Nature

10 Nov 2022

Volume 611 | Issue 7935

Articles

1.Shock cooling of a red-supergiant supernova at redshift 3 in lensed images下载原文

First /Corresponding Author:

Wenlei Chen

Affiliations:

School of Physics and Astronomy, University of Minnesota, Minneapolis, MN, USA

Abstract:

The core-collapse supernova of a massive star rapidly brightens when a shock, produced following the collapse of its core, reaches the stellar surface. As the shock-heated star subsequently expands and cools, its early-time light curve should have a simple dependence on the size of the progenitor and therefore final evolutionary state. Measurements of the radius of the progenitor from early light curves exist for only a small sample of nearby supernovae, and almost all lack constraining ultraviolet observations within a day of explosion. The several-day time delays and magnifying ability of galaxy-scale gravitational lenses, however, should provide a powerful tool for measuring the early light curves of distant supernovae, and thereby studying massive stellar populations at high redshift. Here we analyse individual rest-frame exposures in the ultraviolet to the optical taken with the Hubble Space Telescope, which simultaneously capture, in three separate gravitationally lensed images, the early phases of a supernova at redshift z≈3 beginning within 5.8±3.1hours of explosion. The supernova, seen at a lookback time of approximately 11.5billion years, is strongly lensed by an early-type galaxy in the Abell370 cluster. We constrain the pre-explosion radius to be 533(+154/−119)solar radii, consistent with a red supergiant. Highly confined and massive circumstellar material at the same radius can also reproduce the light curve, but because no similar low-redshift examples are known, this is unlikely.

2.Quantum field simulator for dynamics in curved spacetime下载原文

First / Corresponding Author:

Celia Viermann

Affiliations:

Kirchhoff-Institut für Physik, Universität Heidelberg, Heidelberg, Germany

Abstract:

In most cosmological models, rapid expansion of space marks the first moments of the Universe and leads to the amplification of quantum fluctuations. The description of subsequent dynamics and related questions in cosmology requires an understanding of the quantum fields of the standard model and dark matter in curved spacetime. Even the reduced problem of a scalar quantum field in an explicitly time-dependent spacetime metric is a theoretical challenge, and thus a quantum field simulator can lead to insights. Here we demonstrate such a quantum field simulator in a two-dimensional Bose–Einstein condensate with a configurable trap and adjustable interaction strength to implement this model system. We explicitly show the realization of spacetimes with positive and negative spatial curvature by wave-packet propagation and observe particle-pair production in controlled power-law expansion of space, using Sakharov oscillations to extract amplitude and phase information of the produced state. We find quantitative agreement with analytical predictions for different curvatures in time and space. This benchmarks and thereby establishes a quantum field simulator of a new class. In the future, straightforward upgrades offer the possibility to enter unexplored regimes that give further insight into relativistic quantum field dynamics.

3.Measured proton electromagnetic structure deviates from theoretical predictions下载原文

First / Corresponding Author:

N. Sparveris

Affiliation:

Temple University, Philadelphia, PA, USA

Abstract:

The visible world is founded on the proton, the only composite building block of matter that is stable in nature. Consequently, understanding the formation of matter relies on explaining the dynamics and the properties of the proton’s bound state. A fundamental property of the proton involves the response of the system to an external electromagnetic field. It is characterized by the electromagnetic polarizabilities that describe how easily the charge and magnetization distributions inside the system are distorted by the electromagnetic field. Moreover, the generalized polarizabilities map out the resulting deformation of the densities in a proton subject to an electromagnetic field. They disclose essential information about the underlying system dynamics and provide a key for decoding the proton structure in terms of the theory of the strong interaction that binds its elementary quark and gluon constituents. Of particular interest is a puzzle in the electric generalized polarizability of the proton that remains unresolved for two decades. Here we report measurements of the proton’s electromagnetic generalized polarizabilities at low four-momentum transfer squared. We show evidence of an anomaly to the behaviour of the proton’s electric generalized polarizability that contradicts the predictions of nuclear theory and derive its signature in the spatial distribution of the induced polarization in the proton. The reported measurements suggest the presence of a new, not-yet-understood dynamical mechanism in the proton and present notable challenges to the nuclear theory.

