Quantum simulation in a 71-site optical lattice certifies gauge invariance, showing how this essential property of lattice gauge theories can be maintained across a quantum phase transition. The modern description of elementary particles, as formulated in the standard model of particle physics, is built on gauge theories(1). Gauge theories implement fundamental laws of physics by local symmetry constraints. For example, in quantum electrodynamics Gauss's law introduces an intrinsic local relation between charged matter and electromagnetic fields, which protects many salient physical properties, including massless photons and a long-ranged Coulomb law. Solving gauge theories using classical computers is an extremely arduous task(2), which has stimulated an effort to simulate gauge-theory dynamics in microscopically engineered quantum devices(3-6). Previous achievements implemented density-dependent Peierls phases without defining a local symmetry(7,8), realized mappings onto effective models to integrate out either matter or electric fields(9-12), or were limited to very small systems(13-16). However, the essential gauge symmetry has not been observed experimentally. Here we report the quantum simulation of an extended U(1) lattice gauge theory, and experimentally quantify the gauge invariance in a many-body system comprising matter and gauge fields. These fields are realized in defect-free arrays of bosonic atoms in an optical superlattice of 71 sites. We demonstrate full tunability of the model parameters and benchmark the matter-gauge interactions by sweeping across a quantum phase transition. Using high-fidelity manipulation techniques, we measure the degree to which Gauss's law is violated by extracting probabilities of locally gauge-invariant states from correlated atom occupations. Our work provides a way to explore gauge symmetry in the interplay of fundamental particles using controllable large-scale quantum simulators.
Although maternal antibodies protect newborn babies from infection(1,2), little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice that lack the capacity to produce IgG are protected from infection with the enteric pathogen enterotoxigenic Escherichia coli by maternal natural IgG antibodies against the maternal microbiota when antibodies are delivered either across the placenta or through breast milk. By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that IgG derived from breast milk was crucial for protection against mucosal disease induced by enterotoxigenic E. coli. IgG also provides protection against systemic infection by E. coli. Pups used the neonatal Fc receptor to transfer IgG from milk into serum. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by enterotoxigenic E. coli and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers protection against enterotoxigenic E. coli in pups. This role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defence mechanism against infection in neonates. Neonatal mice are protected against infection with the enteric pathogen enterotoxigenic Escherichia coli by maternally derived natural antibodies as well as by maternal commensal microbiota that induce antibodies that recognize antigens expressed by Enterobacteriaceae.
Our understanding of how human embryos develop before gastrulation, including spatial self-organization and cell type ontogeny, remains limited by available two-dimensional technological platforms(1,2) that do not recapitulate the in vivo conditions(3-5). Here we report a three-dimensional (3D) blastocyst-culture system that enables human blastocyst development up to the primitive streak anlage stage. These 3D embryos mimic developmental landmarks and 3D architectures in vivo, including the embryonic disc, amnion, basement membrane, primary and primate unique secondary yolk sac, formation of anterior-posterior polarity and primitive streak anlage. Using single-cell transcriptome profiling, we delineate ontology and regulatory networks that underlie the segregation of epiblast, primitive endoderm and trophoblast. Compared with epiblasts, the amniotic epithelium shows unique and characteristic phenotypes. After implantation, specific pathways and transcription factors trigger the differentiation of cytotrophoblasts, extravillous cytotrophoblasts and syncytiotrophoblasts. Epiblasts undergo a transition to pluripotency upon implantation, and the transcriptome of these cells is maintained until the generation of the primitive streak anlage. These developmental processes are driven by different pluripotency factors. Together, findings from our 3D-culture approach help to determine the molecular and morphogenetic developmental landscape that occurs during human embryogenesis. A 3D culture system to model human embryonic development, together with single-cell transcriptome profiling, provides insights into the molecular developmental landscape during human post-implantation embryogenesis.
The hippocampus is an important part of the limbic system in the human brain that has essential roles in spatial navigation and the consolidation of information from short-term memory to long-term memory(1,2). Here we use single-cell RNA sequencing and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analysis to illustrate the cell types, cell linage, molecular features and transcriptional regulation of the developing human hippocampus. Using the transcriptomes of 30,416 cells from the human hippocampus at gestational weeks 16-27, we identify 47 cell subtypes and their developmental trajectories. We also identify the migrating paths and cell lineages of PAX6(+) and HOPX+ hippocampal progenitors, and regional markers of CA1, CA3 and dentate gyrus neurons. Multiomic data have uncovered transcriptional regulatory networks of the dentate gyrus marker PROX1. We also illustrate spatially specific gene expression in the developing human prefrontal cortex and hippocampus. The molecular features of the human hippocampus at gestational weeks 16-20 are similar to those of the mouse at postnatal days 0-5 and reveal gene expression differences between the two species. Transient expression of the primate-specific gene NBPF1 leads to a marked increase in PROX1(+) cells in the mouse hippocampus. These data provides a blueprint for understanding human hippocampal development and a tool for investigating related diseases. Single-cell RNA sequencing is used to catalogue and explore the developmental trajectories of more than 30,000 cells in the developing human hippocampus.
