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Recently various topological polar structures have been discovered in oxide thin films. Despite the increasing evidence of their switchability under electrical and/or mechanical fields, the dynamic property of isolated ones, which is usually required for applications such as data storage, is still absent. Here, we show the controlled nucleation and motion of isolated three-fold vertices under an applied electric field. At the PbTiO3/SrRuO3interface, a two-unit-cell thick SrTiO3layer provides electrical boundary conditions for the formation of three-fold vertices. Utilizing the SrTiO3layer and in situ electrical testing system, we find that isolated three-fold vertices can move in a controllable and reversible manner with a velocity up to ~629 nm s−1. Microstructural evolution of the nucleation and propagation of isolated three-fold vertices is further revealed by phase-field simulations. This work demonstrates the ability to electrically manipulate isolated three-fold vertices, shedding light on the dynamic property of isolated topological polar structures.

Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer’s disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD., Despite the identification of genetic risk loci for late-onset Alzheimer’s disease (LOAD), the genetic architecture and prediction remains unclear. Here, the authors use genetic risk scores for prediction of LOAD across three datasets and show evidence suggesting oligogenic variant architecture for this disease.

In conventional ferromagnet/spacer/ferromagnet sandwiches, noncollinear couplings are commonly absent because of the low coupling energy and strong magnetization. For antiferromagnets (AFM), the small net moment can embody a low coupling energy as a sizable coupling field, however, such AFM sandwich structures have been scarcely explored. Here we demonstrate orthogonal interlayer coupling at room temperature in an all-antiferromagnetic junction Fe2O3/Cr2O3/Fe2O3, where the Néel vectors in the top and bottom Fe2O3 layers are strongly orthogonally coupled and the coupling strength is significantly affected by the thickness of the antiferromagnetic Cr2O3 spacer. From the energy and symmetry analysis, the direct coupling via uniform magnetic ordering in Cr2O3 spacer in our junction is excluded. The coupling is proposed to be mediated by the non-uniform domain wall state in the spacer. The strong long-range coupling in an antiferromagnetic junction provides an unexplored approach for designing antiferromagnetic structures and makes it a promising building block for antiferromagnetic devices.

Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance., Dysregulated phosphorylation is well-known in cancers, but it has largely been studied in isolation from mutations. Here the authors introduce HotPho, a tool that can discover spatial interactions between phosphosites and mutations, which are associated with activating mutation and genetic dependencies in cancer.

Interferons (IFNs) are critical soluble factors in the immune system and are composed of three types, (I, II and III) that utilize different receptor complexes IFN-αR1/IFN-αR2, IFN-γR1/IFN-γR2, and IFN-λR1/IL-10R2, respectively. Here we identify IFN-υ from the genomic sequences of vertebrates. The members of class II cytokine receptors, IFN-υR1 and IL-10R2, are identified as the receptor complex of IFN-υ, and are associated with IFN-υ stimulated gene expression and antiviral activity in zebrafish (Danio rerio) and African clawed frog (Xenopus laevis). IFN-υ and IFN-υR1 are separately located at unique and highly conserved loci, being distinct from all other three-type IFNs. IFN-υ and IFN-υR1 are phylogenetically clustered with class II cytokines and class II cytokine receptors, respectively. Therefore, the finding of this IFN ligand-receptor system may be considered as a type IV IFN, in addition to the currently recognized three types of IFNs in vertebrates.

In-vitro metabolite and drug detection rely on designed materials-based analytical platforms, which are universally used in biomedical research and clinical practice. However, metabolic analysis in bio-samples needs tedious sample preparation, due to the sample complexity and low molecular abundance. A further challenge is to construct diagnostic tools. Herein, we developed a platform using silver nanoshells. We synthesized SiO2@Ag with tunable shell structures by multi-cycled silver mirror reactions. Optimized nanoshells achieved direct laser desorption/ionization mass spectrometry in 0.5 μL of bio-fluids. We applied these nanoshells for disease diagnosis and therapeutic evaluation. We identified patients with postoperative brain infection through daily monitoring and glucose quantitation in cerebrospinal fluid. We measured drug distribution in blood and cerebrospinal fluid systems and validated the function of blood-brain/cerebrospinal fluid-barriers for pharmacokinetics. Our work sheds light on the design of materials for advanced metabolic analysis and precision diagnostics., Preparation of samples for diagnosis can affect the detection of biomarkers and metabolites. Here, the authors use a silver nanoparticle plasmonics approach for the detection of biomarkers in patients as well as investigate the distribution of drugs in serum and cerebral spinal fluid.

Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities., National Cancer Institute (U.S.) (Grant R01CA180006)

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a global threat to wheat production. Aegilops tauschii, one of the wheat progenitors, carries the YrAS2388 locus for resistance to Pst on chromosome 4DS. We reveal that YrAS2388 encodes a typical nucleotide oligomerization domain-like receptor (NLR). The Pst-resistant allele YrAS2388R has duplicated 3’ untranslated regions and is characterized by alternative splicing in the nucleotide-binding domain. Mutation of the YrAS2388R allele disrupts its resistance to Pst in synthetic hexaploid wheat; transgenic plants with YrAS2388R show resistance to eleven Pst races in common wheat and one race of P. striiformis f. sp. hordei in barley. The YrAS2388R allele occurs only in Ae. tauschii and the Ae. tauschii-derived synthetic wheat; it is absent in 100% (n = 461) of common wheat lines tested. The cloning of YrAS2388R will facilitate breeding for stripe rust resistance in wheat and other Triticeae species., Stripe rust is a serious threat to wheat production. Here, the authors reveal that the resistance gene, only present in the wheat progenitor Aegilops tauschii and its derived synthetic wheat, encodes a nucleotide oligomerization domain-like receptor and confers resistance in common wheat and barley.

