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The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Fertilization introduces parental genetic information into the zygote to guide embryogenesis. Parental contributions to postfertilization development have been discussed for decades, and the data available show that both parents contribute to the zygotic transcriptome, suggesting a paternal role in early embryogenesis 1-6 . However, because the specific paternal effects on postfertilization development and the molecular pathways underpinning these effects remain poorly understood, paternal contribution to early embryogenesis and plant development has not yet been adequately demonstrated 7 . Here our research shows that TREE1 and its homologue DAZ3 are expressed exclusively in Arabidopsis sperm. Despite presenting no evident defects in sperm development and fertilization, tree1 daz3 unexpectedly led to aberrant differentiation of the embryo root stem cell niche. This defect persisted in seedlings and disrupted root tip regeneration, comparable to congenital defects in animals. TREE1 and DAZ3 function by suppression of maternal RKD2 transcription, thus mitigating the detrimental maternal effects from RKD2 on root stem cell niche. Therefore, our findings illuminate how genetic deficiencies in sperm can exert enduring paternal effects on specific plant organ differentiation and how parental-of-origin genes interact to ensure normal embryogenesis. This work also provides a new concept of how gamete quality or genetic deficiency can affect specific plant organ formation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Harnessing genetic diversity in major staple crops through the development of new breeding capabilities is essential to ensure food security 1 . Here we examined the genetic and phenotypic diversity of the A. E. Watkins landrace collection 2 of bread wheat (Triticum aestivum), a major global cereal, by whole-genome re-sequencing of 827 Watkins landraces and 208 modern cultivars and in-depth field evaluation spanning a decade. We found that modern cultivars are derived from two of the seven ancestral groups of wheat and maintain very long-range haplotype integrity. The remaining five groups represent untapped genetic sources, providing access to landrace-specific alleles and haplotypes for breeding. Linkage disequilibrium-based haplotypes and association genetics analyses link Watkins genomes to the thousands of identified high-resolution quantitative trait loci and significant marker-trait associations. Using these structured germplasm, genotyping and informatics resources, we revealed many Watkins-unique beneficial haplotypes that can confer superior traits in modern wheat. Furthermore, we assessed the phenotypic effects of 44,338 Watkins-unique haplotypes, introgressed from 143 prioritized quantitative trait loci in the context of modern cultivars, bridging the gap between landrace diversity and current breeding. This study establishes a framework for systematically utilizing genetic diversity in crop improvement to achieve sustainable food security., (© 2024. The Author(s).)

Anthropogenic activities have substantially enhanced the loadings of reactive nitrogen (Nr) in the Earth system since pre-industrial times 1,2 , contributing to widespread eutrophication and air pollution 3-6 . Increased Nr can also influence global climate through a variety of effects on atmospheric and land processes but the cumulative net climate effect is yet to be unravelled. Here we show that anthropogenic Nr causes a net negative direct radiative forcing of -0.34 [-0.20, -0.50] W m -2 in the year 2019 relative to the year 1850. This net cooling effect is the result of increased aerosol loading, reduced methane lifetime and increased terrestrial carbon sequestration associated with increases in anthropogenic Nr, which are not offset by the warming effects of enhanced atmospheric nitrous oxide and ozone. Future predictions using three representative scenarios show that this cooling effect may be weakened primarily as a result of reduced aerosol loading and increased lifetime of methane, whereas in particular N 2 O-induced warming will probably continue to increase under all scenarios. Our results indicate that future reductions in anthropogenic Nr to achieve environmental protection goals need to be accompanied by enhanced efforts to reduce anthropogenic greenhouse gas emissions to achieve climate change mitigation in line with the Paris Agreement., (© 2024. The Author(s).)

