Nature
27 October 2022
Volume 610 | Issue 7933
1.General-relativistic precession in a black-hole binary
下载原文
First/Corresponding Author:
Mark Hannam
Affiliation:
Gravity Exploration Institute, Cardiff University, Cardiff, UK
Abstract:
The general-relativistic phenomenon of spin-induced orbital precession hasnot yet been observed in strong-field gravity. Gravitational-wave observations of binary black holes (BBHs) are prime candidates, as we expect the astrophysical binary population to contain precessing binaries. Imprints of precession have been investigated in several signals, but no definitive identification of orbital precession has been reported in any of the 84 BBH observations so far by the Advanced LIGO and Virgo detectors. Here we report the measurement of strong-field precession in the LIGO–Virgo–Kagra gravitational-wave signal GW200129. The binary’s orbit precesses at a rate ten orders of magnitude faster than previous weak-field measurements from binary pulsars. We also find that the primary black hole is probably highly spinning. According to current binary population estimates, a GW200129-like signal is extremely unlikely, and therefore presents a direct challenge to many current binary-formation models.
2. Measurement of 19F(p, γ)20Ne reaction suggests CNO breakout in first stars下载原文
First Author:
Corresponding Author:
Jianjun He②
Affiliations:
Key Laboratory of Beam Technology of Ministry of Education, College of Nuclear Science and Technology, Beijing Normal University, Beijing, China①②
Abstract:
Proposed mechanisms for the production of calcium in the first stars (population III stars)—primordial stars that formed out of the matter of the Big Bang—are at odds with observations. Advanced nuclear burning and supernovae were thought to be the dominant source of the calcium production seen in all stars. Here we suggest a qualitatively different path to calcium production through breakout from the ‘warm’ carbon–nitrogen–oxygen (CNO) cycle through a direct experimental measurement of the 19F(p, γ)20Ne breakout reaction down to a very low energy point of 186 kiloelectronvolts, reporting a key resonance at 225 kiloelectronvolts. In the domain of astrophysical interest, at around 0.1 gigakelvin, this thermonuclear 19F(p, γ)20Ne rate is up to a factor of 7.4 larger than the previous recommended rate. Our stellar models show a stronger breakout during stellar hydrogen burning than previously thought, and may reveal the nature of calcium production in population III stars imprinted on the oldest known ultra-iron-poor star, SMSS0313-6708. Our experimental result was obtained in the China JinPing Underground Laboratory, which offers an environment with an extremely low cosmic-ray-induced background. Our rate showcases the effect that faint population III star supernovae can have on the nucleosynthesis observed in the oldest known stars and first galaxies, which are key mission targets of the James Webb Space Telescope.
3. Free-space dissemination of time and frequency with 10−19 instability over 113 km下载原文
First Author:
Qi Shen①
Corresponding Author:
Jian-Wei Pan②
Affiliations:
Hefei National Research Center for Physical Sciences at the Microscale and School of Physical Sciences, University of Science and Technology of China, Hefei, China①②
Shanghai Research Center for Quantum Science and CAS Center for Excellence in Quantum Information and Quantum Physics, University of Science and Technology of China, Shanghai, China①②
Hefei National Laboratory, University of Science and Technology of China, Hefei, China①②
Abstract:
Networks of optical clocks find applications in precise navigation, in efforts to redefine the fundamental unit of the ‘second’ and in gravitational tests. As the frequency instability for state-of-the-art optical clocks has reached the 10−19 level, the vision of a global-scale optical network that achieves comparable performances requires the dissemination of time and frequency over a long-distance free-space link with a similar instability of 10−19. However, previous attempts at free-space dissemination of time and frequency at high precision did not extend beyond dozens of kilometres. Here we report time–frequency dissemination with an offset of 6.3 × 10−20 ± 3.4 × 10−19 and an instability of less than 4 × 10−19 at 10,000 s through a free-space link of 113 km. Key technologies essential to this achievement include the deployment of high-power frequency combs, high-stability and high-efficiency optical transceiver systems and efficient linear optical sampling. We observe that the stability we have reached is retained for channel losses up to 89 dB. The technique we report can not only be directly used in ground-based applications, but could also lay the groundwork for future satellite time–frequency dissemination.
