Nature
20 Oct 2022
Volume 610 | Issue 7932
1.A 0.6 Mpc H i structure associated with Stephan’s Quintet 
下载原文
First Author：
C. K. Xu①
Corresponding Author:
C. Cheng②
Affiliations:
Chinese Academy of Sciences South America Center for A stronomy, National Astronomical Observatories, CAS, Beijing, People’s Republic of China①②
National Astronomical Observatories, Chinese Academy of Sciences (NAOC), Beijing, People’s Republic of China①②
Abstract:
Stephan’s Quintet (SQ, co-moving radial distance = 85 ± 6 Mpc, taken from the NASA/IPAC Extragalactic Database (NED)) is unique among compact groups of galaxies. Observations have previously shown that interactions between multiple members, including a high-speed intruder galaxy currently colliding into the intragroup medium, have probably generated tidal debris in the form of multiple gaseous and stellar filaments, the formation of tidal dwarfs and intragroup-medium starbursts, as well as widespread intergalactic shocked gas. The details and timing of the interactions and collisions remain poorly understood because of their multiple nature. Here we report atomic hydrogen (H i) observations in the vicinity of SQ with a smoothed sensitivity of 1σ = 4.2 × 1016 cm−2 per channel (velocity bin-width Δv = 20 km s−1; angular resolution = 4′), which are about two orders of magnitude deeper than previous observations. The data show a large H i structure (with linear scale of around 0.6 Mpc) encompassing an extended source of size approximately 0.4 Mpc associated with the debris field and a curved diffuse feature of length around 0.5 Mpc attached to the south edge of the extended source. The diffuse feature was probably produced by tidal interactions in early stages of the formation of SQ (>1 Gyr ago), although it is not clear how the low-density H i gas (NH i ≲ 1018 cm−2) can survive the ionization by the intergalactic ultraviolet background on such a long time scale. Our observations require a rethinking of properties of gas in outer parts of galaxy groups and demand complex modelling of different phases of the intragroup medium in simulations of group formation.
2.A dense 0.1-solar-mass star in a 51-minute-orbital-period eclipsing binary 下载原文
First Author/ Corresponding Author:
Kevin B. Burdge
Affiliations:
Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA
Kavli Institute for Astrophysics and Space Research, M assachusetts Institute of Technology, Cambridge, MA, USA
Abstract:
Of more than a thousand known cataclysmic variables (CVs), where a white dwarf is accreting from a hydrogen-rich star, only a dozen have orbital periods below 75 minutes. One way to achieve these short periods requires the donor star to have undergone substantial nuclear evolution before interacting with the white dwarf, and it is expected that these objects will transition to helium accretion. These transitional CVs have been proposed as progenitors of helium CVs3. However, no known transitional CV is expected to reach an orbital period short enough to account for most of the helium CV population, leaving the role of this evolutionary pathway unclear. Here we report observations of ZTF J1813+4251, a 51-minute-orbital-period, fully eclipsing binary system consisting of a star with a temperature comparable to that of the Sun but a density 100 times greater owing to its helium-rich composition, accreting onto a white dwarf. Phase-resolved spectra, multi-band light curves and the broadband spectral energy distribution allow us to obtain precise and robust constraints on the masses, radii and temperatures of both components. Evolutionary modelling shows that ZTF J1813+4251 is destined to become a helium CV binary, reaching an orbital period under 20 minutes, rendering ZTF J1813+4251 a previously missing link between helium CV binaries and hydrogen-rich CVs.
3.Entanglement-enhanced matter-wave interferometry in a high-finesse cavity 下载原文
First Author:
Graham P. Greve①
Corresponding Author:
James K. Thompson②
Affiliation:
JILA, NIST and Department of Physics, University of Colorado, Boulder, CO, USA①②
Abstract:
An ensemble of atoms can operate as a quantum sensor by placing atoms in a superposition of two different states. Upon measurement of the sensor, each atom is individually projected into one of the two states. Creating quantum correlations between the atoms, that is entangling them, could lead to resolutions surpassing the standard quantum limit set by projections of individual atoms. Large amounts of entanglement involving the internal degrees of freedom of laser-cooled atomic ensembles have been generated in collective cavity quantum-electrodynamics systems, in which many atoms simultaneously interact with a single optical cavity mode. Here we report a matter-wave interferometer in a cavity quantum-electrodynamics system of 700 atoms that are entangled in their external degrees of freedom. In our system, each individual atom falls freely under gravity and simultaneously traverses two paths through space while entangled with the other atoms. We demonstrate both quantum non-demolition measurements and cavity-mediated spin interactions for generating squeezed momentum states with directly observed sensitivity 3.4+1.1−0.9 dB and 2.5+0.6−0.6 dB below the standard quantum limit, respectively. We successfully inject an entangled state into a Mach–Zehnder light-pulse interferometer with directly observed sensitivity 1.7+0.5−0.5 dB below the standard quantum limit. The combination of particle delocalization and entanglement in our approach may influence developments of enhanced inertial sensors, searches for new physics, particles and fields, future advanced gravitational wave detectors and accessing beyond mean-field quantum many-body physics.