Increasing planting density is a key strategy for enhancing maize yields 1-3 . An ideotype for dense planting requires a 'smart canopy' with leaf angles at different canopy layers differentially optimized to maximize light interception and photosynthesis 4-6 , among other features. Here we identified leaf angle architecture of smart canopy 1 (lac1), a natural mutant with upright upper leaves, less erect middle leaves and relatively flat lower leaves. lac1 has improved photosynthetic capacity and attenuated responses to shade under dense planting. lac1 encodes a brassinosteroid C-22 hydroxylase that predominantly regulates upper leaf angle. Phytochrome A photoreceptors accumulate in shade and interact with the transcription factor RAVL1 to promote its degradation via the 26S proteasome, thereby inhibiting activation of lac1 by RAVL1 and decreasing brassinosteroid levels. This ultimately decreases upper leaf angle in dense fields. Large-scale field trials demonstrate that lac1 boosts maize yields under high planting densities. To quickly introduce lac1 into breeding germplasm, we transformed a haploid inducer and recovered homozygous lac1 edits from 20 diverse inbred lines. The tested doubled haploids uniformly acquired smart-canopy-like plant architecture. We provide an important target and an accelerated strategy for developing high-density-tolerant cultivars, with lac1 serving as a genetic chassis for further engineering of a smart canopy in maize., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Ordered layered structures serve as essential components in lithium (Li)-ion cathodes 1-3 . However, on charging, the inherently delicate Li-deficient frameworks become vulnerable to lattice strain and structural and/or chemo-mechanical degradation, resulting in rapid capacity deterioration and thus short battery life 2,4 . Here we report an approach that addresses these issues using the integration of chemical short-range disorder (CSRD) into oxide cathodes, which involves the localized distribution of elements in a crystalline lattice over spatial dimensions, spanning a few nearest-neighbour spacings. This is guided by fundamental principles of structural chemistry and achieved through an improved ceramic synthesis process. To demonstrate its viability, we showcase how the introduction of CSRD substantially affects the crystal structure of layered Li cobalt oxide cathodes. This is manifested in the transition metal environment and its interactions with oxygen, effectively preventing detrimental sliding of crystal slabs and structural deterioration during Li removal. Meanwhile, it affects the electronic structure, leading to improved electronic conductivity. These attributes are highly beneficial for Li-ion storage capabilities, markedly improving cycle life and rate capability. Moreover, we find that CSRD can be introduced in additional layered oxide materials through improved chemical co-doping, further illustrating its potential to enhance structural and electrochemical stability. These findings open up new avenues for the design of oxide cathodes, offering insights into the effects of CSRD on the crystal and electronic structure of advanced functional materials., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Within the family of two-dimensional dielectrics, rhombohedral boron nitride (rBN) is considerably promising owing to having not only the superior properties of hexagonal boron nitride 1-4 -including low permittivity and dissipation, strong electrical insulation, good chemical stability, high thermal conductivity and atomic flatness without dangling bonds-but also useful optical nonlinearity and interfacial ferroelectricity originating from the broken in-plane and out-of-plane centrosymmetry 5-23 . However, the preparation of large-sized single-crystal rBN layers remains a challenge 24-26 , owing to the requisite unprecedented growth controls to coordinate the lattice orientation of each layer and the sliding vector of every interface. Here we report a facile methodology using bevel-edge epitaxy to prepare centimetre-sized single-crystal rBN layers with exact interlayer ABC stacking on a vicinal nickel surface. We realized successful accurate fabrication over a single-crystal nickel substrate