4. The time-programmable frequency comb and its use in quantum-limited ranging下载原文
First Author:
Emily D. Caldwell①
Corresponding Author:
Laura C. Sinclair②
Affiliations:
National Institute of Standards and Technology (NIST), Boulder, CO, USA①②
Department of Electrical, Computer and Energy Engineering, University of Colorado, Boulder, CO, USA①
Abstract:
Two decades after its invention, the classic self-referenced frequency comb laser is an unrivalled ruler for frequency, time and distance metrology owing to the rigid spacing of its optical output. As a consequence, it is now used in numerous sensing applications that require a combination of high bandwidth and high precision. Many of these applications, however, are limited by the trade-offs inherent in the rigidity of the comb output and operate far from quantum-limited sensitivity. Here we demonstrate an agile programmable frequency comb where the pulse time and phase are digitally controlled with ±2-attosecond accuracy. This agility enables quantum-limited sensitivity in sensing applications as the programmable comb can be configured to coherently track weak returning pulse trains at the shot-noise limit. To highlight its capabilities, we use this programmable comb in a ranging system, reducing the required power to reach a given precision by about 5,000-fold compared with a conventional dual-comb system. This enables ranging at a mean photon per pulse number of 1/77 while retaining the full accuracy and precision of a rigid frequency comb. Beyond ranging and imaging, applications in time and frequency metrology, comb-based spectroscopy, pump–probe experiments and compressive sensing should benefit from coherent control of the comb-pulse time and phase.
5. Shape memory in self-adapting colloidal crystals下载原文
First Author:
Seungkyu Lee①
Corresponding Author:
Chad A. Mirkin②
Affiliations:
Department of Chemistry, Northwestern University, Evanston, USA①②
International Institute for Nanotechnology, Northwestern University, Evanston, USA①②
Department of Chemical and Biological Engineering, Northwestern University, Evanston, USA①
Abstract:
Reconfigurable, mechanically responsive crystalline materials are central components in many sensing, soft robotic, and energy conversion and storage devices. Crystalline materials can readily deform under various stimuli and the extent of recoverable deformation is highly dependent upon bond type. Indeed, for structures held together via simple electrostatic interactions, minimal deformations are tolerated. By contrast, structures held together by molecular bonds can, in principle, sustain much larger deformations and more easily recover their original configurations. Here we study the deformation properties of well-faceted colloidal crystals engineered with DNA. These crystals are large in size (greater than 100 µm) and have a body-centred cubic (bcc) structure with a high viscoelastic volume fraction (of more than 97%). Therefore, they can be compressed into irregular shapes with wrinkles and creases, and, notably, these deformed crystals, upon rehydration, assume their initial well-formed crystalline morphology and internal nanoscale order within seconds. For most crystals, such compression and deformation would lead to permanent, irreversible damage. The substantial structural changes to the colloidal crystals are accompanied by notable and reversible optical property changes. For example, whereas the original and structurally recovered crystals exhibit near-perfect (over 98%) broadband absorption in the ultraviolet–visible region, the deformed crystals exhibit significantly increased reflection (up to 50% of incident light at certain wavelengths), mainly because of increases in their refractive index and inhomogeneity.
6. Screening for generality in asymmetric catalysis 下载原文
First Author:
Corin C. Wagen①
Corresponding Author:
Eugene E. Kwan②
Affiliations:
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA①
Process Research and Development, Merck & Co. Inc, Boston, MA, USA②
Abstract:
Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals and natural products. A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized. We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized. Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalytic reactions from the outset. Multisubstrate screening is achieved by conducting high-throughput chiral analyses by supercritical fluid chromatography–mass spectrometry with pooled samples. When applied to Pictet–Spengler reactions, the multisubstrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation, which even displayed high enantioselectivity for substrate combinations outside of the screening set.