A synthetic approach is described, for efficiently converting non-van der Waals solids into two-dimensional van der Waals transition-metal chalcogenide layers with specific phases, enabling the high-throughput production of monolayers. Although two-dimensional (2D) atomic layers, such as transition-metal chalcogenides, have been widely synthesized using techniques such as exfoliation(1-3) and vapour-phase growth(4,5), it is still challenging to obtain phase-controlled 2D structures(6-8). Here we demonstrate an effective synthesis strategy via the progressive transformation of non-van der Waals (non-vdW) solids to 2D vdW transition-metal chalcogenide layers with identified 2H (trigonal prismatic)/1T (octahedral) phases. The transformation, achieved by exposing non-vdW solids to chalcogen vapours, can be controlled using the enthalpies and vapour pressures of the reaction products. Heteroatom-substituted (such as yttrium and phosphorus) transition-metal chalcogenides can also be synthesized in this way, thus enabling a generic synthesis approach to engineering phase-selected 2D transition-metal chalcogenide structures with good stability at high temperatures (up to 1,373 kelvin) and achieving high-throughput production of monolayers. We anticipate that these 2D transition-metal chalcogenides will have broad applications for electronics, catalysis and energy storage.
Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by 'reader' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatinreader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.
Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways(1). Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development(2,3). However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomaldominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
Water lilies belong to the angiosperm order Nymphaeales. Amborellales, Nymphaeales and Austrobaileyales together form the so-called ANA-grade of angiosperms, which are extant representatives of lineages that diverged the earliest from the lineage leading to the extant mesangiosperms(1-3). Here we report the 409-megabase genome sequence of the blue-petal water lily (Nymphaea colorata). Our phylogenomic analyses support Amborellales and Nymphaeales as successive sister lineages to all other extant angiosperms. The N. colorata genome and 19 other water lily transcriptomes reveal a Nymphaealean whole-genome duplication event, which is shared by Nymphaeaceae and possibly Cabombaceae. Among the genes retained from this whole-genome duplication are homologues of genes that regulate flowering transition and flower development. The broad expression of homologues of floral ABCE genes in N. colorata might support a similarly broadly active ancestral ABCE model of floral organ determination in early angiosperms. Water lilies have evolved attractive floral scents and colours, which are features shared with mesangiosperms, and we identified their putative biosynthetic genes in N. colorata. The chemical compounds and biosynthetic genes behind floral scents suggest that they have evolved in parallel to those in mesangiosperms. Because of its unique phylogenetic position, the N. colorata genome sheds light on the early evolution of angiosperms.
To address global challenges(1-4), 193 countries have committed to the 17 United Nations Sustainable Development Goals (SDGs)(5). Quantifying progress towards achieving the SDGs is essential to track global efforts towards sustainable development and guide policy development and implementation. However, systematic methods for assessing spatio-temporal progress towards achieving the SDGs are lacking. Here we develop and test systematic methods to quantify progress towards the 17 SDGs at national and subnational levels in China. Our analyses indicate that China's SDG Index score (an aggregate score representing the overall performance towards achieving all 17 SDGs) increased at the national level from 2000 to 2015. Every province also increased its SDG Index score over this period. There were large spatio-temporal variations across regions. For example, eastern China had a higher SDG Index score than western China in the 2000s, and southern China had a higher SDG Index score than northern China in 2015. At the national level, the scores of 13 of the 17 SDGs improved over time, but the scores of four SDGs declined. This study suggests the need to track the spatio-temporal dynamics of progress towards SDGs at the global level and in other nations.