with bunched step edges of the terrace facet (100) at the bevel facet (110), which simultaneously guided the consistent boron-nitrogen bond orientation in each BN layer and the rhombohedral stacking of BN layers via nucleation near each bevel facet. The pure rhombohedral phase of the as-grown BN layers was verified, and consequently showed robust, homogeneous and switchable ferroelectricity with a high Curie temperature. Our work provides an effective route for accurate stacking-controlled growth of single-crystal two-dimensional layers and presents a foundation for applicable multifunctional devices based on stacked two-dimensional materials., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Although modern humans left Africa multiple times over 100,000 years ago, those broadly ancestral to non-Africans dispersed less than 100,000 years ago 1 . Most models hold that these events occurred through green corridors created during humid periods because arid intervals constrained population movements 2 . Here we report an archaeological site-Shinfa-Metema 1, in the lowlands of northwest Ethiopia, with Youngest Toba Tuff cryptotephra dated to around 74,000 years ago-that provides early and rare evidence of intensive riverine-based foraging aided by the likely adoption of the bow and arrow. The diet included a wide range of terrestrial and aquatic animals. Stable oxygen isotopes from fossil mammal teeth and ostrich eggshell show that the site was occupied during a period of high seasonal aridity. The unusual abundance of fish suggests that capture occurred in the ever smaller and shallower waterholes of a seasonal river during a long dry season, revealing flexible adaptations to challenging climatic conditions during the Middle Stone Age. Adaptive foraging along dry-season waterholes would have transformed seasonal rivers into 'blue highway' corridors, potentially facilitating an out-of-Africa dispersal and suggesting that the event was not restricted to times of humid climates. The behavioural flexibility required to survive seasonally arid conditions in general, and the apparent short-term effects of the Toba supereruption in particular were probably key to the most recent dispersal and subsequent worldwide expansion of modern humans., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project 1-3 . We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Stable aluminosilicate zeolites with extra-large pores that are open through rings of more than 12 tetrahedra could be used to process molecules larger than those currently manageable in zeolite materials. However, until very recently 1-3 , they proved elusive. In analogy to the interlayer expansion of layered zeolite precursors 4,5 , we report a strategy that yields thermally and hydrothermally stable silicates by expansion of a one-dimensional silicate chain with an intercalated silylating agent that separates and connects the chains. As a result, zeolites with extra-large pores delimited by 20, 16 and 16 Si tetrahedra along the three crystallographic directions are obtained. The as-made interchain-expanded zeolite contains dangling Si-CH 3 groups that, by calcination, connect to each other, resulting in a true, fully connected (except possible defects) three-dimensional zeolite framework with a very low density. Additionally, it features triple four-ring units not seen before in any type of zeolite. The silicate expansion-condensation approach we report may be amenable to further extra-large-pore zeolite formation. Ti can be introduced in this zeolite, leading to a catalyst that is active in liquid-phase alkene oxidations involving bulky molecules, which shows promise in the industrially relevant clean production of propylene oxide using cumene hydroperoxide as an oxidant., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Noncoding DNA is central to our understanding of human gene regulation and complex diseases 1,2 , and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome 3-9 . Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA 10 , the relatively short timescales separating primate species 11 , and the previously limited availability of whole-genome sequences 12 . Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals., (© 2023. The Author(s).)

Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous β-phenylethylamine (β-PEA) 1 as well as methamphetamine 2 , an abused substance that has posed a severe threat to human health and society 3 . Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction 2,4,5 . Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and β-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT 1A R (refs. 6,7 ). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets 1-5 . Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development 6,7 . Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (G s ) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G s . The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Scalable generation of genuine multipartite entanglement with an increasing number of qubits is important for both fundamental interest and practical use in quantum-information technologies 1,2 . On the one hand, multipartite entanglement shows a strong contradiction between the prediction of quantum mechanics and local realization and can be used for the study of quantum-to-classical transition 3,4 . On the other hand, realizing large-scale entanglement is a benchmark for the quality and controllability of the quantum system and is essential for realizing universal quantum computing 5-8 . However, scalable generation of genuine multipartite entanglement on a state-of-the-art quantum device can be challenging, requiring accurate quantum gates and efficient verification protocols. Here we show a scalable approach for preparing and verifying intermediate-scale genuine entanglement on a 66-qubit superconducting quantum processor. We used high-fidelity parallel quantum gates and optimized the fidelitites of parallel single- and two-qubit gates to be 99.91% and 99.05%, respectively. With efficient randomized fidelity estimation 9 , we realized 51-qubit one-dimensional and 30-qubit two-dimensional cluster states and achieved fidelities of 0.637 ± 0.030 and 0.671 ± 0.006, respectively. On the basis of high-fidelity cluster states, we further show a proof-of-principle realization of measurement-based variational quantum eigensolver 10 for perturbed planar codes. Our work provides a feasible approach for preparing and verifying entanglement with a few hundred qubits, enabling medium-scale quantum computing with superconducting quantum systems., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The entry of SARS-CoV-2 into host cells depends on the refolding of the virus-encoded spike protein from a prefusion conformation, which is metastable after cleavage, to a lower-energy stable postfusion conformation 1,2 . This transition overcomes kinetic barriers for fusion of viral and target cell membranes 3,4 . Here we report a cryogenic electron microscopy (cryo-EM) structure of the intact postfusion spike in a lipid bilayer that represents the single-membrane product of the fusion reaction. The structure provides structural definition of the functionally critical membrane-interacting segments, including the fusion peptide and transmembrane anchor. The internal fusion peptide forms a hairpin-like wedge that spans almost the entire lipid bilayer and the transmembrane segment wraps around the fusion peptide at the last stage of membrane fusion. These results advance our understanding of the spike protein in a membrane environment and may guide development of intervention strategies., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Bacteroidetes are abundant members of the human microbiota, utilizing a myriad of diet- and host-derived glycans in the distal gut 1 . Glycan uptake across the bacterial outer membrane of these bacteria is mediated by SusCD protein complexes, comprising a membrane-embedded barrel and a lipoprotein lid, which is thought to open and close to facilitate substrate binding and transport. However, surface-exposed glycan-binding proteins and glycoside hydrolases also play critical roles in the capture, processing and transport of large glycan chains. The interactions between these components in the outer membrane are poorly understood, despite being crucial for nutrient acquisition by our colonic microbiota. Here we show that for both the levan and dextran utilization systems of Bacteroides thetaiotaomicron, the additional outer membrane components assemble on the core SusCD transporter, forming stable glycan-utilizing machines that we term utilisomes. Single-particle cryogenic electron microscopy structures in the absence and presence of substrate reveal concerted conformational changes that demonstrate the mechanism of substrate capture, and rationalize the role of each component in the utilisome., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds androgens mediating gene expression for sexual, somatic and behavioural functions, and is involved in various conditions including androgen insensitivity syndrome and prostate cancer 1 . Here we identified functional mutations in the formin and actin nucleator DAAM2 in patients with androgen insensitivity syndrome. DAAM2 was enriched in the nucleus, where its localization correlated with that of the AR to form actin-dependent transcriptional droplets in response to dihydrotestosterone. DAAM2 AR droplets ranged from 0.02 to 0.06 µm 3 in size and associated with active RNA polymerase II. DAAM2 polymerized actin directly at the AR to promote droplet coalescence in a highly dynamic manner, and nuclear actin polymerization is required for prostate-specific antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Chemical modifications of RNA have key roles in many biological processes 1-3 . N 7 -methylguanosine (m 7 G) is required for integrity and stability of a large subset of tRNAs 4-7 . The methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types 8-14 . Mutations in WDR4 cause human developmental phenotypes including microcephaly 15-17 . How METTL1-WDR4 modifies tRNA substrates and is regulated remains elusive 18 . Here we show,  through structural, biochemical and cellular studies of human METTL1-WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the αC region of METTL1 transforms into a helix, which together with the α6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1-WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Phytohormone signalling pathways have an important role in defence against pathogens mediated by cell-surface pattern recognition receptors and intracellular nucleotide-binding leucine-rich repeat class immune receptors 1,2 (NLR). Pathogens have evolved counter-defence strategies to manipulate phytohormone signalling pathways to dampen immunity and promote virulence 3 . However, little is known about the surveillance of pathogen interference of phytohormone signalling by the plant innate immune system. The pepper (Capsicum chinense) NLR Tsw, which recognizes the effector nonstructural protein NSs encoded by tomato spotted wilt orthotospovirus (TSWV), contains an unusually large leucine-rich repeat (LRR) domain. Structural modelling predicts similarity between the LRR domain of Tsw and those of the jasmonic acid receptor COI1, the auxin receptor TIR1 and the strigolactone receptor partner MAX2. This suggested that NSs could directly target hormone receptor signalling to promote infection, and that Tsw has evolved a LRR resembling those of phytohormone receptors LRR to induce immunity. Here we show that NSs associates with COI1, TIR1 and MAX2 through a common repressor-TCP21-which interacts directly with these phytohormone receptors. NSs enhances the interaction of COI1, TIR1 or MAX2 with TCP21 and blocks the degradation of corresponding transcriptional repressors to disable phytohormone-mediated host immunity to the virus. Tsw also interacts directly with TCP21 and this interaction is enhanced by viral NSs. Downregulation of TCP21 compromised Tsw-mediated defence against TSWV. Together, our findings reveal that a pathogen effector targets TCP21 to inhibit phytohormone receptor function, promoting virulence, and a plant NLR protein has evolved to recognize this interference as a counter-virulence strategy, thereby activating immunity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

