Nature
3 Nov 2022
Volume 611 | Issue 7934
1.An optical atomic clock based on a highly charged ion
下载原文
First Author:
Steven A. King①
Corresponding Author:
Lukas J. Spieß②
Affiliations:
Oxford Ionics, Begbroke, UK①
Physikalisch-Technische Bundesanstalt, Braunschweig, Germany①②
Abstract:
Optical atomic clocks are the most accurate measurement devices ever constructed and have found many applications in fundamental science and technology. The use of highly charged ions (HCI) as a new class of references for highest-accuracy clocks and precision tests of fundamental physics has long been motivated by their extreme atomic properties and reduced sensitivity to perturbations from external electric and magnetic fields compared with singly charged ions or neutral atoms. Here we present the realization of this new class of clocks, based on an optical magnetic-dipole transition in Ar13+. Its comprehensively evaluated systematic frequency uncertainty of 2.2 × 10−17 is comparable with that of many optical clocks in operation. From clock comparisons, we improve by eight and nine orders of magnitude on the uncertainties for the absolute transition frequency and isotope shift (40Ar versus 36Ar) , respectively. These measurements allow us to investigate the largely unexplored quantum electrodynamic (QED) nuclear recoil, presented as part of improved calculations of the isotope shift, which reduce the uncertainty of previous theory by a factor of three. This work establishes forbidden optical transitions in HCI as references for cutting-edge optical clocks and future high-sensitivity searches for physics beyond the standard model.
2. Spontaneous generation and active manipulation of real-space optical vortices下载原文
First / Corresponding Author:
Dongha Kim
Affiliations:
Department of Physics, KAIST, Daejeon, Republic of Korea
Abstract:
Optical vortices are beams of light that carry orbital angular momentum, which represents an extra degree of freedom that can be generated and manipulated for photonic applications. Unlike vortices in other physical entities, the generation of optical vortices requires structural singularities, but this affects their quasiparticle nature and hampers the possibility of altering their dynamics or making them interacting. Here we report a platform that allows the spontaneous generation and active manipulation of an optical vortex–antivortex pair using an external field. An aluminium/silicon dioxide/nickel/silicon dioxide multilayer structure realizes a gradient-thickness optical cavity, where the magneto-optic effects of the nickel layer affect the transition between a trivial and a non-trivial topological phase. Rather than a structural singularity, the vortex–antivortex pairs present in the light reflected by our device are generated through mathematical singularities in the generalized parameter space of the top and bottom silicon dioxide layers, which can be mapped onto real space and exhibit polarization-dependent and topology-dependent dynamics driven by external magnetic fields. We expect that the field-induced engineering of optical vortices that we report will facilitate the study of topological photonic interactions and inspire further efforts to bestow quasiparticle-like properties to various topological photonic textures such as toroidal vortices, polarization and vortex knots, and optical skyrmions.
3.Coherent surface plasmon polariton amplification via free-electron pumping下载原文
First Author:
Dongdong Zhang①
Corresponding Author:
Yafeng Bai②
Affiliations:
State Key Laboratory of High Field Laser Physics and CAS Center for Excellence in Ultra-intense Laser Science, Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Shanghai, People’s Republic of China①②
Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, People’s Republic of China①
Abstract:
Surface plasmonics with its unique confinement of light is expected to be a cornerstone for future compact radiation sources and integrated photonics devices. The energy transfer between light and matter is a defining aspect that underlies recent studies on optical surface-wave-mediated spontaneous emissions. However, coherent stimulated emission of free electrons, which is essential for free-electron light sources, and its dynamical amplification process remain to be disclosed in a clear, unambiguous and calibrated manner. Here we present the coherent amplification of terahertz surface plasmon polaritons via free-electron-stimulated emission: a femtosecond optical pulse creates an in-phase free-electron pulse with an initial terahertz surface wave, and their ensuing interactions intensify the terahertz surface wave coherently. The underlying dynamics of the amplification, including a twofold redshift in the radiation frequency over a one-millimetre interaction length, are resolved as electromagnetic-field-profile evolutions using an optical pump–probe method. By extending the approach to a properly phase-matched electron bunch, our theoretical analysis predicts a super-radiant surface-wave growth, which lays the ground for a stimulated surface-wave light source and may facilitate capable means for matter manipulation, especially in the terahertz band.
