Nature

13 October 2022

Volume 610 | Issue 7931

1. Radiation-driven acceleration in the expanding WR140 dust shell 下载原文

First Author/ Corresponding Author:

Yinuo Han

Affiliations:

Institute of Astronomy, University of Cambridge, Cambridge, UK

Sydney Institute for Astronomy, School of Physics, The University of

Sydney, Sydney, New South Wales, Australia

Abstract:

The Wolf–Rayet (WR) binary system WR140 is a close (0.9–16.7 mas; ref.) binary star consisting of an O5 primary and WC7 companion and is known as the archetype of episodic dust-producing WRs. Dust in WR binaries is known to form in a confined stream originating from the collision of the two stellar winds, with orbital motion of the binary sculpting the large-scale dust structure into arcs as dust is swept radially outwards. It is understood that sensitive conditions required for dust production in WR140 are only met around periastron when the two stars are sufficiently close. Here we present multiepoch imagery of the circumstellar dust shell of WR140. We constructed geometric models that closely trace the expansion of the intricately structured dust plume, showing that complex effects induced by orbital modulation may result in a ‘Goldilocks zone’ for dust production. We find that the expansion of the dust plume cannot be reproduced under the assumption of a simple uniform-speed outflow, finding instead the dust to be accelerating. This constitutes a direct kinematic record of dust motion under acceleration by radiation pressure and further highlights the complexity of the physical conditions in colliding-wind binaries.

2. Optical superluminal motion measurement in the neutron-star merger GW170817 下载原文

First Authors/ Corresponding Authors:

Kunal P. Mooley①, Jay Anderson②

Affiliations:

Caltech, Pasadena, CA, USA①

National Radio Astronomy Observatory, Socorro, NM, USA①

Space Telescope Science Institute, Baltimore, MD, USA②

Abstract:

The afterglow of the binary neutron-star merger GW170817 gave evidence for a structured relativistic jet and a link between such mergers and short gamma-ray bursts. Superluminal motion, found using radio very long baseline interferometry (VLBI), together with the afterglow light curve provided constraints on the viewing angle (14–28 degrees), the opening angle of the jet core (less than 5 degrees) and a modest limit on the initial Lorentz factor of the jet core (more than 4). Here we report on another superluminal motion measurement, at seven times the speed of light, leveraging Hubble Space Telescope precision astrometry and previous radio VLBI data for GW170817. We thereby obtain a measurement of the Lorentz factor of the wing of the structured jet, as well as substantially improved constraints on the viewing angle (19–25 degrees) and the initial Lorentz factor of the jet core (more than 40).

3. Personalizing exoskeleton assistance while walking in the real world 下载原文

First Author:

Patrick Slade①

Corresponding Author: Steven H. Collins②

Affiliations:

Department of Mechanical Engineering, Stanford University, Stanford, CA, USA①②

Department of Bioengineering, Stanford University, Stanford, CA, USA①

Abstract:

Personalized exoskeleton assistance provides users with the largest improvements in walking speed and energy economy but requires lengthy tests under unnatural laboratory conditions. Here we show that exoskeleton optimization can be performed rapidly and under real-world conditions. We designed a portable ankle exoskeleton based on insights from tests with a versatile laboratory testbed. We developed a data-driven method for optimizing exoskeleton assistance outdoors using wearable sensors and found that it was equally effective as laboratory methods, but identified optimal parameters four times faster. We performed real-world optimization using data collected during many short bouts of walking at varying speeds. Assistance optimized during one hour of naturalistic walking in a public setting increased self-selected speed by 9 ± 4% and reduced the energy used to travel a given distance by 17 ± 5% compared with normal shoes. This assistance reduced metabolic energy consumption by 23 ± 8% when participants walked on a treadmill at a standard speed of 1.5 m s−1. Human movements encode information that can be used to personalize assistive devices and enhance performance.