4.A solution-processed n-type conducting polymer with ultrahigh conductivity下载原文

First Author:

Haoran Tang①

Corresponding Author:

Fei Huang②

Affiliations:

Institute of Polymer Optoelectronic Materials and Devices, State Key Laboratory of Luminescent Materials and Devices, South China University of Technology (SCUT), Guangzhou, China①②

Abstract:

Conducting polymers (CPs) with high conductivity and solution processability have made great advances since the pioneering work on doped polyacetylene, thus creating the new field of ‘organic synthetic metals. Various high-performance CPs have been realized, which enable the applications of several organic electronic devices. Nevertheless, most CPs exhibit hole-dominant (p-type) transport behaviour, whereas the development of n-type analogues lags far behind and only a few exhibit metallic state, typically limited by low doping efficiency and ambient instability. Here we present a facilely synthesized highly conductive n-type polymer poly(benzodifurandione) (PBFDO). The reaction combines oxidative polymerization and in situ reductive n-doping, greatly increasing the doping efficiency, and a doping level of almost 0.9 charges per repeating unit can be achieved. The resultant polymer exhibits a breakthrough conductivity of more than 2,000Scm−1 with excellent stability and an unexpected solution processability without extra side chains or surfactants. Furthermore, detailed investigations on PBFDO show coherent charge-transport properties and existence of metallic state. The benchmark performances in electrochemical transistors and thermoelectric generators are further demonstrated, thus paving the way for application of the n-type CPs in organic electronics.

5.Surface reaction for efficient and stable inverted perovskite solar cells下载原文

First Author:

Qi Jiang①

Corresponding Author:

Yanfa Yan②

Affiliations:

Chemistry and Nanoscience Center, National Renewable Energy Laboratory, Golden, CO, USA①

Department of Physics and Astronomy and Wright Center for Photovoltaics Innovation and Commercialization,

University of Toledo, Toledo, OH, USA②

Abstract:

Perovskite solar cells (PSCs) with an inverted structure (often referred to as the p–i–n architecture) are attractive for future commercialization owing to their easily scalable fabrication, reliable operation and compatibility with a wide range of perovskite-based tandem device architectures. However, the power conversion efficiency (PCE) of p–i–n PSCs falls behind that of n–i–p (or normal) structure counterparts. This large performance gap could undermine efforts to adopt p–i–n architectures, despite their other advantages. Given the remarkable advances in perovskite bulk materials optimization over the past decade, interface engineering has become the most important strategy to push PSC performance to its limit. Here we report a reactive surface engineering approach based on a simple post-growth treatment of 3-(aminomethyl) pyridine (3-APy) on top of a perovskite thin film. First, the 3-APy molecule selectively reacts with surface formamidinium ions, reducing perovskite surface roughness and surface potential fluctuations associated with surface steps and terraces. Second, the reaction product on the perovskite surface decreases the formation energy of charged iodine vacancies, leading to effective n-type doping with a reduced work function in the surface region. With this reactive surface engineering, the resulting p–i–n PSCs obtained a PCE of over 25per cent, along with retaining 87per cent of the initial PCE after over 2,400hours of 1-sun operation at about 55degrees Celsius in air.

6. Functional CeOx nanoglues for robust atomically dispersed catalysts下载原文

First Author:

Xu Li①

Corresponding Author:

Jie Zeng②

Affiliations:

Department of Physics, Arizona State University, Tempe, AZ, USA①

Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, P. R. China①

Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, P. R. China②

Key Laboratory of Surface and Interface Chemistry and Energy Catalysis of Anhui Higher Education Institutes, University of Science and Technology of China, Hefei, P. R. China②

Department of Chemical Physics, University of Science and Technology of China, Hefei, P. R. China②

Abstract:

Single-atom catalysts make exceptionally efficient use of expensive noble metals and can bring out unique properties. However, applications are usually compromised by limited catalyst stability, which is due to sintering. Although sintering can be suppressed by anchoring the metal atoms to oxide supports, strong metal–oxygen interactions often leave too few metal sites available for reactant binding and catalysis, and when exposed to reducing conditions at sufficiently high temperatures, even oxide-anchored single-atom catalysts eventually sinter. Here we show that the beneficial effects of anchoring can be enhanced by confining the atomically dispersed metal atoms on oxide nanoclusters or ‘nanoglues’, which themselves are dispersed and immobilized on a robust, high-surface-area support. We demonstrate the strategy by grafting isolated and defective CeOx nanoglue islands onto high-surface-area SiO2; the nanoglue islands then each host on average one Pt atom. We find that the Pt atoms remain dispersed under both oxidizing and reducing environments at high temperatures, and that the activated catalyst exhibits markedly increased activity for CO oxidation. We attribute the improved stability under reducing conditions to the support structure and the much stronger affinity of Pt atoms for CeOx than for SiO2, which ensures the Pt atoms can move but remain confined to their respective nanoglue islands. The strategy of using functional nanoglues to confine atomically dispersed metals and simultaneously enhance their reactivity is general, and we anticipate that it will take single-atom catalysts a step closer to practical applications.

