss-of-function and gain-of-function transgenes with precise spatial-temporal resolution in vivo. However, at present, each existing platform relies on a defined exogenous transcription activator capable of binding a unique recognition sequence. Consequently, none of these technologies alone can be used to simultaneously target different tissues or cell types in the same organism. Here, we report a modular system based on programmable transcription activator-like effector (TALE) proteins, which enables parallel expression of multiple transgenes in spatially distinct tissues in vivo. Using endogenous enhancers coupled to TALE drivers, we demonstrate multiplexed orthogonal activation of several transgenes carrying cognate variable activating sequences (VAS) in distinct neighbouring cell types of the Drosophila central nervous system. Since the number of combinatorial TALE-VAS pairs is virtually unlimited, this platform provides an experimental framework for highly complex genetic manipulation studies in vivo.
Balancing economic development with international commitments to protect biodiversity is a global challenge. Achieving this balance requires an understanding of the possible consequences of alternative future scenarios for a range of stakeholders. We employ an integrated economic and environmental planning approach to evaluate four alternative futures for the mega-diverse island of Borneo. We show what could be achieved if the three national jurisdictions of Borneo coordinate efforts to achieve their public policy targets and allow a partial reallocation of planned land uses. We reveal the potential for Borneo to simultaneously retain ∼50% of its land as forests, protect adequate habitat for the Bornean orangutan (Pongo pygmaeus) and Bornean elephant (Elephas maximus borneensis), and achieve an opportunity cost saving of over US$43 billion. Such coordination would depend on enhanced information sharing and reforms to land-use planning, which could be supported by the increasingly international nature of economies and conservation efforts.
The spatial scaling of stability is key to understanding ecological sustainability across scales and the sensitivity of ecosystems to habitat destruction. Here we propose the invariability-area relationship (IAR) as a novel approach to investigate the spatial scaling of stability. The shape and slope of IAR are largely determined by patterns of spatial synchrony across scales. When synchrony decays exponentially with distance, IARs exhibit three phases, characterized by steeper increases in invariability at both small and large scales. Such triphasic IARs are observed for primary productivity from plot to continental scales. When synchrony decays as a power law with distance, IARs are quasilinear on a log-log scale. Such quasilinear IARs are observed for North American bird biomass at both species and community levels. The IAR provides a quantitative tool to predict the effects of habitat loss on population and ecosystem stability and to detect regime shifts in spatial ecological systems, which are goals of relevance to conservation and policy.
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.
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.
The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
The original version of this Article contained an error in the third sentence of the abstract and incorrectly read "Here, using long-term plot monitoring records of up to half a century, we find that intact forests in Borneo gained 0.43 Mg C ha-1 year-1 (95% CI 0.14-0.72, mean period 1988-2010) above-ground live biomass", rather than the correct "Here, using long-term plot monitoring records of up to half a century, we find that intact forests in Borneo gained 0.43 Mg C ha-1 year-1 (95% CI 0.14-0.72, mean period 1988-2010) in above-ground live biomass carbon". This has now been corrected in both the PDF and HTML versions of the Article.
A central question in stem cell biology is the relationship between stem cells and their niche. Although previous reports have uncovered how signaling molecules released by niche cells support stem cell function, the role of the extra-cellular matrix (ECM) within the niche is unclear. Here, we show that upon activation, skeletal muscle stem cells (satellite cells) induce local remodeling of the ECM and the deposition of laminin-α1 and laminin-α5 into the basal lamina of the satellite cell niche. Genetic ablation of laminin-α1, disruption of integrin-α6 signaling or blocking matrix metalloproteinase activity impairs satellite cell expansion and self-renewal. Collectively, our findings establish that remodeling of the ECM is an integral process of stem cell activity to support propagation and self-renewal, and may explain the effect laminin-α1-containing supports have on embryonic and adult stem cells, as well as the regenerative activity of exogenous laminin-111 therapy.