The strong coupling between antiferromagnetism and ferroelectricity at room temperature found in BiFeO3 generates high expectations for the design and development of technological devices with novel functionalities. However, the multi-domain nature of the material tends to nullify the properties of interest and complicates the thorough understanding of the mechanisms that are responsible for those properties. Here we report the realization of a BiFeO3 material in thin film form with single-domain behaviour in both its magnetism and ferroelectricity: the entire film shows its antiferromagnetic axis aligned along the crystallographic b axis and its ferroelectric polarization along the c axis. With this we are able to reveal that the canted ferromagnetic moment due to the Dzyaloshinskii–Moriya interaction is parallel to the a axis. Furthermore, by fabricating a Co/BiFeO3 heterostructure, we demonstrate that the ferromagnetic moment of the Co film does couple directly to the canted moment of BiFeO3., The coupling of ferroelectric and antiferromagnetic order in BiFeO3 makes it appealing for applications however the presence of domain structure acts to undermine this potential. Here, the authors demonstrate BiFeO3 thin films with a single domain of electrical polarization and canted antiferromagnetic order.

Electric-field control of magnetism requires deterministic control of the magnetic order and understanding of the magnetoelectric coupling in multiferroics like BiFeO

Although the size effect in ferroelectric thin films has been known for long time, the underlying mechanism is not yet fully understood and whether or not there is a critical thickness below which the ferroelectricity vanishes is still under debate. Here, we directly measure the thickness-dependent polarization in ultrathin PbZr0.2Ti0.8O3 films via quantitative annular bright field imaging. We find that the polarization is significantly suppressed for films, Understanding ferroelectricity at reduced dimensions will be important for future sub-nanoscale devices based on ferroelectrics. Using high resolution electron microscopy; Gao et al., observe the existence of a measurable polarization at a thickness of just 1.5-unit cells

Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities., Patient-derived xenografts recapitulate major genomic signatures and transcriptome profiles of their original tumours. Here, the authors, performing proteomic and phosphoproteomic analyses of 24 breast cancer PDX models, demonstrate that druggable candidates can be identified based on a comprehensive proteogenomic profiling.

The number of phalanges and joints are key features of digit ‘identity' and are central to limb functionality and evolutionary adaptation. Prior chick work indicated that digit phalanges and their associated joints arise in a different manner than the more sparsely jointed long bones, and their identity is regulated by differential signalling from adjacent interdigits. Currently, there is no genetic evidence for this model, and the molecular mechanisms governing digit joint specification remain poorly understood. Using genetic approaches in mouse, here we show that functional 5′Hoxd–Gli3 antagonism acts indirectly, through Bmp signalling from the interdigital mesenchyme, to regulate specification of joint progenitors, which arise in conjunction with phalangeal precursors at the digit tip. Phalanx number, although co-regulated, can be uncoupled from joint specification. We propose that 5′Hoxd genes and Gli3 are part of an interdigital signalling centre that sets net Bmp signalling levels from different interdigits to coordinately regulate phalanx and joint formation., The molecular mechanisms governing digit joint specification are poorly understood. Here, the authors identify the 5′Hoxd–Gli3 balance as a key regulator of the net interdigital Bmp signalling level in mouse, which in turn regulates phalanx and joint formation.

The interaction between Earth's magnetic field and the solar wind results in the formation of a collisionless bow shock 60,000–100,000 km upstream of our planet, as long as the solar wind fast magnetosonic Mach (hereafter Mach) number exceeds unity. Here, we present one of those extremely rare instances, when the solar wind Mach number reached steady values, The interaction between the Earth's magnetic field and the solar wind results in the formation of a collisionless bow shock. Here, the authors study an even in which the solar wind Mach number remained steadily below one, leading to the evanescence of the bow shock and loss of electrons in the outer belts.

At the ferroelectric surface, the broken translational symmetry induced bound charge should significantly alter the local atomic configurations. Experimentally revealing the atomic structure of ferroelectric surface, however, is very challenging due to the strong spatial variety between nano-sized domains, and strong interactions between the polarization and other structural parameters. Here, we study surface structures of Pb(Zr0.2Ti0.8)O3 thin film by using the annular bright-field imaging. We find that six atomic layers with suppressed polarization and a charged 180° domain wall are at negatively poled surfaces, no reconstruction exists at positively poled surfaces, and seven atomic layers with suppressed polarization and a charged 90° domain wall exist at nominally neutral surfaces in ferroelastic domains. Our results provide critical insights into engineering ferroelectric thin films, fine grain ceramics and surface chemistry devices. The state-of-the-art methodology demonstrated here can greatly advance our understanding of surface science for oxides., Miniature of electronic devices is attractive yet challenging due to structural variation at nanoscale. Here, Gao et al. report atomic imaging of reconstruction and unusual domain walls on Pb(Zr0.2Ti0.8)O3 surfaces, providing possibilities to engineer nanoscale structural change.

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine., Published sequencing data sets of cancer samples could be used to identify genetic variants associated with the risk of developing cancer. Here, Lu et al. analyse over 4,000 tumour-normal pairs to reveal variable frequencies of inherited susceptibilities across 12 cancer types and find enrichment of functionally validated missense variants of unknown significance.

Nature Communications 8: Article number: 14864 (2017)); Published: 28 March 2017; Updated: 25 April 2017 The original version of this Article contained a typographical error in the spelling of the author Beifang Niu, which was incorrectly given as Beifung Niu. This has now been corrected in both thePDF and HTML versions of the Article.