How cell-to-cell copy number alterations that underpin genomic instability 1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer 2 , remains understudied. Here, by applying scaled single-cell whole-genome sequencing 3 to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct 'foreground' mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells., (© 2022. The Author(s).)

Acute myeloid leukaemia (AML) represents a set of heterogeneous myeloid malignancies, and hallmarks include mutations in epigenetic modifiers, transcription factors and kinases 1-5 . The extent to which mutations in AML drive alterations in chromatin 3D structure and contribute to myeloid transformation is unclear. Here we use Hi-C and whole-genome sequencing to analyse 25 samples from patients with AML and 7 samples from healthy donors. Recurrent and subtype-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing, ATAC with sequencing and CUT&Tag for CTCF, H3K27ac and H3K27me3 in the same AML samples also revealed extensive and recurrent AML-specific promoter-enhancer and promoter-silencer loops. We validated the role of repressive loops on their target genes by CRISPR deletion and interference. Structural variation-induced enhancer-hijacking and silencer-hijacking events were further identified in AML samples. Hijacked enhancers play a part in AML cell growth, as demonstrated by CRISPR screening, whereas hijacked silencers have a downregulating role, as evidenced by CRISPR-interference-mediated de-repression. Finally, whole-genome bisulfite sequencing of 20 AML and normal samples revealed the delicate relationship between DNA methylation, CTCF binding and 3D genome structure. Treatment of AML cells with a DNA hypomethylating agent and triple knockdown of DNMT1, DNMT3A and DNMT3B enabled the manipulation of DNA methylation to revert 3D genome organization and gene expression. Overall, this study provides a resource for leukaemia studies and highlights the role of repressive loops and hijacked cis elements in human diseases., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Polar auxin transport is unique to plants and coordinates their growth and development 1,2 . The PIN-FORMED (PIN) auxin transporters exhibit highly asymmetrical localizations at the plasma membrane and drive polar auxin transport 3,4 ; however, their structures and transport mechanisms remain largely unknown. Here, we report three inward-facing conformation structures of Arabidopsis thaliana PIN1: the apo state, bound to the natural auxin indole-3-acetic acid (IAA), and in complex with the polar auxin transport inhibitor N-1-naphthylphthalamic acid (NPA). The transmembrane domain of PIN1 shares a conserved NhaA fold 5 . In the substrate-bound structure, IAA is coordinated by both hydrophobic stacking and hydrogen bonding. NPA competes with IAA for the same site at the intracellular pocket, but with a much higher affinity. These findings inform our understanding of the substrate recognition and transport mechanisms of PINs and set up a framework for future research on directional auxin transport, one of the most crucial processes underlying plant development., (© 2022. The Author(s).)

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated 1 . Gestational diabetes has profound and enduring effects on the long-term health of the offspring 2,3 . However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote 4 , is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma 1-4 . Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial 5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries 6 . Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively 7-11 . Treatment combining 1 mg kg -1 nivolumab with 3 mg kg -1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer 12 . Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma., (© 2022. The Author(s).)

