In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
Overhunting reduces important plant-animal interactions such as vertebrate seed dispersal and seed predation, thereby altering plant regeneration and even above-ground biomass. It remains unclear, however, if non-hunted species can compensate for lost vertebrates in defaunated ecosystems. We use a nested exclusion experiment to isolate the effects of different seed enemies in a Bornean rainforest. In four of five tree species, vertebrates kill many seeds (13-66%). Nonetheless, when large mammals are excluded, seed mortality from insects and fungi fully compensates for the lost vertebrate predation, such that defaunation has no effect on seedling establishment. The switch from seed predation by generalist vertebrates to specialist insects and fungi in defaunated systems may alter Janzen-Connell effects and density-dependence in plants. Previous work using simulation models to explore how lost seed dispersal will affect tree species composition and carbon storage may require reevaluation in the context of functional redundancy within complex species interactions networks.
A panel of influenza virus-like sequences were recently documented in fish and amphibians. Of these, the Wuhan spiny eel influenza virus (WSEIV) was found to phylogenetically cluster with influenza B viruses as a sister clade. Influenza B viruses have been documented to circulate only in humans, with certain virus isolates found in harbor seals. It is therefore interesting that a similar virus was potentially found in fish. Here we characterize the putative hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins of the WSEIV. Functionally, we show that the WSEIV NA-like protein has sialidase activity comparable to B/Malaysia/2506/2004 influenza B virus NA, making it a bona fide neuraminidase that is sensitive to NA inhibitors. We tested the functionality of the HA by addressing the receptor specificity, stability, preferential airway protease cleavage, and fusogenicity. We show highly specific binding to monosialic ganglioside 2 (GM2) and fusogenicity at a range of different pH conditions. In addition, we found limited antigenic conservation of the WSEIV HA and NA relative to the B/Malaysia/2506/2004 virus HA and NA. In summary, we perform a functional and antigenic characterization of the glycoproteins of WSEIV to assess if it is indeed a bona fide influenza virus potentially circulating in ray-finned fish.
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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.
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
Recent literature on marine fish farming brands it as potentially compatible with sustainable resource use, conservation, and human nutrition goals, and aligns with the emerging policy discourse of 'blue growth'. We advance a two-pronged critique. First, contemporary narratives tend to overstate marine finfish aquaculture's potential to deliver food security and environmental sustainability. Second, they often align with efforts to enclose maritime space that could facilitate its allocation to extractive industries and conservation interests and exclude fishers. Policies and investments that seek to increase the availability and accessibility of affordable and sustainable farmed aquatic foods should focus on freshwater aquaculture.
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.
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.
Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.
The realization of operationally stable blue organic light-emitting diodes is a challenging issue across the field. While device optimization has been a focus to effectively prolong device lifetime, strategies based on molecular engineering of chemical structures, particularly at the subatomic level, remains little. Herein, we explore the effect of targeted deuteration on donor and/or acceptor units of thermally activated delayed fluorescence emitters and investigate the structure-property relationship between intrinsic molecular stability, based on isotopic effect, and device operational stability. We show that the deuteration of the acceptor unit is critical to enhance the photostability of thermally activated delayed fluorescence compounds and hence device lifetime in addition to that of the donor units, which is commonly neglected due to the limited availability and synthetic complexity of deuterated acceptors. Based on these isotopic analogues, we observe a gradual increase in the device operational stability and achieve the long-lifetime time to 90% of the initial luminance of 23.4 h at the luminance of 1000 cd m-2 for thermally activated delayed fluorescence-sensitized organic light-emitting diodes. We anticipate our strategic deuteration approach provides insights and demonstrates the importance on structural modification materials at a subatomic level towards prolonging the device operational stability.
Groundwater provides critical freshwater supply, particularly in dry regions where surface water availability is limited. Climate change impacts on GWS (groundwater storage) could affect the sustainability of freshwater resources. Here, we used a fully-coupled climate model to investigate GWS changes over seven critical aquifers identified as significantly distressed by satellite observations. We assessed the potential climate-driven impacts on GWS changes throughout the 21st century under the business-as-usual scenario (RCP8.5). Results show that the climate-driven impacts on GWS changes do not necessarily reflect the long-term trend in precipitation; instead, the trend may result from enhancement of evapotranspiration, and reduction in snowmelt, which collectively lead to divergent responses of GWS changes across different aquifers. Finally, we compare the climate-driven and anthropogenic pumping impacts. The reduction in GWS is mainly due to the combined impacts of over-pumping and climate effects; however, the contribution of pumping could easily far exceed the natural replenishment.
The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS.
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.
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.
Biogeographic history can lead to variation in biodiversity across regions, but it remains unclear how the degree of biogeographic isolation among communities may lead to differences in biodiversity. Biogeographic analyses generally treat regions as discrete units, but species assemblages differ in how much biogeographic history they share, just as species differ in how much evolutionary history they share. Here, we use a continuous measure of biogeographic distance, phylobetadiversity, to analyze the influence of biogeographic isolation on the taxonomic and functional diversity of global mammal and bird assemblages. On average, biodiversity is better predicted by environment than by isolation, especially for birds. However, mammals in deeply isolated regions are strongly influenced by isolation; mammal assemblages in Australia and Madagascar, for example, are much less diverse than predicted by environment alone and contain unique combinations of functional traits compared to other regions. Neotropical bat assemblages are far more functionally diverse than Paleotropical assemblages, reflecting the different trajectories of bat communities that have developed in isolation over tens of millions of years. Our results elucidate how long-lasting biogeographic barriers can lead to divergent diversity patterns, against the backdrop of environmental determinism that predominantly structures diversity across most of the world.
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.
There has been little analysis of neurochemical correlates of compulsive behaviour to illuminate its underlying neural mechanisms. We use 7-Tesla proton magnetic resonance spectroscopy (1H-MRS) to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate and GABA levels in anterior cingulate cortex (ACC) and supplementary motor area (SMA) of healthy volunteers and participants with Obsessive-Compulsive Disorder (OCD). Within the SMA, trait and clinical measures of compulsive behaviour are related to glutamate levels, whereas a behavioural index of habitual control correlates with the glutamate:GABA ratio. Participants with OCD also show the latter relationship in the ACC while exhibiting elevated glutamate and lower GABA levels in that region. This study highlights SMA mechanisms of habitual control relevant to compulsive behaviour, common to the healthy sub-clinical and OCD populations. The results also demonstrate additional involvement of anterior cingulate in the balance between goal-directed and habitual responding in OCD.
Despite their fundamental importance the links between forest productivity, diversity and climate remain contentious. We consider whether variation in productivity across climates reflects adjustment among tree species and individuals, or changes in tree community structure. We analysed data from 60 plots of humid old-growth forests spanning mean annual temperatures (MAT) from 2.0 to 26.6 °C. Comparing forests at equivalent aboveground biomass (160 Mg C ha-1), tropical forests ≥24 °C MAT averaged more than double the aboveground woody productivity of forests <12 °C (3.7 ± 0.3 versus 1.6 ± 0.1 Mg C ha-1 yr-1). Nonetheless, species with similar standing biomass and maximum stature had similar productivity across plots regardless of temperature. We find that differences in the relative contribution of smaller- and larger-biomass species explained 86% of the observed productivity differences. Species-rich tropical forests are more productive than other forests due to the high relative productivity of many short-stature, small-biomass species.
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.