4.Enhanced interactions of interlayer excitons in free-standing heterobilayers 下载原文
First Author:
Xueqian Sun①
Corresponding Author:
Yuerui Lu②
Affiliations:
School of Engineering, College of Engineering and Computer Science, the Australian National University, Canberra, Australian Capital Territory, Australia①
Australian Research Council Centre of Excellence for Quantum Computation and Communication Technology, the Australian National University, Canberra, Australian Capital Territory, Australia①②
Abstract:
Strong, long-range dipole–dipole interactions between interlayer excitons (IXs) can lead to new multiparticle correlation regimes, which drive the system into distinct quantum and classical phases, including dipolar liquids, crystals and superfluids. Both repulsive and attractive dipole–dipole interactions have been theoretically predicted between IXs in a semiconductor bilayer, but only repulsive interactions have been reported experimentally so far. This study investigated free-standing, twisted (51°, 53°, 45°) tungsten diselenide/tungsten disulfide (WSe2/WS2) heterobilayers, in which we observed a transition in the nature of dipolar interactions among IXs, from repulsive to attractive. This was caused by quantum-exchange-correlation effects, leading to the appearance of a robust interlayer biexciton phase (formed by two IXs), which has been theoretically predicted but never observed before in experiments. The reduced dielectric screening in a free-standing heterobilayer not only resulted in a much higher formation efficiency of IXs, but also led to strongly enhanced dipole–dipole interactions, which enabled us to observe the many-body correlations of pristine IXs at the two-dimensional quantum limit. In addition, we firstly observed several emission peaks from moiré-trapped IXs at room temperature in a well-aligned, free-standing WSe2/WS2 heterobilayer. Our findings open avenues for exploring new quantum phases with potential for applications in non-linear optics.
5.Accommodating unobservability to control flight attitude with optic flow 下载原文
First / Corresponding Author:
Guido C. H. E. de Croon
Affiliation:
Micro Air Vehicle Laboratory, Control and Simulation, Faculty of Aerospace Engineering, Delft University of Technology, Delft, the Netherlands
Abstract:
Attitude control is an essential flight capability. Whereas flying robots commonly rely on accelerometers for estimating attitude, flying insects lack an unambiguous sense of gravity. Despite the established role of several sense organs in attitude stabilization, the dependence of flying insects on an internal gravity direction estimate remains unclear. Here we show how attitude can be extracted from optic flow when combined with a motion model that relates attitude to acceleration direction. Although there are conditions such as hover in which the attitude is unobservable, we prove that the ensuing control system is still stable, continuously moving into and out of these conditions. Flying robot experiments confirm that accommodating unobservability in this manner leads to stable, but slightly oscillatory, attitude control. Moreover, experiments with a bio-inspired flapping-wing robot show that residual, high-frequency attitude oscillations from flapping motion improve observability. The presented approach holds a promise for robotics, with accelerometer-less autopilots paving the road for insect-scale autonomous flying robots. Finally, it forms a hypothesis on insect attitude estimation and control, with the potential to provide further insight into known biological phenomena and to generate new predictions such as reduced head and body attitude variance at higher flight speeds.