Superconductivity is a remarkably widespread phenomenon that is observed in most metals cooled to very low temperatures. The ubiquity of such conventional superconductors, and the wide range of associated critical temperatures, is readily understood in terms of the well-known Bardeen-Cooper-Schrieffer theory. Occasionally, however, unconventional superconductors are found, such as the iron-based materials, which extend and defy this understanding in unexpected ways. In the case of the iron-based superconductors, this includes the different ways in which the presence of multiple atomic orbitals can manifest in unconventional superconductivity, giving rise to a rich landscape of gap structures that share the same dominant pairing mechanism. In addition, these materials have also led to insights into the unusual metallic state governed by the Hund's interaction, the control and mechanisms of electronic nematicity, the impact of magnetic fluctuations and quantum criticality, and the importance of topology in correlated states. Over the fourteen years since their discovery, iron-based superconductors have proven to be a testing ground for the development of novel experimental tools and theoretical approaches, both of which have extensively influenced the wider field of quantum materials., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Nutrients are emerging regulators of adaptive immunity 1 . Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism 2-4 , but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (T reg ) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and T reg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse T reg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The identity of the earliest inhabitants of Xinjiang, in the heart of Inner Asia, and the languages that they spoke have long been debated and remain contentious 1 . Here we present genomic data from 5 individuals dating to around 3000-2800 BC from the Dzungarian Basin and 13 individuals dating to around 2100-1700 BC from the Tarim Basin, representing the earliest yet discovered human remains from North and South Xinjiang, respectively. We find that the Early Bronze Age Dzungarian individuals exhibit a predominantly Afanasievo ancestry with an additional local contribution, and the Early-Middle Bronze Age Tarim individuals contain only a local ancestry. The Tarim individuals from the site of Xiaohe further exhibit strong evidence of milk proteins in their dental calculus, indicating a reliance on dairy pastoralism at the site since its founding. Our results do not support previous hypotheses for the origin of the Tarim mummies, who were argued to be Proto-Tocharian-speaking pastoralists descended from the Afanasievo 1,2 or to have originated among the Bactria-Margiana Archaeological Complex 3 or Inner Asian Mountain Corridor cultures 4 . Instead, although Tocharian may have been plausibly introduced to the Dzungarian Basin by Afanasievo migrants during the Early Bronze Age, we find that the earliest Tarim Basin cultures appear to have arisen from a genetically isolated local population that adopted neighbouring pastoralist and agriculturalist practices, which allowed them to settle and thrive along the shifting riverine oases of the Taklamakan Desert., (© 2021. The Author(s).)

The phytohormone auxin controls many processes in plants, at least in part through its regulation of cell expansion 1 . The acid growth hypothesis has been proposed to explain auxin-stimulated cell expansion for five decades, but the mechanism that underlies auxin-induced cell-wall acidification is poorly characterized. Auxin induces the phosphorylation and activation of the plasma membrane H + -ATPase that pumps protons into the apoplast 2 , yet how auxin activates its phosphorylation remains unclear. Here we show that the transmembrane kinase (TMK) auxin-signalling proteins interact with plasma membrane H + -ATPases, inducing their phosphorylation, and thereby promoting cell-wall acidification and hypocotyl cell elongation in Arabidopsis. Auxin induced interactions between TMKs and H + -ATPases in the plasma membrane within seconds, as well as TMK-dependent phosphorylation of the penultimate threonine residue on the H+-ATPases. Our genetic, biochemical and molecular evidence demonstrates that TMKs directly phosphorylate plasma membrane H + -ATPase and are required for auxin-induced H + -ATPase activation, apoplastic acidification and cell expansion. Thus, our findings reveal a crucial connection between auxin and plasma membrane H + -ATPase activation in regulating apoplastic pH changes and cell expansion through TMK-based cell surface auxin signalling., (© 2021. The Author(s).)