7. Comprehensive evidence implies a higher social cost of CO2下载原文
First Author:
Kevin Rennert①
Corresponding Author:
David Anthoff②
Affiliations:
Resources for the Future, Washington, DC, USA①
Energy and Resources Group, University of California, Berkeley, CA, USA②
Abstract:
The social cost of carbon dioxide (SC-CO2) measures the monetized value of the damages to society caused by an incremental metric tonne of CO2 emissions and is a key metric informing climate policy. Used by governments and other decision-makers in benefit–cost analysis for over a decade, SC-CO2 estimates draw on climate science, economics, demography and other disciplines. However, a 2017 report by the US National Academies of Sciences, Engineering, and Medicine (NASEM) highlighted that current SC-CO2 estimates no longer reflect the latest research. The report provided a series of recommendations for improving the scientific basis, transparency and uncertainty characterization of SC-CO2 estimates. Here we show that improved probabilistic socioeconomic projections, climate models, damage functions, and discounting methods that collectively reflect theoretically consistent valuation of risk, substantially increase estimates of the SC-CO2. Our preferred mean SC-CO2 estimate is $185 per tonne of CO2 ($44–$413 per tCO2: 5%–95% range, 2020 US dollars) at a near-term risk-free discount rate of 2%, a value 3.6 times higher than the US government’s current value of $51 per tCO2. Our estimates incorporate updated scientific understanding throughout all components of SC-CO2 estimation in the new open-source Greenhouse Gas Impact Value Estimator (GIVE) model, in a manner fully responsive to the near-term NASEM recommendations. Our higher SC-CO2 values, compared with estimates currently used in policy evaluation, substantially increase the estimated benefits of greenhouse gas mitigation and thereby increase the expected net benefits of more stringent climate policies.
8. Global hotspots for soil nature conservation下载原文
First / Corresponding Author:
Carlos A. Guerra
Affiliations:
German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
Institute of Biology, Martin Luther University Halle Wittenberg, Halle(Saale), Germany
Institute of Biology, Leipzig University, Leipzig, Germany
Abstract:
Soils are the foundation of all terrestrial ecosystems. However, unlike for plants and animals, a global assessment of hotspots for soil nature conservation is still lacking. This hampers our ability to establish nature conservation priorities for the multiple dimensions that support the soil system: from soil biodiversity to ecosystem services. Here, to identify global hotspots for soil nature conservation, we performed a global field survey that includes observations of biodiversity (archaea, bacteria, fungi, protists and invertebrates) and functions (critical for six ecosystem services) in 615 composite samples of topsoil from a standardized survey in all continents. We found that each of the different ecological dimensions of soils—that is, species richness (alpha diversity, measured as amplicon sequence variants), community dissimilarity and ecosystem services—peaked in contrasting regions of the planet, and were associated with different environmental factors. Temperate ecosystems showed the highest species richness, whereas community dissimilarity peaked in the tropics, and colder high-latitudinal ecosystems were identified as hotspots of ecosystem services. These findings highlight the complexities that are involved in simultaneously protecting multiple ecological dimensions of soil. We further show that most of these hotspots are not adequately covered by protected areas (more than 70%), and are vulnerable in the context of several scenarios of global change. Our global estimation of priorities for soil nature conservation highlights the importance of accounting for the multidimensionality of soil biodiversity and ecosystem services to conserve soils for future generations.
9. Ion regulation at gills precedes gas exchange and the origin of vertebrates下载原文
First / Corresponding Author:
Michael A. Sackville
Affiliation:
Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
Abstract:
Gas exchange and ion regulation at gills have key roles in the evolution of vertebrates. Gills are hypothesized to have first acquired these important homeostatic functions from the skin in stem vertebrates, facilitating the evolution of larger, more-active modes of life. However, this hypothesis lacks functional support in relevant taxa. Here we characterize the function of gills and skin in a vertebrate (lamprey ammocoete; Entosphenus tridentatus), a cephalochordate (amphioxus; Branchiostoma floridae) and a hemichordate (acorn worm; Saccoglossus kowalevskii) with the presumed burrowing, filter-feeding traits of vertebrate ancestors. We provide functional support for a vertebrate origin of gas exchange at the gills with increasing body size and activity, as direct measurements in vivo reveal that gills are the dominant site of gas exchange only in ammocoetes, and only with increasing body size or challenges to oxygen supply and demand. Conversely, gills of all three taxa are implicated in ion regulation. Ammocoete gills are responsible for all ion flux at all body sizes, whereas molecular markers for ion regulation are higher in the gills than in the skin of amphioxus and acorn worms. This suggests that ion regulation at gills has an earlier origin than gas exchange that is unrelated to vertebrate size and activity—perhaps at the very inception of pharyngeal pores in stem deuterostomes.