4. Multi-environment robotic transitions through adaptive morphogenesis 下载原文

First Author:

Robert Baines①

Corresponding Author:

Rebecca Kramer-Bottiglio②

Affiliation:

School of Engineering and Applied Science, Yale University, New Haven, CT, USA①②

Abstract:

The current proliferation of mobile robots spans ecological monitoring, warehouse management and extreme environment exploration, to an individual consumer’s home. This expanding frontier of applications requires robots to transit multiple environments, a substantial challenge that traditional robot design strategies have not effectively addressed. For example, biomimetic design—copying an animal’s morphology, propulsion mechanism and gait—constitutes one approach, but it loses the benefits of engineered materials and mechanisms that can be exploited to surpass animal performance. Other approaches add a unique propulsive mechanism for each environment to the same robot body, which can result in energy-inefficient designs. Overall, predominant robot design strategies favour immutable structures and behaviours, resulting in systems incapable of specializing across environments. Here, to achieve specialized multi-environment locomotion through terrestrial, aquatic and the in-between transition zones, we implemented ‘adaptive morphogenesis’, a design strategy in which adaptive robot morphology and behaviours are realized through unified structural and actuation systems. Taking inspiration from terrestrial and aquatic turtles, we built a robot that fuses traditional rigid components and soft materials to radically augment the shape of its limbs and shift its gaits for multi-environment locomotion. The interplay of gait, limb shape and the environmental medium revealed vital parameters that govern the robot’s cost of transport. The results attest that adaptive morphogenesis is a powerful method to enhance the efficiency of mobile robots encountering unstructured, changing environments.

5. Attosecond clocking of correlations between Bloch electrons 下载原文

First Author:

J. Freudenstein①

Corresponding Author: D. Afanasiev②, M. Kira③, R. Huber④

Affiliations:

Department of Physics, University of Regensburg, Regensburg, Germany①②④

Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA③

Abstract:

Delocalized Bloch electrons and the low-energy correlations between them determine key optical, electronic and entanglement functionalities of solids, all the way through to phase transitions. To directly capture how many-body correlations affect the actual motion of Bloch electrons, subfemtosecond (1 fs = 10−15 s) temporal precision is desirable. Yet, probing with attosecond (1 as = 10−18 s) high-energy photons has not been energy-selective enough to resolve the relevant millielectronvolt-scale interactions of electrons near the Fermi energy. Here, we use multi-terahertz light fields to force electron–hole pairs in crystalline semiconductors onto closed trajectories, and clock the delay between separation and recollision with 300 as precision, corresponding to 0.7% of the driving field’s oscillation period. We detect that strong Coulomb correlations emergent in atomically thin WSe2 shift the optimal timing of recollisions by up to 1.2 ± 0.3 fs compared to the bulk material. A quantitative analysis with quantum-dynamic many-body computations in a Wigner-function representation yields a direct and intuitive view on how the Coulomb interaction, non-classical aspects, the strength of the driving field and the valley polarization influence the dynamics. The resulting attosecond chronoscopy of delocalized electrons could revolutionize the understanding of unexpected phase transitions and emergent quantum-dynamic phenomena for future electronic, optoelectronic and quantum-information technologies.

6. Spatiotemporal imaging of charge transfer in photocatalyst particles 下载原文

First Author:

Ruotian Chen①

Corresponding Authors: Fengtao Fan②, Can Li③

Affiliations:

State Key Laboratory of Catalysis, Dalian National Laboratory for Clean Energy, iChEM, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China①②③

University of Chinese Academy of Sciences, Beijing, China③

Abstract:

The water-splitting reaction using photocatalyst particles is a promising route for solar fuel production. Photo-induced charge transfer from a photocatalyst to catalytic surface sites is key in ensuring photocatalytic efficiency; however, it is challenging to understand this process, which spans a wide spatiotemporal range from nanometres to micrometres and from femtoseconds to seconds. Although the steady-state charge distribution on single photocatalyst particles has been mapped by microscopic techniques, and the charge transfer dynamics in photocatalyst aggregations have been revealed by time-resolved spectroscopy, spatiotemporally evolving charge transfer processes in single photocatalyst particles cannot be tracked, and their exact mechanism is unknown. Here we perform spatiotemporally resolved surface photovoltage measurements on cuprous oxide photocatalyst particles to map holistic charge transfer processes on the femtosecond to second timescale at the single-particle level. We find that photogenerated electrons are transferred to the catalytic surface quasi-ballistically through inter-facet hot electron transfer on a subpicosecond timescale, whereas photogenerated holes are transferred to a spatially separated surface and stabilized through selective trapping on a microsecond timescale. We demonstrate that these ultrafast-hot-electron-transfer and anisotropic-trapping regimes, which challenge the classical perception of a drift–diffusion model, contribute to the efficient charge separation in photocatalysis and improve photocatalytic performance. We anticipate that our findings will be used to illustrate the universality of other photoelectronic devices and facilitate the rational design of photocatalysts.

7. An asymmetric sp3–sp3 cross-electrophile coupling using ‘ene’-reductases 下载原文

First Author:

Haigen Fu①

Corresponding Author:

Todd K. Hyster②

Affiliation:

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA①②

Abstract:

The catalytic asymmetric construction of Csp3–Csp3 bonds remains one of the foremost challenges in organic synthesis. Metal-catalysed cross-electrophile couplings (XECs) have emerged as a powerful tool for C–C bond formation. However, coupling two distinct Csp3 electrophiles with high cross-selectivity and stereoselectivity continues as an unmet challenge. Here we report a highly chemoselective and enantioselective Csp3–Csp3 XEC between alkyl halides and nitroalkanes catalysed by flavin-dependent ‘ene’-reductases (EREDs). Photoexcitation of the enzyme-templated charge-transfer complex between an alkyl halide and a flavin cofactor enables the chemoselective reduction of alkyl halide over the thermodynamically favoured nitroalkane partner. The key C–C bond-forming step occurs by means of the reaction of an alkyl radical with an in situ-generated nitronate to form a nitro radical anion that collapses to form nitrite and an alkyl radical. An enzyme-controlled hydrogen atom transfer (HAT) affords high levels of enantioselectivity. This reactivity is unknown in small-molecule catalysis and highlights the potential for enzymes to use new mechanisms to address long-standing synthetic challenges.

8. Maturation and circuit integration of transplanted human cortical organoids 下载原文

First Author:

Omer Revah

Corresponding Author:

Sergiu P. Pașca

Affiliations:

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute and Bio-X, Stanford University, Stanford, CA, USA

Abstract:

Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.

9. CRISPR screens in Drosophila cells identify Vsg as a Tc toxin receptor 下载原文

First Author:

Ying Xu①

Corresponding Authors: Stefan Raunser②, Norbert Perrimon③, Min Dong④

Affiliations:

Department of Urology, Boston Children’s Hospital, Boston, MA, USA①

Department of Surgery and Department of Microbiology, Harvard Medical School, Boston, MA, USA①④

Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany②

Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA③

Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA③

Abstract:

Entomopathogenic nematodes are widely used as biopesticides. Their insecticidal activity depends on symbiotic bacteria such as Photorhabdus luminescens, which produces toxin complex (Tc) toxins as major virulence factors. No protein receptors are known for any Tc toxins, which limits our understanding of their specificity and pathogenesis. Here we use genome-wide CRISPR–Cas9-mediated knockout screening in Drosophila melanogaster S2R+ cells and identify Visgun (Vsg) as a receptor for an archetypal P. luminescens Tc toxin (pTc). The toxin recognizes the extracellular O-glycosylated mucin-like domain of Vsg that contains high-density repeats of proline, threonine and serine (HD-PTS). Vsg orthologues in mosquitoes and beetles contain HD-PTS and can function as pTc receptors, whereas orthologues without HD-PTS, such as moth and human versions, are not pTc receptors. Vsg is expressed in immune cells, including haemocytes and fat body cells. Haemocytes from Vsg knockout Drosophila are resistant to pTc and maintain phagocytosis in the presence of pTc, and their sensitivity to pTc is restored through the transgenic expression of mosquito Vsg. Last, Vsg knockout Drosophila show reduced bacterial loads and lethality from P. luminescens infection. Our findings identify a proteinaceous Tc toxin receptor, reveal how Tc toxins contribute to P. luminescens pathogenesis, and establish a genome-wide CRISPR screening approach for investigating insecticidal toxins and pathogens.

10. Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome 下载原文

First Author:

Hua Su①

Corresponding Authors:

Beicheng Sun②, Michael Karin③

Affiliations:

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA①

Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China②

Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China②

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA③

Abstract:

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support or restrain the progression of PDAC and may impede blood supply and nutrient availability. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood. Here we show that matrix-metalloprotease-cleaved Col I (cCol I) and intact Col I (iCol I) exert opposing effects on PDAC bioenergetics, macropinocytosis, tumour growth and metastasis. Whereas cCol I activates discoidin domain receptor 1 (DDR1)–NF-κB–p62–NRF2 signalling to promote the growth of PDAC, iCol I triggers the degradation of DDR1 and restrains the growth of PDAC. Patients whose tumours are enriched for iCol I and express low levels of DDR1 and NRF2 have improved median survival compared to those whose tumours have high levels of cCol I, DDR1 and NRF2. Inhibition of the DDR1-stimulated expression of NF-κB or mitochondrial biogenesis blocks tumorigenesis in wild-type mice, but not in mice that express MMP-resistant Col I. The diverse effects of the tumour stroma on the growth and metastasis of PDAC and on the survival of patients are mediated through the Col I–DDR1–NF-κB–NRF2 mitochondrial biogenesis pathway, and targeting components of this pathway could provide therapeutic opportunities.

11. STING-induced regulatory B cells compromise NK function in cancer immunity 下载原文

First Author:

Sirui Li①

Corresponding Authors:

Yuliya Pylayeva-Gupta②, Jenny P.-Y. Ting③

Affiliations:

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA①②③

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA①②③

Department of Microbiology-Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA①③

Division of Craniofacial and Surgical Care, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Abstract:

An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers. Agonists of the stimulator of interferon genes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression. Although these agonists hold promise as potential cancer therapies, tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) is unclear. Here we show that the administration of five distinct STING agonists, including cGAMP, results in an expansion of human and mouse interleukin (IL)-35+regulatory B cells in pancreatic cancer. Mechanistically, cGAMP drives expression of IL-35 by B cells in an IRF3-dependent but type I interferon-independent manner. In several preclinical cancer models, the loss of STING signalling in B cells increases tumour control. Furthermore, anti-IL-35 blockade or genetic ablation of IL-35 in B cells also reduces tumour growth. Unexpectedly, the STING–IL-35 axis in B cells reduces proliferation of natural killer (NK) cells and attenuates the NK-driven anti-tumour response. These findings reveal an intrinsic barrier to systemic STING agonist monotherapy and provide a combinatorial strategy to overcome immunosuppression in tumours.

12. SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry 下载原文

First Author:

John Kee①

Corresponding Author:

Erica Korb②

Affiliations:

Department of Genetics at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA①②

Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA①②

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins, particularly those containing post-translational modifications required for transcriptional regulation. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.

13. NMR-guided directed evolution 下载原文

First Author:

Sagar Bhattacharya①

Corresponding Authors:

Alexander N. Volkov②, Olga V. Makhlynets③, Ivan V. Korendovych④

Affiliations:

Department of Chemistry, Syracuse University, Syracuse, NY, USA①③④

VIB Centre for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), Brussels, Belgium②

Jean Jeener NMR Centre, Vrije Universiteit Brussel (VUB), Brussels, Belgium②

Abstract:

Directed evolution is a powerful tool for improving existing properties and imparting completely new functionalities to proteins. Nonetheless, its potential in even small proteins is inherently limited by the astronomical number of possible amino acid sequences. Sampling the complete sequence space of a 100-residue protein would require testing of 20100 combinations, which is beyond any existing experimental approach. In practice, selective modification of relatively few residues is sufficient for efficient improvement, functional enhancement and repurposing of existing proteins. Moreover, computational methods have been developed to predict the locations and, in certain cases, identities of potentially productive mutations. Importantly, all current approaches for prediction of hot spots and productive mutations rely heavily on structural information and/or bioinformatics, which is not always available for proteins of interest. Moreover, they offer a limited ability to identify beneficial mutations far from the active site, even though such changes may markedly improve the catalytic properties of an enzyme. Machine learning methods have recently showed promise in predicting productive mutations, but they frequently require large, high-quality training datasets, which are difficult to obtain in directed evolution experiments. Here we show that mutagenic hot spots in enzymes can be identified using NMR spectroscopy. In a proof-of-concept study, we converted myoglobin, a non-enzymatic oxygen storage protein, into a highly efficient Kemp eliminase using only three mutations. The observed levels of catalytic efficiency exceed those of proteins designed using current approaches and are similar with those of natural enzymes for the reactions that they are evolved to catalyse. Given the simplicity of this experimental approach, which requires no a priori structural or bioinformatic knowledge, we expect it to be widely applicable and to enable the full potential of directed enzyme evolution.

14. Structure of the Ebola virus polymerase complex 下载原文

First Author:

Bin Yuan①

Corresponding Authors:

George F. Gao②, Yi Shi③

Affiliations:

CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China①②③

Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China①②③

Center for Influenza Research and Early-Warning (CASCIRE), CAS–TWAS Center of Excellence for Emerging Infectious Disease (CEEID), Chinese Academy of Sciences, Beijing, China②③

Research Unit of Adaptive Evolution and Control of Emerging Viruses, Chinese Academy of Medical Sciences, Beijing, China②③

Abstract:

Filoviruses, including Ebola virus, pose an increasing threat to the public health. Although two therapeutic monoclonal antibodies have been approved to treat the Ebola virus disease, there are no approved broadly reactive drugs to control diverse filovirus infection. Filovirus has a large polymerase (L) protein and the cofactor viral protein 35 (VP35), which constitute the basic functional unit responsible for virus genome RNA synthesis3. Owing to its conservation, the L–VP35 polymerase complex is a promising target for broadly reactive antiviral drugs. Here we determined the structure of Ebola virus L protein in complex with tetrameric VP35 using cryo-electron microscopy (state 1). Structural analysis revealed that Ebola virus L possesses a filovirus-specific insertion element that is essential for RNA synthesis, and that VP35 interacts extensively with the N-terminal region of L by three protomers of the VP35 tetramer. Notably, we captured the complex structure in a second conformation with the unambiguous priming loop and supporting helix away from polymerase active site (state 2). Moreover, we demonstrated that the century-old drug suramin could inhibit the activity of the Ebola virus polymerase in an enzymatic assay. The structure of the L–VP35–suramin complex reveals that suramin can bind at the highly conserved NTP entry channel to prevent substrates from entering the active site. These findings reveal the mechanism of Ebola virus replication and may guide the development of more powerful anti-filovirus drugs.

15.Layered subsurface in Utopia Basin of Mars revealed by Zhurong rover radar下载原文

First Author:

Chao Li①

Corresponding Author:

Ling Chen②

Affiliations:

Key Laboratory of Earth and Planetary Physics, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing, China①

College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, China②

State Key Laboratory of Lithospheric Evolution, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing, China②

Abstract:

Exploring the subsurface structure and stratification of Mars advances our understanding of Martian geology, hydrological evolution and palaeoclimatic changes, and has been a main task for past and continuing Mars exploration missions. Utopia Planitia, the smooth plains of volcanic and sedimentary strata that infilled the Utopia impact crater, has been a prime target for such exploration as it is inferred to have hosted an ancient ocean on Mars. However, 45 years have passed since Viking-2 provided ground-based detection results. Here we report an in situ ground-penetrating radar survey of Martian subsurface structure in a southern marginal area of Utopia Planitia conducted by the Zhurong rover of the Tianwen-1 mission. A detailed subsurface image profile is constructed along the roughly 1,171 m traverse of the rover, showing an approximately 70-m-thick, multi-layered structure below a less than 10-m-thick regolith. Although alternative models deserve further scrutiny, the new radar image suggests the occurrence of episodic hydraulic flooding sedimentation that is interpreted to represent the basin infilling of Utopia Planitia during the Late Hesperian to Amazonian. While no direct evidence for the existence of liquid water was found within the radar detection depth range, we cannot rule out the presence of saline ice in the subsurface of the landing area.

16.Scleromochlus and the early evolution of Pterosauromorpha下载原文

First / Corresponding Author:

Davide Foffa

Affiliations:

Department of Natural Sciences, National Museums Scotland, Edinburgh, UK

School of Geography, Earth and Environmental Sciences, University of Birmingham, Birmingham, UK

Department of Geosciences, Virginia Tech, Blacksburg, VA, USA

Abstract:

Pterosaurs, the first vertebrates to evolve powered flight, were key components of Mesozoic terrestrial ecosystems from their sudden appearance in the Late Triassic until their demise at the end of the Cretaceous. However, the origin and early evolution of pterosaurs are poorly understood owing to a substantial stratigraphic and morphological gap between these reptiles and their closest relatives6, Lagerpetidae. Scleromochlus taylori, a tiny reptile from the early Late Triassic of Scotland discovered over a century ago, was hypothesized to be a key taxon closely related to pterosaurs, but its poor preservation has limited previous studies and resulted in controversy over its phylogenetic position, with some even doubting its identification as an archosaur. Here we use microcomputed tomographic scans to provide the first accurate whole-skeletal reconstruction and a revised diagnosis of Scleromochlus, revealing new anatomical details that conclusively identify it as a close pterosaur relative within Pterosauromorpha (the lagerpetid + pterosaur clade). Scleromochlus is anatomically more similar to lagerpetids than to pterosaurs and retains numerous features that were probably present in very early diverging members of Avemetatarsalia (bird-line archosaurs). These results support the hypothesis that the first flying reptiles evolved from tiny, probably facultatively bipedal, cursorial ancestors

17.Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry下载原文

First Author:

Lindsay N. Hayes①

Corresponding Author:

Akira Sawa②

Affiliations:

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA①②

Abstract:

Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood. Several maternal environmental factors—such as an aberrant microbiome, immune activation and poor nutrition—can influence prenatal brain development. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that, after maternal immune activation (MIA) in mice, microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was accompanied by changes in chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA-sequencing analysis revealed that MIA does not induce a distinct subpopulation but, rather, decreases the contribution to inflammatory microglia states. Prenatal replacement of microglia from MIA offspring with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment affect the long-term microglia reactivity and proper striatal circuit development.

18.Plant receptor-like protein activation by a microbial glycoside hydrolase下载原文

First Author:

Yue Sun①

Corresponding Author:

Yan Wang②

Affiliations:

Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing, China①

Department of Plant Pathology, Nanjing Agricultural University, Nanjing, China②

The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China②

Abstract:

Plants rely on cell-surface-localized pattern recognition receptors to detect pathogen- or host-derived danger signals and trigger an immune response. Receptor-like proteins (RLPs) with a leucine-rich repeat (LRR) ectodomain constitute a subgroup of pattern recognition receptors and play a critical role in plant immunity. Mechanisms underlying ligand recognition and activation of LRR-RLPs remain elusive. Here we report a crystal structure of the LRR-RLP RXEG1 from Nicotiana benthamiana that recognizes XEG1 xyloglucanase from the pathogen Phytophthora sojae. The structure reveals that specific XEG1 recognition is predominantly mediated by an amino-terminal and a carboxy-terminal loop-out region (RXEG1(ID)) of RXEG1. The two loops bind to the active-site groove of XEG1, inhibiting its enzymatic activity and suppressing Phytophthora infection of N. benthamiana. Binding of XEG1 promotes association of RXEG1(LRR) with the LRR-type co-receptor BAK1 through RXEG1(ID) and the last four conserved LRRs to trigger RXEG1-mediated immune responses. Comparison of the structures of apo-RXEG1(LRR), XEG1–RXEG1(LRR) and XEG1–BAK1–RXEG1(LRR) shows that binding of XEG1 induces conformational changes in the N-terminal region of RXEG1(ID) and enhances structural flexibility of the BAK1-associating regions of RXEG1(LRR). These changes allow fold switching of RXEG1(ID) for recruitment of BAK1(LRR). Our data reveal a conserved mechanism of ligand-induced heterodimerization of an LRR-RLP with BAK1 and suggest a dual function for the LRR-RLP in plant immunity.

19.Genomics to select treatment for patients with metastatic breast cancer下载原文

First / Corresponding Author:

Fabrice Andre

Affiliations:

Department of Medical Oncology, Gustave Roussy, Villejuif, France

INSERM U981, Gustave Roussy, Villejuif, France

PRISM Center for personalized medicine, Gustave Roussy, Villejuif, France

Medical School, Université Paris Saclay, Kremlin Bicetre, France

Abstract:

Cancer progression is driven in part by genomic alterations. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations, leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies. Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27–0.61, P < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56–1.06, P = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76–1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n = 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14–0.89; gBRCA2: HR = 0.37, 90% CI: 0.17–0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer.

20.CRISPR screens in Drosophila cells identify Vsg as a Tc toxin receptor下载原文

First Author:

Ying Xu①

Corresponding Author:

Stefan Raunser②

Affiliations:

Department of Urology, Boston Children’s Hospital, Boston, MA, USA①

Department of Surgery and Department of Microbiology, Harvard Medical School, Boston, MA, USA①

Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany②

Abstract:

21.Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis下载原文

First Author:

Aveline Filliol①

Corresponding Author:

Robert F. Schwabe②

Affiliations:

Department of Medicine, Columbia University, New York, NY, USA①②

Institute of Human Nutrition, Columbia University, New York, NY, USA②

Abstract:

Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion.

22.Structural basis for directional chitin biosynthesis下载原文

First Author:

Wei Chen①

Corresponding Author:

Yong Gong②

Affiliations:

State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China①

Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China①

Center for Multi-disciplinary Research, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China②

Abstract:

Chitin, the most abundant aminopolysaccharide in nature, is an extracellular polymer consisting of N-acetylglucosamine (GlcNAc) units. The key reactions of chitin biosynthesis are catalysed by chitin synthase, a membrane-integrated glycosyltransferase that transfers GlcNAc from UDP-GlcNAc to a growing chitin chain. However, the precise mechanism of this process has yet to be elucidated. Here we report five cryo-electron microscopy structures of a chitin synthase from the devastating soybean root rot pathogenic oomycete Phytophthora sojae (PsChs1). They represent the apo, GlcNAc-bound, nascent chitin oligomer-bound, UDP-bound (post-synthesis) and chitin synthase inhibitor nikkomycin Z-bound states of the enzyme, providing detailed views into the multiple steps of chitin biosynthesis and its competitive inhibition. The structures reveal the chitin synthesis reaction chamber that has the substrate-binding site, the catalytic centre and the entrance to the polymer-translocating channel that allows the product polymer to be discharged. This arrangement reflects consecutive key events in chitin biosynthesis from UDP-GlcNAc binding and polymer elongation to the release of the product. We identified a swinging loop within the chitin-translocating channel, which acts as a ‘gate lock’ that prevents the substrate from leaving while directing the product polymer into the translocating channel for discharge to the extracellular side of the cell membrane. This work reveals the directional multistep mechanism of chitin biosynthesis and provides a structural basis for inhibition of chitin synthesis.