Growth regulation tailors development in plants to their environment. A prominent example of this is the response to gravity, in which shoots bend up and roots bend down 1 . This paradox is based on opposite effects of the phytohormone auxin, which promotes cell expansion in shoots while inhibiting it in roots via a yet unknown cellular mechanism 2 . Here, by combining microfluidics, live imaging, genetic engineering and phosphoproteomics in Arabidopsis thaliana, we advance understanding of how auxin inhibits root growth. We show that auxin activates two distinct, antagonistically acting signalling pathways that converge on rapid regulation of apoplastic pH, a causative determinant of growth. Cell surface-based TRANSMEMBRANE KINASE1 (TMK1) interacts with and mediates phosphorylation and activation of plasma membrane H + -ATPases for apoplast acidification, while intracellular canonical auxin signalling promotes net cellular H + influx, causing apoplast alkalinization. Simultaneous activation of these two counteracting mechanisms poises roots for rapid, fine-tuned growth modulation in navigating complex soil environments., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The kagome lattice of transition metal atoms provides an exciting platform to study electronic correlations in the presence of geometric frustration and nontrivial band topology 1-18 , which continues to bear surprises. Here, using spectroscopic imaging scanning tunnelling microscopy, we discover a temperature-dependent cascade of different symmetry-broken electronic states in a new kagome superconductor, CsV 3 Sb 5 . We reveal, at a temperature far above the superconducting transition temperature T c  ~ 2.5 K, a tri-directional charge order with a 2a 0 period that breaks the translation symmetry of the lattice. As the system is cooled down towards T c , we observe a prominent V-shaped spectral gap opening at the Fermi level and an additional breaking of the six-fold rotational symmetry, which persists through the superconducting transition. This rotational symmetry breaking is observed as the emergence of an additional 4a 0 unidirectional charge order and strongly anisotropic scattering in differential conductance maps. The latter can be directly attributed to the orbital-selective renormalization of the vanadium kagome bands. Our experiments reveal a complex landscape of electronic states that can coexist on a kagome lattice, and highlight intriguing parallels to high-T c superconductors and twisted bilayer graphene., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The neocortex is disproportionately expanded in human compared with mouse 1,2 , both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth 3 . Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer's disease 4,5 . Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease., (© 2021. The Author(s).)

The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system 1 . These receptors probably exist as both homo- and heterodimers that have unique pharmacological and functional properties 2-4 . Here we report four cryo-electron microscopy structures of the human mGlu subtypes mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers; mGlu2 homodimer bound to an agonist and a positive allosteric modulator; and inactive mGlu2-mGlu7 heterodimer. We observed a subtype-dependent dimerization mode for these mGlus, as a unique dimer interface that is mediated by helix IV (and that is important for limiting receptor activity) exists only in the inactive mGlu2 structure. The structures provide molecular details of the inter- and intra-subunit conformational changes that are required for receptor activation, which distinguish class C G-protein-coupled receptors from those in classes A and B. Furthermore, our structure and functional studies of the mGlu2-mGlu7 heterodimer suggest that the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the heterodimer. These insights into mGlu homo- and heterodimers highlight the complex landscape of mGlu dimerization and activation.

The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system) 1 . It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation 2 . However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric G i protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu-G i structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs.

Alzheimer's disease (AD) is the most prevalent cause of dementia 1 . Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy 2,3 . Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain 4 , but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.

Upon gamete fusion, animal egg cells secrete proteases from cortical granules to establish a fertilization envelope as a block to polyspermy 1-4 . Fertilization in flowering plants is more complex and involves the delivery of two non-motile sperm cells by pollen tubes 5,6 . Simultaneous penetration of ovules by multiple pollen tubes (polytubey) is usually avoided, thus indirectly preventing polyspermy 7,8 . How plant egg cells regulate the rejection of extra tubes after successful fertilization is not known. Here we report that the aspartic endopeptidases ECS1 and ECS2 are secreted to the extracellular space from a cortical network located at the apical domain of the Arabidopsis egg cell. This reaction is triggered only after successful fertilization. ECS1 and ECS2 are exclusively expressed in the egg cell and transcripts are degraded immediately after gamete fusion. ECS1 and ESC2 specifically cleave the pollen tube attractor LURE1. As a consequence, polytubey is frequent in ecs1 ecs2 double mutants. Ectopic secretion of these endopeptidases from synergid cells led to a decrease in the levels of LURE1 and reduced the rate of pollen tube attraction. Together, these findings demonstrate that plant egg cells sense successful fertilization and elucidate a mechanism as to how a relatively fast post-fertilization block to polytubey is established by fertilization-induced degradation of attraction factors.

Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells 1 . By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis 1 . Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8 + T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (T reg ) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of T reg cells is dependent on T reg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with T reg cell function in the presence of glucose.

The intensive application of inorganic nitrogen underlies marked increases in crop production, but imposes detrimental effects on ecosystems 1,2 : it is therefore crucial for future sustainable agriculture to improve the nitrogen-use efficiency of crop plants. Here we report the genetic basis of nitrogen-use efficiency associated with adaptation to local soils in rice (Oryza sativa L.). Using a panel of diverse rice germplasm collected from different ecogeographical regions, we performed a genome-wide association study on the tillering response to nitrogen-the trait that is most closely correlated with nitrogen-use efficiency in rice-and identified OsTCP19 as a modulator of this tillering response through its transcriptional response to nitrogen and its targeting to the tiller-promoting gene DWARF AND LOW-TILLERING (DLT) 3,4 . A 29-bp insertion and/or deletion in the OsTCP19 promoter confers a differential transcriptional response and variation in the tillering response to nitrogen among rice varieties. The allele of OsTCP19 associated with a high tillering response to nitrogen is prevalent in wild rice populations, but has largely been lost in modern cultivars: this loss correlates with increased local soil nitrogen content, which suggests that it might have contributed to geographical adaptation in rice. Introgression of the allele associated with a high tillering response into modern rice cultivars boosts grain yield and nitrogen-use efficiency under low or moderate levels of nitrogen, which demonstrates substantial potential for rice breeding and the amelioration of negative environment effects by reducing the application of nitrogen to crops.

Cancer arises from malignant cells that exist in dynamic multilevel interactions with the host tissue. Cancer therapies aiming to directly kill cancer cells, including oncogene-targeted therapy and immune-checkpoint therapy that revives tumour-reactive cytotoxic T lymphocytes, are effective in some patients 1,2 , but acquired resistance frequently develops 3,4 . An alternative therapeutic strategy aims to rectify the host tissue pathology, including abnormalities in the vasculature that foster cancer progression 5,6 ; however, neutralization of proangiogenic factors such as vascular endothelial growth factor A (VEGFA) has had limited clinical benefits 7,8 . Here, following the finding that transforming growth factor-β (TGF-β) suppresses T helper 2 (T H 2)-cell-mediated cancer immunity 9 , we show that blocking TGF-β signalling in CD4 + T cells remodels the tumour microenvironment and restrains cancer progression. In a mouse model of breast cancer resistant to immune-checkpoint or anti-VEGF therapies 10,11 , inducible genetic deletion of the TGF-β receptor II (TGFBR2) in CD4 + T cells suppressed tumour growth. For pharmacological blockade, we engineered a bispecific receptor decoy by attaching the TGF-β-neutralizing TGFBR2 extracellular domain to ibalizumab, a non-immunosuppressive CD4 antibody 12,13 , and named it CD4 TGF-β Trap (4T-Trap). Compared with a non-targeted TGF-β-Trap, 4T-Trap selectively inhibited T H cell TGF-β signalling in tumour-draining lymph nodes, causing reorganization of tumour vasculature and cancer cell death, a process dependent on the T H 2 cytokine interleukin-4 (IL-4). Notably, the 4T-Trap-induced tumour tissue hypoxia led to increased VEGFA expression. VEGF inhibition enhanced the starvation-triggered cancer cell death and amplified the antitumour effect of 4T-Trap. Thus, targeted TGF-β signalling blockade in helper T cells elicits an effective tissue-level cancer defence response that can provide a basis for therapies directed towards the cancer environment.