4.Strain-retardant coherent perovskite phase stabilized Ni-rich cathode下载原文
First Author:
Liguang Wang①
Corresponding Author:
Tianpin Wu②
Affiliations:
College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China①②
X‐ray Science Division, Argonne National Laboratory, Lemont, IL, USA①②
Institute of Zhejiang University-Quzhou, Quzhou, China①
Abstract:
The use of state-of-the-art Ni-rich layered oxides (LiNixCoyMn1−x−yO2,x > 0.5) as the cathode material for lithium-ion batteries can push the energy and power density to a higher level than is currently available. However, volume variation associated with anisotropic lattice strain and stress that is being developed during lithium (de)intercalation induces severe structural instability and electrochemical decay of the cathode materials, which is amplified further when the battery is operating at a high voltage (above 4.5 V), which is essential for unlocking its high energy. Even after much effort by the research community, an intrinsic strain-retardant method for directly alleviating the continuous accumulation of lattice strain remains elusive. Here, by introducing a coherent perovskite phase into the layered structure functioning as a ‘rivet’, we significantly mitigate the pernicious structural evolutions by a pinning effect. The lattice strain evolution in every single cycle is markedly reduced by nearly 70% when compared with conventional materials, which significantly enhances morphological integrity leading to a notable improvement in battery cyclability. This strain-retardant approach broadens the perspective for lattice engineering to release the strain raised from lithium (de)intercalation and paves the way for the development of high-energy-density cathodes with long durability.
5.3D-printed machines that manipulate microscopic objects using capillary forces下载原文
First Author:
Cheng Zeng①
Corresponding Author:
Vinothan N. Manoharan②
Affiliations:
Harvard John A. Paulson School of Engineering and Applied Sciences,Harvard University, Cambridge, MA, USA①②
Department of Physics, Harvard University, Cambridge, MA, US②
Abstract:
Objects that deform a liquid interface are subject to capillary forces, which can be harnessed to assemble the objects. Once assembled, such structures are generally static. Here we dynamically modulate these forces to move objects in programmable two-dimensional patterns. We 3D-print devices containing channels that trap floating objects using repulsive capillary forces, then move these devices vertically in a water bath. Because the channel cross-sections vary with height, the trapped objects can be steered in two dimensions. The device and interface therefore constitute a simple machine that converts vertical to lateral motion. We design machines that translate, rotate and separate multiple floating objects and that do work on submerged objects through cyclic vertical motion. We combine these elementary machines to make centimetre-scale compound machines that braid micrometre-scale filaments into prescribed topologies, including non-repeating braids. Capillary machines are distinct from mechanical, optical or fluidic micromanipulators in that a meniscus links the object to the machine. Therefore, the channel shapes need only be controlled on the scale of the capillary length (a few millimetres), even when the objects are microscopic. Consequently, such machines can be built quickly and inexpensively. This approach could be used to manipulate micrometre-scale particles or to braid microwires for high-frequency electronics.
6.Volcanic trigger of ocean deoxygenation during Cordilleran ice sheet retreat下载原文
First / Corresponding Author:
Jianghui Du
Affiliations:
College of Earth, Ocean, and Atmospheric Sciences, Oregon State University, Corvallis, OR, USA
Institute of Geochemistry and Petrology, Department of Earth Sciences, ETH Zürich, Zürich, Switzerland
Abstract:
North Pacific deoxygenation events during the last deglaciation were sustained over millennia by high export productivity, but the triggering mechanisms and their links to deglacial warming remain uncertain. Here we find that initial deoxygenation in the North Pacific immediately after the Cordilleran ice sheet (CIS) retreat was associated with increased volcanic ash in seafloor sediments. Timing of volcanic inputs relative to CIS retreat suggests that regional explosive volcanism was initiated by ice unloading. We posit that iron fertilization by volcanic ash during CIS retreat fuelled ocean productivity in this otherwise iron-limited region, and tipped the marine system towards sustained deoxygenation. We also identify older deoxygenation events linked to CIS retreat over the past approximately 50,000 years . Our findings suggest that the apparent coupling between the atmosphere, ocean, cryosphere and solid-Earth systems occurs on relatively short timescales and can act as an important driver for ocean biogeochemical change.