6.Low-hysteresis shape-memory ceramics designed by multimode modelling 下载原文
First Author:
Edward L. Pang①
Corresponding Author:
Christopher A. Schuh②
Affiliation:
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA①②
Abstract:
Zirconia ceramics exhibit a martensitic phase transformation that enables large strains of order 10%, making them prospects for shape-memory and superelastic applications at high temperature. Similarly to other martensitic materials, this transformation strain can be engineered by carefully alloying to produce a more commensurate transformation with reduced hysteresis (difference in transformation temperature on heating and cooling). However, such ‘lattice engineering’ in zirconia is complicated by additional physical constraints: there is a secondary need to manage a large transformation volume change, and to achieve transformation temperatures high enough to avoid kinetic barriers. Here we present a method of augmenting the lattice engineering approach to martensite design to address these additional constraints, incorporating modern computational thermodynamics and data science tools to span complex multicomponent spaces for which no data yet exist. The result is a new zirconia composition with record low hysteresis of 15 K, which is about ten times less transformation hysteresis compared to typical values (and approximately five times less than the best values reported so far). This finding demonstrates that zirconia ceramics can exhibit hysteresis values of the order of those of widely deployed shape-memory alloys, paving the way for their use as viable high-temperature shape-memory materials.
7.Nonlinear decision-making with enzymatic neural networks 下载原文
First Author:
S. Okumura①
Corresponding Author:
A. J. Genot②
Affiliations:
LIMMS, CNRS-Institute of Industrial Science, University of Tokyo, Tokyo, Japan①②
Abstract:
Artificial neural networks have revolutionized electronic computing. Similarly, molecular networks with neuromorphic architectures may enable molecular decision-making on a level comparable to gene regulatory networks. Non-enzymatic networks could in principle support neuromorphic architectures, and seminal proofs-of-principle have been reported. However, leakages (that is, the unwanted release of species), as well as issues with sensitivity, speed, preparation and the lack of strong nonlinear responses, make the composition of layers delicate, and molecular classifications equivalent to a multilayer neural network remain elusive (for example, the partitioning of a concentration space into regions that cannot be linearly separated). Here we introduce DNA-encoded enzymatic neurons with tuneable weights and biases, and which are assembled in multilayer architectures to classify nonlinearly separable regions. We first leverage the sharp decision margin of a neuron to compute various majority functions on 10 bits. We then compose neurons into a two-layer network and synthetize a parametric family of rectangular functions on a microRNA input. Finally, we connect neural and logical computations into a hybrid circuit that recursively partitions a concentration plane according to a decision tree in cell-sized droplets. This computational power and extreme miniaturization open avenues to query and manage molecular systems with complex contents, such as liquid biopsies or DNA databases.
8.Self-assembly of emulsion droplets through programmable folding下载原文
First Author:
Angus McMullen①
Corresponding Authors:
Zorana Zeravcic②, Jasna Brujic③
Affiliations:
Center for Soft Matter Research, New York University, New York, NY, USA①
Gulliver UMR CNRS 7083, ESPCI Paris, Université PSL, Paris, France②
PMMH UMR CNRS 7636, ESPCI Paris, Université PSL, Paris, France③
Abstract:
In the realm of particle self-assembly, it is possible to reliably construct nearly arbitrary structures if all the pieces are distinct, but systems with fewer flavours of building blocks have so far been limited to the assembly of exotic crystals. Here we introduce a minimal model system of colloidal droplet chains, with programmable DNA interactions that guide their downhill folding into specific geometries. Droplets are observed in real space and time, unravelling the rules of folding. Combining experiments, simulations and theory, we show that controlling the order in which interactions are switched on directs folding into unique structures, which we call colloidal foldamers. The simplest alternating sequences (ABAB...) of up to 13 droplets yield 11 foldamers in two dimensions and one in three dimensions. Optimizing the droplet sequence and adding an extra flavour uniquely encodes more than half of the 619 possible two-dimensional geometries. Foldamers consisting of at least 13 droplets exhibit open structures with holes, offering porous design. Numerical simulations show that foldamers can further interact to make complex supracolloidal architectures, such as dimers, ribbons and mosaics. Our results are independent of the dynamics and therefore apply to polymeric materials with hierarchical interactions on all length scales, from organic molecules all the way to Rubik’s Snakes. This toolbox enables the encoding of large-scale design into sequences of short polymers, placing folding at the forefront of materials self-assembly.