10. A saturated map of common genetic variants associated with human height 下载原文
First / Corresponding Author:
Loïc Yengo
Affiliation:
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
Abstract:
Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
11. Programmable RNA sensing for cell monitoring and manipulation下载原文
First Author:
Yongjun Qian①
Corresponding Author:
Z. Josh Huang②
Affiliations:
Department of Neurobiology, Duke University Medical Center, Durham, NC, USA①②
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA①②
Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, NC, USA②
Abstract:
RNA is a central and universal mediator of genetic information underlying the diversity of cell types and cell states, which together shape tissue organization and organismal function across species and lifespans. Despite numerous advances in RNA sequencing technologies and the massive accumulation of transcriptome datasets across the life sciences, the dearth of technologies that use RNAs to observe and manipulate cell types remains a bottleneck in biology and medicine. Here we describe CellREADR (Cell access through RNA sensing by Endogenous ADAR), a programmable RNA-sensing technology that leverages RNA editing mediated by ADAR to couple the detection of cell-defining RNAs with the translation of effector proteins. Viral delivery of CellREADR conferred specific cell-type access in mouse and rat brains and in ex vivo human brain tissues. Furthermore, CellREADR enabled the recording and control of specific types of neurons in behaving mice. CellREADR thus highlights the potential for RNA-based monitoring and editing of animal cells in ways that are specific, versatile, simple and generalizable across organ systems and species, with wide applications in biology, biotechnology and programmable RNA medicine.
12. Gut–brain circuits for fat preference下载原文
First Author:
Mengtong Li①
Corresponding Author:
Charles S. Zuker②
Affiliations:
Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, Chevy Chase, MD, USA①②
Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY, USA①②
Department of Neuroscience, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA②
Abstract:
The perception of fat evokes strong appetitive and consummatory responses. Here we show that fat stimuli can induce behavioural attraction even in the absence of a functional taste system. We demonstrate that fat acts after ingestion via the gut–brain axis to drive preference for fat. Using single-cell data, we identified the vagal neurons responding to intestinal delivery of fat, and showed that genetic silencing of this gut-to-brain circuit abolished the development of fat preference. Next, we compared the gut-to-brain pathways driving preference for fat versus sugar, and uncovered two parallel systems, one functioning as a general sensor of essential nutrients, responding to intestinal stimulation with sugar, fat and amino acids, whereas the other is activated only by fat stimuli. Finally, we engineered mice lacking candidate receptors to detect the presence of intestinal fat, and validated their role as the mediators of gut-to-brain fat-evoked responses. Together, these findings reveal distinct cells and receptors that use the gut–brain axis as a fundamental conduit for the development of fat preference.
13. Borgs are giant genetic elements with potential to expand metabolic capacity下载原文
First Author:
Basem Al-Shayeb①
Corresponding Author:
Jillian F. Banfield②
Affiliations:
Innovative Genomics Institute, University of California, Berkeley, CA, USA①②
Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA①
Environmental Science, Policy and Management, University of California, Berkeley, CA, USA②
Earth and Planetary Science, University of California, Berkeley, CA, USA②
Lawrence Berkeley National Laboratory, Berkeley, CA, USA②
The University of Melbourne, Melbourne, Victoria, Australia②
Abstract:
Anaerobic methane oxidation exerts a key control on greenhouse gas emissions, yet factors that modulate the activity of microorganisms performing this function remain poorly understood. Here we discovered extraordinarily large, diverse DNA sequences that primarily encode hypothetical proteins through studying groundwater, sediments and wetland soil where methane production and oxidation occur. Four curated, complete genomes are linear, up to approximately 1 Mb in length and share genome organization, including replichore structure, long inverted terminal repeats and genome-wide unique perfect tandem direct repeats that are intergenic or generate amino acid repeats. We infer that these are highly divergent archaeal extrachromosomal elements with a distinct evolutionary origin. Gene sequence similarity, phylogeny and local divergence of sequence composition indicate that many of their genes were assimilated from methane-oxidizing Methanoperedens archaea. We refer to these elements as ‘Borgs’. We identified at least 19 different Borg types coexisting with Methanoperedens spp. in four distinct ecosystems. Borgs provide methane-oxidizing Methanoperedens archaea access to genes encoding proteins involved in redox reactions and energy conservation (for example, clusters of multihaem cytochromes and methyl coenzyme M reductase). These data suggest that Borgs might have previously unrecognized roles in the metabolism of this group of archaea, which are known to modulate greenhouse gas emissions, but further studies are now needed to establish their functional relevance.