7.Global trends of cropland phosphorus use and sustainability challenges下载原文
First Author:
T. Zou①
Corresponding Author:
X. Zhang②
Affiliations:
Appalachian Laboratory, University of Maryland Center for Environmental Science, Frostburg, MD, USA①②
Abstract:
To meet the growing food demand while addressing the multiple challenges of exacerbating phosphorus (P) pollution and depleting P rock reserves, P use efficiency (PUE, the ratio of productive P output to P input in a defined system) in crop production needs to be improved. Although many efforts have been devoted to improving nutrient management practices on farms, few studies have examined the historical trajectories of PUE and their socioeconomic and agronomic drivers on a national scale. Here we present a database of the P budget (the input and output of the crop production system) and PUE by country and by crop type for 1961–2019, and examine the substantial contribution of several drivers for PUE, such as economic development stages and crop portfolios. To address the P management challenges, we found that global PUE in crop production must increase to 68–81%, and recent trends indicate some meaningful progress towards this goal. However, P management challenges and opportunities in croplands vary widely among countries.
8.Calcium dissolution in bridgmanite in the Earth’s deep mantle下载原文
First / Corresponding Author:
Byeongkwan Ko
Affiliations:
Department of Earth and Environmental Sciences, Michigan State University, East Lansing, MI, USA
School of Earth and Space Exploration, Arizona State University, Tempe, AZ, USA
Abstract:
Accurate knowledge of the mineralogy is essential for understanding the lower mantle, which represents more than half of Earth’s volume. CaSiO3 perovskite is believed to be the third-most-abundant mineral throughout the lower mantle, following bridgmanite and ferropericlase. Here we experimentally show that the calcium solubility in bridgmanite increases steeply at about 2,300 kelvin and above 40 gigapascals to a level sufficient for a complete dissolution of all CaSiO3 component in pyrolite into bridgmanite, resulting in the disappearance of CaSiO3 perovskite at depths greater than about 1,800 kilometres along the geotherm. Hence we propose a change from a two-perovskite domain (TPD; bridgmanite plus CaSiO3 perovskite) at the shallower lower mantle to a single-perovskite domain (SPD; calcium-rich bridgmanite) at the deeper lower mantle. Iron seems to have a key role in increasing the calcium solubility in bridgmanite. The temperature-driven nature can cause large lateral variations in the depth of the TPD-to-SPD change in response to temperature variations (by more than 500 kilometres). Furthermore, the SPD should have been thicker in the past when the mantle was warmer. Our finding requires revision of the deep-mantle mineralogy models and will have an impact on our understanding of the composition, structure, dynamics and evolution of the region.
9.Extreme escalation of heat failure rates in ectotherms with global warming下载原文
First Author:
Lisa Bjerregaard Jørgensen①
Corresponding Author:
Johannes Overgaard②
Affiliations:
Section for Zoophysiology, Department of Biology, Aarhus University, Aarhus, Denmark①②
Abstract:
Temperature affects the rate of all biochemical processes in ectotherms and is therefore critical for determining their current and future distribution under global climate change. Here we show that the rate of biological processes maintaining growth, homeostasis and ageing in the permissive temperature range increases by 7% per degree Celsius (median activation energyEa = 0.48 eV from 1,351 rates across 314 species). By contrast, the processes underlying heat failure rate within the stressful temperature range are extremely temperature sensitive, such that heat failure increases by more than 100% per degree Celsius across a broad range of taxa (medianEa = 6.13 eV from 123 rates across 112 species). The extreme thermal sensitivity of heat failure rates implies that the projected increase in the frequency and intensity of heatwaves can exacerbate heat mortality for many ectothermic species with severe and disproportionate consequences. Combining the extreme thermal sensitivities with projected increases in maximum temperatures globally, we predict that moderate warming scenarios can increase heat failure rates by 774% (terrestrial) and 180% (aquatic) by 2100. This finding suggests that we are likely to underestimate the potential impact of even a modest global warming scenario.