7. Separating water isotopologues using diffusion-regulatory porous materials下载原文

First Author:

Yan Su①

Corresponding Author:

Cheng Gu②

Affiliations:

State Key Laboratory of Luminescent Materials and Devices, Institute of Polymer Optoelectronic Materials and Devices, South China University of Technology, Guangzhou, P. R. China①②

Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, South China University of Technology, Guangzhou, P. R. China②

Abstract:

The discovery of a method to separate isotopologues, molecular entities that differ in only isotopic composition, is fundamentally and technologically essential but remains challenging. Water isotopologues, which are very important in biological processes, industry, medical care, etc. are among the most difficult isotopologue pairs to separate because of their very similar physicochemical properties and chemical exchange equilibrium. Herein, we report efficient separation of water isotopologues at room temperature by constructing two porous coordination polymers (PCPs, or metal–organic frameworks) in which flip-flop molecular motions within the frameworks provide diffusion-regulatory functionality. Guest traffic is regulated by the local motions of dynamic gates on contracted pore apertures, thereby amplifying the slight differences in the diffusion rates of water isotopologues. Significant temperature-responsive adsorption occurs on both PCPs: H2O vapour is preferentially adsorbed into the PCPs, with substantially increased uptake compared to that of D2O vapour, facilitating kinetics-based vapour separation of H2O/HDO/D2O ternary mixtures with high H2O separation factors of around 210 at room temperature.

8.Two annual cycles of the Pacific cold tongue under orbital precession下载原文

First /Corresponding Author:

John C. H. Chiang

Affiliations:

Department of Geography, University of California, Berkeley, CA, USA

Research Institute for Environmental Changes, Academia Sinica, Taipei, Taiwan ROC

Abstract:

The Pacific cold tongue annual cycle in sea surface temperature is presumed to be driven by Earth’s axial tilt (tilt effect), and thus its phasing should be fixed relative to the calendar. However, its phase and amplitude change dramatically and consistently under various configurations of orbital precession in several Earth System models. Here, we show that the cold tongue possesses another annual cycle driven by the variation in Earth–Sun distance (distance effect) from orbital eccentricity. As the two cycles possess slightly different periodicities, their interference results in a complex evolution of the net seasonality over a precession cycle. The amplitude from the distance effect increases linearly with eccentricity and is comparable to the amplitude from the tilt effect for the largest eccentricity values over the last million years (e value approximately 0.05). Mechanistically, the distance effect on the cold tongue arises through a seasonal longitudinal shift in the Walker circulation and subsequent annual wind forcing on the tropical Pacific dynamic ocean–atmosphere system. The finding calls for reassessment of current understanding of the Pacific cold tongue annual cycle and re-evaluation of tropical Pacific palaeoclimate records for annual cycle phase changes.

9.Light competition drives herbivore and nutrient effects on plant diversity下载原文

First / Corresponding Author:

Anu Eskelinen

Affiliations:

Department of Ecology and Genetics, University of Oulu, Oulu, Finland

Department of Physiological Diversity, Helmholtz Centre for Environmental Research–UFZ, Leipzig, Germany

German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany

Department of Ecology and Genetics, University of Oulu, Oulu, Finland

Abstract:

Enrichment of nutrients and loss of herbivores are assumed to cause a loss of plant diversity in grassland ecosystems because they increase plant cover, which leads to a decrease of light in the understory. Empirical tests of the role of competition for light in natural systems are based on indirect evidence, and have been a topic of debate for the last 40 years. Here we show that experimentally restoring light to understory plants in a natural grassland mitigates the loss of plant diversity that is caused by either nutrient enrichment or the absence of mammalian herbivores. The initial effect of light addition on restoring diversity under fertilization was transitory and outweighed by the greater effect of herbivory on light levels, indicating that herbivory is a major factor that controls diversity, partly through light. Our results provide direct experimental evidence, in a natural system, that competition for light is a key mechanism that contributes to the loss of biodiversity after cessation of mammalian herbivory. Our findings also show that the effects of herbivores can outpace the effects of fertilization on competition for light. Management practices that target maintaining grazing by native or domestic herbivores could therefore have applications in protecting biodiversity in grassland ecosystems, because they alleviate competition for light in the understory.