9. From planetary to regional boundaries for agricultural nitrogen pollution 下载原文
First / Corresponding Author:
L. F. Schulte-Uebbing
Affiliations:
Environmental Systems Analysis Group, Wageningen University and Research, Wageningen, The Netherlands
PBL Netherlands Environmental Assessment Agency, The Hague, The Netherlands
Abstract:
Excessive agricultural nitrogen use causes environmental problems globally, to an extent that it has been suggested that a safe planetary boundary has been exceeded. Earlier estimates for the planetary nitrogen boundary, however, did not account for the spatial variability in both ecosystems’ sensitivity to nitrogen pollution and agricultural nitrogen losses. Here we use a spatially explicit model to establish regional boundaries for agricultural nitrogen surplus from thresholds for eutrophication of terrestrial and aquatic ecosystems and nitrate in groundwater. We estimate regional boundaries for agricultural nitrogen pollution and find both overuse and room for intensification of agricultural nitrogen. The aggregated global surplus boundary with respect to all thresholds is 43 megatonnes of nitrogen per year, which is 64 per cent lower than the current (2010) nitrogen surplus (119 megatonnes of nitrogen per year). Allowing the nitrogen surplus to increase to close yield gaps in regions where environmental thresholds are not exceeded lifts the planetary nitrogen boundary to 57 megatonnes of nitrogen per year. Feeding the world without trespassing regional and planetary nitrogen boundaries requires large increases in nitrogen use efficiencies accompanied by mitigation of non-agricultural nitrogen sources such as sewage water. This asks for coordinated action that recognizes the heterogeneity of agricultural systems, non-agricultural nitrogen losses and environmental vulnerabilities.
10. A function-based typology for Earth’s ecosystems 下载原文
First / Corresponding Author:
David A. Keith
Affiliations:
Centre for Ecosystem Science, University of New South Wales, Sydney, New South Wales, Australia
New South Wales Department of Planning, Industry and Environment, Hurstville, New South Wales, Australia
IUCN Commission on Ecosystem Management, Gland, Switzerland
Abstract:
As the United Nations develops a post-2020 global biodiversity framework for the Convention on Biological Diversity, attention is focusing on how new goals and targets for ecosystem conservation might serve its vision of ‘living in harmony with nature. Advancing dual imperatives to conserve biodiversity and sustain ecosystem services requires reliable and resilient generalizations and predictions about ecosystem responses to environmental change and management. Ecosystems vary in their biota, service provision and relative exposure to risks, yet there is no globally consistent classification of ecosystems that reflects functional responses to change and management. This hampers progress on developing conservation targets and sustainability goals. Here we present the International Union for Conservation of Nature (IUCN) Global Ecosystem Typology, a conceptually robust, scalable, spatially explicit approach for generalizations and predictions about functions, biota, risks and management remedies across the entire biosphere. The outcome of a major cross-disciplinary collaboration, this novel framework places all of Earth’s ecosystems into a unifying theoretical context to guide the transformation of ecosystem policy and management from global to local scales. This new information infrastructure will support knowledge transfer for ecosystem-specific management and restoration, globally standardized ecosystem risk assessments, natural capital accounting and progress on the post-2020 global biodiversity framework.
11. Genetic insights into the social organization of Neanderthals 下载原文
First Author:
Laurits Skov①
Corresponding Author:
Benjamin M. Peter②
Affiliation:
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany①②
Abstract:
Genomic analyses of Neanderthals have previously provided insights into their population history and relationship to modern humans, but the social organization of Neanderthal communities remains poorly understood. Here we present genetic data for 13 Neanderthals from two Middle Palaeolithic sites in the Altai Mountains of southern Siberia: 11 from Chagyrskaya Cave and 2 from Okladnikov Cave—making this one of the largest genetic studies of a Neanderthal population to date. We used hybridization capture to obtain genome-wide nuclear data, as well as mitochondrial and Y-chromosome sequences. Some Chagyrskaya individuals were closely related, including a father–daughter pair and a pair of second-degree relatives, indicating that at least some of the individuals lived at the same time. Up to one-third of these individuals’ genomes had long segments of homozygosity, suggesting that the Chagyrskaya Neanderthals were part of a small community. In addition, the Y-chromosome diversity is an order of magnitude lower than the mitochondrial diversity, a pattern that we found is best explained by female migration between communities. Thus, the genetic data presented here provide a detailed documentation of the social organization of an isolated Neanderthal community at the easternmost extent of their known range.