14. A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation下载原文
First Author:
Ranit Kedmi①
Corresponding Author:
Dan R. Littman②
Affiliations:
Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA①②
Howard Hughes Medical Institute, New York, NY, USA②
Abstract:
The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn’s disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells—probably type 3 innate lymphoid cells and/or Janus cells—require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.
15. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut下载原文
First Author:
Mengze Lyu①
Corresponding Author:
Gregory F. Sonnenberg②
Affiliations:
Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA①②
Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA①②
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA①②
Abstract:
Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood, and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory and malignant diseases. Here we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that respond to the microbiota and express the transcription factor RORγt. We profiled all RORγt+ immune cells at single-cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of T regulatory (Treg) cells and lymphoid tissue inducer-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s are distinct from extrathymic AIRE-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific RORγt+ Treg cells and prevent their expansion as inflammatory T helper 17 cells. This occurs through ILC3-mediated antigen presentation, αV integrin and competition for interleukin-2. Finally, single-cell analyses suggest that interactions between ILC3s and RORγt+ Treg cells are impaired in inflammatory bowel disease. Our results define a paradigm whereby ILC3s select for antigen-specific RORγt+ Treg cells, and against T helper 17 cells, to establish immune tolerance to the microbiota and intestinal health.
16. Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota 下载原文
First Author:
Blossom Akagbosu①
Corresponding Author:
Alexander Y. Rudensky②
Affiliations:
Immuno-Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA①②
Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA②
Abstract:
Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.
17. Clathrin-associated AP-1 controls termination of STING signalling 下载原文
First Author:
Ying Liu①
Corresponding Author:
Andrea Ablasser②
Affiliations:
Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland①②
Abstract:
Stimulator of interferon genes (STING) functions downstream of cyclic GMP-AMP synthase in DNA sensing or as a direct receptor for bacterial cyclic dinucleotides and small molecules to activate immunity during infection, cancer and immunotherapy. Precise regulation of STING is essential to ensure balanced immune responses and prevent detrimental autoinflammation. After activation, STING, a transmembrane protein, traffics from the endoplasmic reticulum to the Golgi, where its phosphorylation by the protein kinase TBK1 enables signal transduction. The mechanism that ends STING signalling at the Golgi remains unknown. Here we show that adaptor protein complex 1 (AP-1) controls the termination of STING-dependent immune activation. We find that AP-1 sorts phosphorylated STING into clathrin-coated transport vesicles for delivery to the endolysosomal system, where STING is degraded. We identify a highly conserved dileucine motif in the cytosolic C-terminal tail (CTT) of STING that, together with TBK1-dependent CTT phosphorylation, dictates the AP-1 engagement of STING. A cryo-electron microscopy structure of AP-1 in complex with phosphorylated STING explains the enhanced recognition of TBK1-activated STING. We show that suppression of AP-1 exacerbates STING-induced immune responses. Our results reveal a structural mechanism of negative regulation of STING and establish that the initiation of signalling is inextricably associated with its termination to enable transient activation of immunity.
18. HRG-9 homologues regulate haem trafficking from haem-enriched compartments下载原文
First Author:
Fengxiu Sun①
Corresponding Author:
Caiyong Chen②
Affiliations:
MOE Key Laboratory of Biosystems Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China①②
Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China②
Abstract:
Haem is an iron-containing tetrapyrrole that is critical for a variety of cellular and physiological processes. Haem binding proteins are present in almost all cellular compartments, but the molecular mechanisms that regulate the transport and use of haem within the cell remain poorly understood. Here we show that haem-responsive gene 9 (HRG-9) (also known as transport and Golgi organization 2 (TANGO2)) is an evolutionarily conserved haem chaperone with a crucial role in trafficking haem out of haem storage or synthesis sites in eukaryotic cells. Loss of Caenorhabditis elegans hrg-9 and its paralogue hrg-10 results in the accumulation of haem in lysosome-related organelles, the haem storage site in worms. Similarly, deletion of the hrg-9 homologue TANGO2 in yeast and mammalian cells induces haem overload in mitochondria, the site of haem synthesis. We demonstrate that TANGO2 binds haem and transfers it from cellular membranes to apo-haemoproteins. Notably, homozygous tango2−/− zebrafish larvae develop pleiotropic symptoms including encephalopathy, cardiac arrhythmia and myopathy, and die during early development. These defects partially resemble the symptoms of human TANGO2-related metabolic encephalopathy and arrhythmias, a hereditary disease caused by mutations in TANGO2. Thus, the identification of HRG-9 as an intracellular haem chaperone provides a biological basis for exploring the aetiology and treatment of TANGO2-related disorders.19.