10.Environmental signal in the evolutionary diversification of bird skeletons下载原文

First / Corresponding Author:

Guillermo Navalón

Affiliations:

Department of Earth Sciences, University of Cambridge, Cambridge, UK

Department of Earth Sciences, University of Oxford, Oxford, UK

Unidad de Paleontología, Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain

Abstract:

Characterizing how variation in the tempo and mode of evolution has structured the phenotypic diversity of extant species is a central goal of macroevolution. However, studies are typically limited to a handful of traits, providing incomplete information. We analyse morphological diversification in living birds, an ecologically diverse group, documenting structural scales from ‘pan-skeletal’ proportions down to the localized three-dimensional shape changes of individual bones. We find substantial variation in evolutionary modes among avian subgroups and among skeletal parts, indicating widespread mosaicism and possible differences in the structure of the macroevolutionary landscape across Earth’s main environments. Water-linked groups, especially Aequorlitornithes (waterbirds), have repeatedly explored a large portion of their total morphospace, emphasizing variation in body proportions and in the shape of bones close to the body core, which are functionally related to the mechanics of locomotion. By contrast, landbirds (Inopinaves) evolved distinct, group-specific body forms early in the aftermath of the K-Pg and subsequently emphasized local shape variation, especially in the head and distal limb bones, which interact more directly with the environment. Passerines, which comprise more than half of all bird species, show a conservative evolutionary dynamic that resulted in low disparity across all skeletal parts. Evidence for early establishment of the morphospace of living birds is clear for some skeletal parts, including beaks and the combined skeletal morphology. However, we find little evidence for early partitioning of that morphospace, contrary to more specific predictions of ‘niche-filling’ models. Nevertheless, early divergence among broad environmental types may have caused an early divergence of evolutionary modes, suggesting an important role for environmental divergence in structuring the radiation of crown-group birds.

11.Evolution of immune genes is associated with the Black Death下载原文

First Author:

Jennifer Klunk①

Corresponding Author:

Luis B. Barreiro②

Affiliations:

McMaster Ancient DNA Centre, Departments of Anthropology, Biology and Biochemistry, McMaster University, Hamilton, Ontario, Canada①

Daicel Arbor Biosciences, Ann Arbor, MI, USA①

Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA②

Department of Human Genetics, University of Chicago, Chicago, IL, USA②

Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA②

Committee on Immunology, University of Chicago, Chicago, IL, USA②

Abstract:

Infectious diseases are among the strongest selective pressures driving human evolution. This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis. This pandemic devastated Afro-Eurasia, killing up to 30–50% of the population. To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.

12.Fast resupply of synaptic vesicles requires synaptotagmin-3下载原文

First Author:

Dennis J. Weingarten①

Corresponding Author:

Skyler L. Jackman②

Affiliations:

Vollum Institute, Oregon Health and Science University, Portland, OR, USA①②

Abstract:

Sustained neuronal activity demands a rapid resupply of synaptic vesicles to maintain reliable synaptic transmission. Such vesicle replenishment is accelerated by submicromolar presynaptic Ca2+ signals by an as-yet unidentified high-affinity Ca2+ sensor. Here we identify synaptotagmin-3 (SYT3) as that presynaptic high-affinity Ca2+ sensor, which drives vesicle replenishment and short-term synaptic plasticity. Synapses in Syt3 knockout mice exhibited enhanced short-term depression, and recovery from depression was slower and insensitive to presynaptic residual Ca2+. During sustained neuronal firing, SYT3 accelerated vesicle replenishment and increased the size of the readily releasable pool. SYT3 also mediated short-term facilitation under conditions of low release probability and promoted synaptic enhancement together with another high-affinity synaptotagmin, SYT7 (ref.). Biophysical modelling predicted that SYT3 mediates both replenishment and facilitation by promoting the transition of loosely docked vesicles to tightly docked, primed states. Our results reveal a crucial role for presynaptic SYT3 in the maintenance of reliable high-frequency synaptic transmission. Moreover, multiple forms of short-term plasticity may converge on a mechanism of reversible, Ca2+-dependent vesicle docking.