10.Synchrotron tomography of a stem lizard elucidates early squamate anatomy下载原文
First / Corresponding Author:
Mateusz Tałanda
Affiliations:
University of Warsaw, Faculty of Biology, Biological and Chemical Research Centre, Institute of Evolutionary Biology, Warsaw, Poland
Centre for Integrative Anatomy, Department of Cell and DevelopmentalBiology, University College London, London, UK
Abstract:
Squamates (lizards and snakes) include more than 10,000 living species, descended from an ancestor that diverged more than 240 million years ago from that of their closest living relative,Sphenodon. However, a deficiency of fossil evidence, combined with serious conflicts between molecular and morphological accounts of squamate phylogeny, has caused uncertainty about the origins and evolutionary assembly of squamate anatomy. Here we report the near-complete skeleton of a stem squamate,Bellairsia gracilis, from the Middle Jurassic epoch of Scotland, documented using high-resolution synchrotron phase-contrast tomography.Bellairsiashares numerous features of the crown group, including traits related to cranial kinesis (an important functional feature of many extant squamates) and those of the braincase and shoulder girdle. Alongside these derived traits,Bellairsiaalso retains inferred ancestral features including a pterygoid–vomer contact and the presence of both cervical and dorsal intercentra. Phylogenetic analyses return strong support forBellairsiaas a stem squamate, suggesting that several features that it shares with extant gekkotans are plesiomorphies, consistent with the molecular phylogenetic hypothesis that gekkotans are early-diverging squamates. We also provide confident support of stem squamate affinities for the enigmaticOculudentavis. Our findings indicate that squamate-like functional features of the suspensorium, braincase and shoulder girdle preceded the origin of their palatal and vertebral traits and indicate the presence of advanced stem squamates as persistent components of terrestrial assemblages up to at least the middle of the Cretaceous period.
11.Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes下载原文
First Author:
Wei Wei①
Corresponding Author:
Patrick F. Chinnery②
Affiliations:
Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, UK①②
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK①②
Abstract:
DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event—the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation. Here we analyse whole-genome sequences from 66,083 people—including 12,509 people with cancer—and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape.
12.Stroke genetics informs drug discovery and risk prediction across ancestries下载原文
First Author:
Aniket Mishra①
Corresponding Author:
Stephanie Debette②
Affiliations:
Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France①②
Department of Neurology, Institute for Neurodegenerative Diseases, CHU de Bordeaux, Bordeaux, France②
Abstract:
Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such asSH3PXD2AandFURIN) and variants (such as atGRK5andNOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
13. Behavioural and dopaminergic signatures of resilience下载原文
First Author:
Lindsay Willmore①
Corresponding Author:
Ilana B. Witten②
Affiliations:
Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA①②
Department of Psychology, Princeton University, Princeton, NJ, USA②
Abstract:
Chronic stress can have lasting adverse consequences in some individuals, yet others are resilient to the same stressor1,2. Susceptible and resilient individuals exhibit differences in the intrinsic properties of mesolimbic dopamine (DA) neurons after the stressful experience is over. However, the causal links between DA, behaviour during stress and individual differences in resilience are unknown. Here we recorded behaviour in mice simultaneously with DA neuron activity in projections to the nucleus accumbens (NAc)and the tail striatum (TS) during social defeat. Supervised and unsupervised behavioural quantification revealed that during stress, resilient and susceptible mice use different behavioural strategies and have distinct activity patterns in DA terminals in the NAc (but not the TS). Neurally, resilient mice have greater activity near the aggressor, including at the onset of fighting back. Conversely, susceptible mice have greater activity at the offset of attacks and onset of fleeing. We also performed optogenetic stimulation of NAc-projecting DA neurons in open loop (randomly timed) during defeat or timed to specific behaviours using real-time behavioural classification. Both open-loop and fighting-back-timed activation promoted resilience and reorganized behaviour during defeat towards resilience-associated patterns. Together, these data provide a link between DA neural activity, resilience and resilience-associated behaviour during the experience of stress.