12. Movement is governed by rotational neural dynamics in spinal motor networks下载原文
First Author:
Henrik Lindén①
Corresponding Author:
Rune W. Berg②
Affiliation:
Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark①②
Abstract:
Although the generation of movements is a fundamental function of the nervous system, the underlying neural principles remain unclear. As flexor and extensor muscle activities alternate during rhythmic movements such as walking, it is often assumed that the responsible neural circuitry is similarly exhibiting alternating activity. Here we present ensemble recordings of neurons in the lumbar spinal cord that indicate that, rather than alternating, the population is performing a low-dimensional ‘rotation’ in neural space, in which the neural activity is cycling through all phases continuously during the rhythmic behaviour. The radius of rotation correlates with the intended muscle force, and a perturbation of the low-dimensional trajectory can modify the motor behaviour. As existing models of spinal motor control do not offer an adequate explanation of rotation, we propose a theory of neural generation of movements from which this and other unresolved issues, such as speed regulation, force control and multifunctionalism, are readily explained.
13. A wheat resistosome defines common principles of immune receptor channels 下载原文
First Author:
Alexander Förderer①
Corresponding Authors:
Yuhang Chen②, Paul Schulze-Lefert③, Jijie Chai④
Affiliations:
Institute of Biochemistry, University of Cologne, Cologne, Germany①
Max Planck Institute for Plant Breeding Research, Cologne, Germany①
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China; ②
Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, China②
College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China②
Max Planck Institute for Plant Breeding Research, Cologne, Germany③
Institute of Biochemistry, University of Cologne, Cologne, Germany④
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing, China④
Abstract:
Plant intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) detect pathogen effectors to trigger immune responses. Indirect recognition of a pathogen effector by the dicotyledonous Arabidopsis thaliana coiled-coil domain containing NLR (CNL) ZAR1 induces the formation of a large hetero-oligomeric protein complex, termed the ZAR1 resistosome, which functions as a calcium channel required for ZAR1-mediated immunity. Whether the resistosome and channel activities are conserved among plant CNLs remains unknown. Here we report the cryo-electron microscopy structure of the wheat CNL Sr35 in complex with the effector AvrSr35 of the wheat stem rust pathogen. Direct effector binding to the leucine-rich repeats of Sr35 results in the formation of a pentameric Sr35–AvrSr35 complex, which we term the Sr35 resistosome. Wheat Sr35 and Arabidopsis ZAR1 resistosomes bear striking structural similarities, including an arginine cluster in the leucine-rich repeats domain not previously recognized as conserved, which co-occurs and forms intramolecular interactions with the 'EDVID' motif in the coiled-coil domain. Electrophysiological measurements show that the Sr35 resistosome exhibits non-selective cation channel activity. These structural insights allowed us to generate new variants of closely related wheat and barley orphan NLRs that recognize AvrSr35. Our data support the evolutionary conservation of CNL resistosomes in plants and demonstrate proof of principle for structure-based engineering of NLRs for crop improvement.
14. Antibiotic combinations reduce Staphylococcus aureus clearance 下载原文
First Author:
Viktória Lázár①
Corresponding Author:
Roy Kishony②
Affiliations:
HCEMM-BRC Pharmacodinamic Drug Interaction Research Group, Szeged, Hungary①
Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary①
Faculty of Biology, Technion–Israel Institute of Technology, Haifa, Israel①②
Abstract:
The spread of antibiotic resistance is attracting increased attention to combination-based treatments. Although drug combinations have been studied extensively for their effects on bacterial growth, much less is known about their effects on bacterial long-term clearance, especially at cidal, clinically relevant concentrations. Here, using en masse microplating and automated image analysis, we systematically quantify Staphylococcus aureus survival during prolonged exposure to pairwise and higher-order cidal drug combinations. By quantifying growth inhibition, early killing and longer-term population clearance by all pairs of 14 antibiotics, we find that clearance interactions are qualitatively different, often showing reciprocal suppression whereby the efficacy of the drug mixture is weaker than any of the individual drugs alone. Furthermore, in contrast to growth inhibitionand early killing, clearance efficacy decreases rather than increases as more drugs are added. However, specific drugs targeting non-growing persisters circumvent these suppressive effects. Competition experiments show that reciprocal suppressive drug combinations select against resistance to any of the individual drugs, even counteracting methicillin-resistant Staphylococcus aureus both in vitro and in a Galleria mellonella larva model. As a consequence, adding a β-lactamase inhibitor that is commonly used to potentiate treatment against β-lactam-resistant strains can reduce rather than increase treatment efficacy. Together, these results underscore the importance of systematic mapping the long-term clearance efficacy of drug combinations for designing more-effective, resistance-proof multidrug regimes.