13. Viruses inhibit TIR gcADPR signalling to overcome bacterial defence下载原文

First Author:

Azita Leavitt①

Corresponding Author:

Philip J. Kranzusch②

Affiliations:

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel①②

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA②

Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, USA②

Abstract:

The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants and animals. In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signalling molecule whose molecular structure remains elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function. We identified a large family of phage-encoded proteins, denoted here as Thoeris anti-defence1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are ‘sponges’ that bind and sequester the immune signalling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. Tad1 can also efficiently sequester molecules derived from a plant TIR-domain protein, and a high-resolution crystal structure of Tad1 bound to a plant-derived molecule showed a unique chemical structure of 1 ′′–2′ glycocyclic ADPR (gcADPR). Our data furthermore suggest that Thoeris TIR proteins produce a closely related molecule, 1′′–3′ gcADPR, which activates ThsA an order of magnitude more efficiently than the plant-derived 1′′–2′ gcADPR. Our results define the chemical structure of a central immune signalling molecule and show a new mode of action by which pathogens can suppress host immunity.

14. A multinational Delphi consensus to end the COVID-19 public health threat下载原文

First / Corresponding Author:

Jeffrey V. Lazarus

Affiliations:

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain

Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain

City University of New York Graduate School of Public Health and Health Policy (CUNY SPH), New York City, NY, USA

Abstract:

Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic. Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches, while maintaining proven prevention measures using a vaccines-plus approach2that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with >5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.

15. Common human genetic variants of APOE impact murine COVID-19 mortality下载原文

First / Corresponding Author:

Benjamin N. Ostendorf

Affiliations:

Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA

Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany

Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin,

Germany

Abstract:

Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world’s population and associated with Alzheimer’s disease, atherosclerosis and anti-tumour immunity, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P=2.6×10−7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.

16. Functional antibodies exhibit light chain coherence下载原文

First / Corresponding Author:

David B. Jaffe

Affiliation:

Genomics, Pleasanton, CA, USA

Abstract:

The vertebrate adaptive immune system modifies the genome of individual B cells to encode antibodies that bind particular antigens. In most mammals, antibodies are composed of heavy and light chains that are generated sequentially by recombination of V, D (for heavy chains), J and C gene segments. Each chain contains three complementarity-determining regions (CDR1–CDR3), which contribute to antigen specificity. Certain heavy and light chains are preferred for particular antigens. Here we consider pairs of B cells that share the same heavy chain V gene and CDRH3 amino acid sequence and were isolated from different donors, also known as public clonotypes. We show that for naive antibodies (those not yet adapted to antigens), the probability that they use the same light chain V gene is around 10%, whereas for memory (functional) antibodies, it is around 80%, even if only one cell per clonotype is used. This property of functional antibodies is a phenomenon that we call light chain coherence. We also observe this phenomenon when similar heavy chains recur within a donor. Thus, although naive antibodies seem to recur by chance, the recurrence of functional antibodies reveals surprising constraint and determinism in the processes of V(D)J recombination and immune selection. For most functional antibodies, the heavy chain determines the light chain.

17. Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes下载原文

First Author:

Teh-Wei Wang①

Corresponding Author:

Yoshikazu Johmura②

Affiliations:

Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan①②

Division of Cancer and Senescence Biology, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa,

Japan②

Abstract:

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1− cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP). Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes. These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.

18. Extracellular fluid viscosity enhances cell migration and cancer dissemination下载原文

First Author:

Kaustav Bera①

Corresponding Author:

Konstantinos Konstantopoulos②

Affiliations:

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD,USA①②

Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA①②

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of

Medicine, Baltimore, MD, USA②

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA②

Abstract:

Cells respond to physical stimuli, such as stiffness, fluid shear stress and hydraulic pressure. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.

19. Structural basis of actin filament assembly and aging下载原文

First Author:

Wout Oosterheert①

Corresponding Author:

Stefan Raunser②

Affiliations:

Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany①②

Abstract:

The dynamic turnover of actin filaments (F-actin) controls cellular motility in eukaryotes and is coupled to changes in the F-actin nucleotide state. It remains unclear how F-actin hydrolyses ATP and subsequently undergoes subtle conformational rearrangements that ultimately lead to filament depolymerization by actin-binding proteins. Here we present cryo-electron microscopy structures of F-actin in all nucleotide states, polymerized in the presence of Mg2+ or Ca2+ at approximately 2.2Å resolution. The structures show that actin polymerization induces the relocation of water molecules in the nucleotide-binding pocket, activating one of them for the nucleophilic attack of ATP. Unexpectedly, the back door for the subsequent release of inorganic phosphate (Pi) is closed in all structures, indicating that Pi release occurs transiently. The small changes in the nucleotide-binding pocket after ATP hydrolysis and Pi release are sensed by a key amino acid, amplified and transmitted to the filament periphery. Furthermore, differences in the positions of water molecules in the nucleotide-binding pocket explain why Ca2+-actin shows slower polymerization rates than Mg2+-actin. Our work elucidates the solvent-driven rearrangements that govern actin filament assembly and aging and lays the foundation for the rational design of drugs and small molecules for imaging and therapeutic applications.