The formation and growth of water-ice layers on surfaces and of low-dimensional ice under confinement are frequent occurrences(1-4). This is exemplified by the extensive reporting of two-dimensional (2D) ice on metals(5-11), insulating surfaces(12-16), graphite and graphene17,18 and under strong confinement(14,19-22). Although structured water adlayers and 2D ice have been imaged, capturing the metastable or intermediate edge structures involved in the 2D ice growth, which could reveal the underlying growth mechanisms, is extremely challenging, owing to the fragility and short lifetime of those edge structures. Here we show that noncontact atomic-force microscopy with a CO-terminated tip (used previously to image interfacial water with minimal perturbation)(12), enables real-space imaging of the edge structures of 2D bilayer hexagonal ice grown on a Au(111) surface. We find that armchair-type edges coexist with the zigzag edges usually observed in 2D hexagonal crystals, and freeze these samples during growth to identify the intermediate edge structures. Combined with simulations, these experiments enable us to reconstruct the growth processes that, in the case of the zigzag edge, involve the addition of water molecules to the existing edge and a collective bridging mechanism. Armchair edge growth, by contrast, involves local seeding and edge reconstruction and thus contrasts with conventional views regarding the growth of bilayer hexagonal ices and 2D hexagonal matter in general.
Phase separation is a cooperative process, the kinetics of which underpin the orderly morphogenesis of domain patterns on mesoscopic scales(1,2). Systems of highly degenerate frozen states may exhibit the rare and counterintuitive inverse-symmetrybreaking phenomenon(3). Proposed a century ago(4), inverse transitions have been found experimentally in disparate materials, ranging from polymeric and colloidal compounds to high-transition-temperature superconductors, proteins, ultrathin magnetic films, liquid crystals and metallic alloys(5,6), with the notable exception of ferroelectric oxides, despite extensive theoretical and experimental work on the latter. Here we show that following a subcritical quench, the non-equilibrium self-assembly of ferroelectric domains in ultrathin films of Pb(Zr0.4Ti0.6)O-3 results in a maze, or labyrinthine pattern, featuring meandering stripe domains. Furthermore, upon increasing the temperature, this highly degenerate labyrinthine phase undergoes an inverse transition whereby it transforms into the less-symmetric parallel-stripe domain structure, before the onset of paraelectricity at higher temperatures. We find that this phase sequence can be ascribed to an enhanced entropic contribution of domain walls, and that domain straightening and coarsening is predominantly driven by the relaxation and diffusion of topological defects. Computational modelling and experimental observation of the inverse dipolar transition in BiFeO3 suggest the universality of the phenomenon in ferroelectric oxides. The multitude of self-patterned states and the various topological defects that they embody may be used beyond current domain and domain-wall-based(7) technologies by enabling fundamentally new design principles and topologically enhanced functionalities within ferroelectric films.
Moire lattices consist of two superimposed identical periodic structures with a relative rotation angle. Moire lattices have several applications in everyday life, including artistic design, the textile industry, architecture, image processing, metrology and interferometry. For scientific studies, they have been produced using coupled graphene-hexagonal boron nitride monolayers(1,2), graphene-graphene layers(3,4) and graphene quasicrystals on a silicon carbide surface(5). The recent surge of interest in moire lattices arises from the possibility of exploring many salient physical phenomena in such systems; examples include commensurable-incommensurable transitions and topological defects(2), the emergence of insulating states owing to band flattening(3,6), unconventional superconductivity(4) controlled by the rotation angle(7,8), the quantum Hall effect(9), the realization of non-Abelian gauge potentials(10) and the appearance of quasicrystals at special rotation angles(11). A fundamental question that remains unexplored concerns the evolution of waves in the potentials defined by moire lattices. Here we experimentally create two-dimensional photonic moire lattices, which-unlike their material counterparts-have readily controllable parameters and symmetry, allowing us to explore transitions between structures with fundamentally different geometries (periodic, general aperiodic and quasicrystal). We observe localization of light in deterministic linear lattices that is based on flatband physics(6), in contrast to previous schemes based on light diffusion in optical quasicrystals(12), where disorder is required(13) for the onset of Anderson localization(14) (that is, wave localization in random media). Using commensurable and incommensurable moire patterns, we experimentally demonstrate the twodimensional localization-delocalization transition of light. Moire lattices may feature an almost arbitrary geometry that is consistent with the crystallographic symmetry groups of the sublattices, and therefore afford a powerful tool for controlling the properties of light patterns and exploring the physics of periodic-aperiodic phase transitions and two-dimensional wavepacket phenomena relevant to several areas of science, including optics, acoustics, condensed matter and atomic physics.
Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer(1-4). EMTs are driven by SNAIL, ZEB and TWIST transcription factors(5,6) together with microRNAs that balance this regulatory network(7,8). Transforming growth factor beta (TGF-beta) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-beta signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer(4,11). TGF-beta depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12-19. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector(20,21), as a key partner of TGF-beta-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-beta-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-beta-SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal-SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-beta pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer. RAS and TGF-beta pathways regulate distinct modes of epithelial-to-mesenchymal transition via RAS-responsive element binding protein 1.