15.The γδ IEL effector API5 masks genetic susceptibility to Paneth cell death 下载原文
First Author:
Yu Matsuzawa-Ishimoto①
Corresponding Authors:
Shohei Koide② , Ken Cadwell③
Affiliations:
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY, USA①③
Department of Microbiology, New York University Grossman School of Medicine, New York, NY, USA①③
Perlmutter Cancer Center, NYU Langone Health, New York, NY,
USA②
Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA②
Abstract:
Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn’s disease, a major type of inflammatory bowel disease. Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium. This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn’s disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte–epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1 risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death.
16.An LKB1–mitochondria axis controls TH17 effector function 下载原文
First Author:
Francesc Baixauli①
Corresponding Author:
Erika L. Pearce②
Affiliations:
Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany①②
Department of Oncology, The Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA② Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA②
Abstract:
CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes. Mitochondrial membrane dynamics sustains mitochondrial processes, including respiration and tricarboxylic acid (TCA) cycle metabolism, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate—a metabolite that influences the epigenetic landscape. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.
17. Gut bacteria alleviate smoking-related NASH by degrading gut nicotine 下载原文
First Author:
Bo Chen①
Corresponding Authors:
Yang Li②, Ming-Hua Zheng③, Chaohui Yu④, Frank J. Gonzalez⑤, Changtao Jiang⑥
Affiliations:
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China①⑥
Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China①
Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China①
The Key Laboratory of Molecular Cardiovascular Science, Peking University, Ministry of Education, Beijing, China①
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, School of Basic Medical Science, Fudan University, Shanghai, China②
NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China③
Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China③
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China④
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA⑤
Abstract:
Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD), but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.
18.Structure of the NuA4 acetyltransferase complex bound to the nucleosome 下载原文
First Author:
Keke Qu①
Corresponding Author:
Xueming Li②, Zhucheng Chen③
Affiliations:
MOE Key Laboratory of Protein Science, School of Life Science, Tsinghua University, Beijing, P. R. China①②③
Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing, P. R. China①③
Abstract:
Deoxyribonucleic acid in eukaryotes wraps around the histone octamer to form nucleosomes, the fundamental unit of chromatin. The N termini of histone H4 interact with nearby nucleosomes and play an important role in the formation of high-order chromatin structure and heterochromatin silencing. NuA4 in yeast and its homologue Tip60 complex in mammalian cells are the key enzymes that catalyse H4 acetylation, which in turn regulates chromatin packaging and function in transcription activation and DNA repair. Here we report the cryo-electron microscopy structure of NuA4 from Saccharomyces cerevisiae bound to the nucleosome. NuA4 comprises two major modules: the catalytic histone acetyltransferase (HAT) module and the transcription activator-binding (TRA) module. The nucleosome is mainly bound by the HAT module and is positioned close to a polybasic surface of the TRA module, which is important for the optimal activity of NuA4. The nucleosomal linker DNA carrying the upstream activation sequence is oriented towards the conserved, transcription activator-binding surface of the Tra1 subunit, which suggests a potential mechanism of NuA4 to act as a transcription co-activator. The HAT module recognizes the disk face of the nucleosome through the H2A–H2B acidic patch and nucleosomal DNA, projecting the catalytic pocket of Esa1 to the N-terminal tail of H4 and supporting its function in selective acetylation of H4. Together, our findings illustrate how NuA4 is assembled and provide mechanistic insights into nucleosome recognition and transcription co-activation by a HAT.
19. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity 下载原文
First Author:
Anat Levit Kaplan①
Corresponding Authors:
William C. Wetsel②, John J. Irwin③, Georgios Skiniotis ④, Jonathan A. Ellman⑤
Affiliations:
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA①③
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA②
Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA②
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA②
Department of Neurobiology, Duke University Medical Center, Durham,
NC, USA②
Department of Molecular and Cellular Physiology, Stanford University
School of Medicine, Stanford, CA, USA④
Department of Chemistry, Yale University, New Haven, CT, USA⑤
Abstract:
There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines—a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C–H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.