19. The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron下载原文
First Author:
Saki Ichikawa①
Corresponding Author:
Christina M. Woo②
Affiliation:
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA①②
Abstract:
The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide, therapeutic agents used in the treatment of haematopoietic malignancies and as ligands for targeted protein degradation. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN remains unknown. Here we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron substitute for thalidomide when embedded within bifunctional chemical degraders. Addition of the degron to the C terminus of proteins induces CRBN-dependent ubiquitination and degradation in vitro and in cells. C-terminal cyclic imides form adventitiously on physiologically relevant timescales throughout the human proteome to afford a degron that is endogenously recognized and removed by CRBN. The discovery of the C-terminal cyclic imide degron defines a regulatory process that may affect the physiological function and therapeutic engagement of CRBN.
20. Activation of γ-globin expression by hypoxia-inducible factor 1α下载原文
First Author:
Ruopeng Feng①
Corresponding Author:
Mitchell J. Weiss②
Affiliations:
Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN, USA①②
Abstract:
Around birth, globin expression in human red blood cells (RBCs) shifts from γ-globin to β-globin, which results in fetal haemoglobin (HbF, α2γ2) being gradually replaced by adult haemoglobin (HbA, α2β2). This process has motivated the development of innovative approaches to treat sickle cell disease and β-thalassaemia by increasing HbF levels in postnatal RBCs. Here we provide therapeutically relevant insights into globin gene switching obtained through a CRISPR–Cas9 screen for ubiquitin–proteasome components that regulate HbF expression. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ubiquitin ligase stabilized its ubiquitination target, hypoxia-inducible factor 1α (HIF1α), to induce γ-globin gene transcription. Mechanistically, HIF1α–HIF1β heterodimers bound cognate DNA elements in BGLT3, a long noncoding RNA gene located 2.7 kb downstream of the tandem γ-globin genes HBG1 and HBG2. This was followed by the recruitment of transcriptional activators, chromatin opening and increased long-range interactions between the γ-globin genes and their upstream enhancer. Similar induction of HbF occurred with hypoxia or with inhibition of prolyl hydroxylase domain enzymes that target HIF1α for ubiquitination by the VHL E3 ubiquitin ligase. Our findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during stress erythropoiesis and suggest a new therapeutic approach for β-haemoglobinopathies.
21. Structures of α-synuclein filaments from human brains with Lewy pathology 下载原文
First Author:
Yang Yang①
Corresponding Author:
Sjors H. W. Scheres②
Affiliations:
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK①②
Abstract:
Parkinson’s disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.
22. Structures of the TMC-1 complex illuminate mechanosensory transduction下载原文
First Author:
Hanbin Jeong①
Corresponding Author:
Eric Gouaux②
Affiliations:
Vollum Institute, Oregon Health and Science University, Portland, OR, USA①
Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR, USA②
Abstract:
The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel. Despite the profound socioeconomic impacts of hearing disorders and the fundamental biological significance of understanding mechanosensory transduction, the composition, structure and mechanism of the mechanosensory transduction complex have remained poorly characterized. Here we report the single-particle cryo-electron microscopy structure of the native transmembrane channel-like protein 1 (TMC-1) mechanosensory transduction complex isolated from Caenorhabditis elegans. The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE. CALM-1 makes extensive contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes additionally includes a single arrestin-like protein, arrestin domain protein (ARRD-6), bound to a CALM-1 subunit. Single-particle reconstructions and molecular dynamics simulations show how the mechanosensory transduction complex deforms the membrane bilayer and suggest crucial roles for lipid–protein interactions in the mechanism by which mechanical force is transduced to ion channel gating.