The animal-pathogenic oomycete Saprolegnia parasitica causes serious losses in aquaculture by infecting and killing freshwater fish. Like plant-pathogenic oomycetes, S. parasitica employs similar infection structures and secretes effector proteins that translocate into host cells to manipulate the host. Here, we show that the host-targeting protein SpHtp3 enters fish cells in a pathogen-independent manner. This uptake process is guided by a gp96-like receptor and can be inhibited by supramolecular tweezers. The C-terminus of SpHtp3 (containing the amino acid sequence YKARK), and not the N-terminal RxLR motif, is responsible for the uptake into host cells. Following translocation, SpHtp3 is released from vesicles into the cytoplasm by another host-targeting protein where it degrades nucleic acids. The effector translocation mechanism described here, is potentially also relevant for other pathogen-host interactions as gp96 is found in both animals and plants.
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Deep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations with immune signatures reveals that low immune infiltration was associated with EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While KRAS mutations are found to be significantly associated with T cell infiltration in ADC samples. The SQCC patients with high antigen presentation machinery and cytotoxic T cell signature scores are found to have a prolonged overall survival time.
Defaunation is causing declines of large-seeded animal-dispersed trees in tropical forests worldwide, but whether and how these declines will affect carbon storage across this biome is unclear. Here we show, using a pan-tropical data set, that simulated declines of large-seeded animal-dispersed trees have contrasting effects on aboveground carbon stocks across Earth's tropical forests. In our simulations, African, American and South Asian forests, which have high proportions of animal-dispersed species, consistently show carbon losses (2-12%), but Southeast Asian and Australian forests, where there are more abiotically dispersed species, show little to no carbon losses or marginal gains (±1%). These patterns result primarily from changes in wood volume, and are underlain by consistent relationships in our empirical data (∼2,100 species), wherein, large-seeded animal-dispersed species are larger as adults than small-seeded animal-dispersed species, but are smaller than abiotically dispersed species. Thus, floristic differences and distinct dispersal mode-seed size-adult size combinations can drive contrasting regional responses to defaunation.
Native species that forage in farmland may increase their local abundances thereby affecting adjacent ecosystems within their landscape. We used two decades of ecological data from a protected primary rainforest in Malaysia to illutrate how subsidies from neighboring oil palm plantations triggered powerful secondary 'cascading' effects on natural habitats located >1.3 km away. We found (i) oil palm fruit drove 100-fold increases in crop-raiding native wild boar (Sus scrofa), (ii) wild boar used thousands of understory plants to construct birthing nests in the pristine forest interior, and (iii) nest building caused a 62% decline in forest tree sapling density over the 24-year study period. The long-term, landscape-scale indirect effects from agriculture suggest its full ecological footprint may be larger in extent than is currently recognized. Cross-boundary subsidy cascades may be widespread in both terrestrial and marine ecosystems and present significant conservation challenges.
Metal nanoparticles prepared by exsolution at the surface of perovskite oxides have been recently shown to enable new dimensions in catalysis and energy conversion and storage technologies owing to their socketed, well-anchored structure. Here we show that contrary to general belief, exsolved particles do not necessarily re-dissolve back into the underlying perovskite upon oxidation. Instead, they may remain pinned to their initial locations, allowing one to subject them to further chemical transformations to alter their composition, structure and functionality dramatically, while preserving their initial spatial arrangement. We refer to this concept as chemistry at a point and illustrate it by tracking individual nanoparticles throughout various chemical transformations. We demonstrate its remarkable practical utility by preparing a nanostructured earth abundant metal catalyst which rivals platinum on a weight basis over hundreds of hours of operation. Our concept enables the design of compositionally diverse confined oxide particles with superior stability and catalytic reactivity.
Ceramic fuel cells offer a clean and efficient means of producing electricity through a variety of fuels. However, miniaturization of cell dimensions for portable device application remains a challenge, as volumetric power densities generated by readily-available planar/tubular ceramic cells are limited. Here, we demonstrate a concept of 'micro-monolithic' ceramic cell design. The mechanical robustness and structural integrity of this design is thoroughly investigated with real-time, synchrotron X-ray diffraction computed tomography, suggesting excellent thermal cycling stability. The successful miniaturization results in an exceptional power density of 1.27 W cm-2 at 800 °C, which is among the highest reported. This holistic design incorporates both mechanical integrity and electrochemical performance, leading to mechanical property enhancement and representing an important step toward commercial development of portable ceramic devices with high volumetric power (>10 W cm-3), fast thermal cycling and marked mechanical reliability.
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.