20.Bending forces and nucleotide state jointly regulate F-actin structure下载原文

First Author:

Matthew J. Reynolds

Corresponding Author:

Gregory M. Alushin

Affiliation:

Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, NY, USA

Abstract:

ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation. In turn, force and actin filament (F-actin) nucleotide state regulate actin dynamics by tuning F-actin’s engagement of actin-binding proteins through mechanisms that are unclear. Here we show that the nucleotide state of actin modulates F-actin structural transitions evoked by bending forces. Cryo-electron microscopy structures of ADP–F-actin and ADP-Pi–F-actin with sufficient resolution to visualize bound solvent reveal intersubunit interfaces bridged by water molecules that could mediate filament lattice flexibility. Despite extensive ordered solvent differences in the nucleotide cleft, these structures feature nearly identical lattices and essentially indistinguishable protein backbone conformations that are unlikely to be discriminable by actin-binding proteins. We next introduce a machine-learning-enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain-level detail. Bent F-actin structures reveal rearrangements at intersubunit interfaces characterized by substantial alterations of helical twist and deformations in individual protomers, transitions that are distinct in ADP–F-actin and ADP-Pi–F-actin. This suggests that phosphate rigidifies actin subunits to alter the bending structural landscape of F-actin. As bending forces evoke nucleotide-state dependent conformational transitions of sufficient magnitude to be detected by actin-binding proteins, we propose that actin nucleotide state can serve as a co-regulator of F-actin mechanical regulation.

21.Subtype-specific 3D genome alteration in acute myeloid leukaemia下载原文

First Author:

Jie Xu①

Corresponding Author:

Feng Yue②

Affiliations:

Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University,

Chicago, IL, USA①

Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Penn State University,

Hershey, PA, USA①②

Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago,

IL, USA②

Abstract:

Acute myeloid leukaemia (AML) represents a set of heterogeneous myeloid malignancies, and hallmarks include mutations in epigenetic modifiers, transcription factors and kinases. 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.

22.Cryo-EM structure of the SEA complex下载原文

First Author:

Lucas Tafur①

Corresponding Author:

Robbie Loewith②

Affiliations:

Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland①②

Swiss National Centre for Competence in Research (NCCR) in Chemical

Biology, University of Geneva, Geneva, Switzerland②

Abstract:

The SEA complex (SEAC) is a growth regulator that acts as a GTPase-activating protein (GAP) towards Gtr1, a Rag GTPase that relays nutrient status to the Target of Rapamycin Complex 1 (TORC1) in yeast. Functionally, the SEAC has been divided into two subcomplexes: SEACIT, which has GAP activity and inhibits TORC1, and SEACAT, which regulates SEACIT. This system is conserved in mammals: the GATOR complex, consisting of GATOR1 (SEACIT) and GATOR2 (SEACAT), transmits amino acid and glucose signals to mTORC1. Despite its importance, the structure of SEAC/GATOR, and thus molecular understanding of its function, is lacking. Here, we solve the cryo-EM structure of the native eight-subunit SEAC. The SEAC has a modular structure in which a COPII-like cage corresponding to SEACAT binds two flexible wings, which correspond to SEACIT. The wings are tethered to the core via Sea3, which forms part of both modules. The GAP mechanism of GATOR1 is conserved in SEACIT, and GAP activity is unaffected by SEACAT in vitro. In vivo, the wings are essential for recruitment of the SEAC to the vacuole, primarily via the EGO complex. Our results indicate that rather than being a direct inhibitor of SEACIT, SEACAT acts as a scaffold for the binding of TORC1 regulators.

23.Nociceptor neurons affect cancer immunosurveillance下载原文

First Author:

Mohammad Balood①

Corresponding Author:

Sebastien Talbot②

Affiliations:

Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada①②

Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, Quebec, Canada①

Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada②

Abstract:

Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)—one such nociceptor-produced neuropeptide—directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1−/− CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+T cells.