14.Adenylate cyclase activity of TIR1/AFB auxin receptors in plants下载原文
First Author:
Linlin Qi①
Corresponding Author:
Jiří Friml②
Affiliations:
Institute of Science and Technology Austria (ISTA), Klosterneuburg, Austria①②
Abstract:
The phytohormone auxin is the major coordinative signal in plant development, mediating transcriptional reprogramming by a well-established canonical signalling pathway. TRANSPORT INHIBITOR RESPONSE 1 (TIR1)/AUXIN-SIGNALING F-BOX (AFB) auxin receptors are F-box subunits of ubiquitin ligase complexes. In response to auxin, they associate with Aux/IAA transcriptional repressors and target them for degradation via ubiquitination. Here we identify adenylate cyclase (AC) activity as an additional function of TIR1/AFB receptors across land plants. Auxin, together with Aux/IAAs, stimulates cAMP production. Three separate mutations in the AC motif of the TIR1 C-terminal region, all of which abolish the AC activity, each render TIR1 ineffective in mediating gravitropism and sustained auxin-induced root growth inhibition, and also affect auxin-induced transcriptional regulation. These results highlight the importance of TIR1/AFB AC activity in canonical auxin signalling. They also identify a unique phytohormone receptor cassette combining F-box and AC motifs, and the role of cAMP as a second messenger in plants.
15. Dysregulated naive B cells and de novo autoreactivity in severe COVID-19下载原文
First Author:
Matthew C. Woodruff①
Corresponding Author:
Ignacio Sanz②
Affiliations:
Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA①②
Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA①②
Abstract:
Severe SARS-CoV-2 infection has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential, although their origins and resolution have remained unclear. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity, as a dominant feature of severe and critical COVID-19. Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10–15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.
16. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity下载原文
First Author:
Akshay T. Krishnamurty①
Corresponding Author:
Shannon J. Turley②
Affiliations:
Genentech, South San Francisco, CA, USA①②
Abstract:
Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15). However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developedLrrc15–diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.
17.Neoadjuvant relatlimab and nivolumab in resectable melanoma下载原文
First / Corresponding Author:
Rodabe N. Amaria
Affiliation:
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Abstract:
Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3–4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.
18.Mechanism of an intramembrane chaperone for multipass membrane proteins下载原文
First Author:
Luka Smalinskaitė①
Corresponding Author:
Ramanujan S. Hegde②
Affiliations:
MRC Laboratory of Molecular Biology, Cell Biology Division, Cambridge, UK①②
Abstract:
Multipass membrane proteins play numerous roles in biology and include receptors, transporters, ion channels and enzymes. How multipass proteins are co-translationally inserted and folded at the endoplasmic reticulum is not well understood. The prevailing model posits that each transmembrane domain (TMD) of a multipass protein successively passes into the lipid bilayer through a front-side lateral gate of the Sec61 protein translocation channel. The PAT complex, an intramembrane chaperone comprising Asterix and CCDC47, engages early TMDs of multipass proteins to promote their biogenesis by an unknown mechanism. Here, biochemical and structural analysis of intermediates during multipass protein biogenesis showed that the nascent chain is not engaged with Sec61, which is occluded and latched closed by CCDC47. Instead, Asterix binds to and redirects the substrate to a location behind Sec61, where the PAT complex contributes to a multipass translocon surrounding a semi-enclosed, lipid-filled cavity. Detection of multiple TMDs in this cavity after their emergence from the ribosome suggests that multipass proteins insert and fold behind Sec61. Accordingly, biogenesis of several multipass proteins was unimpeded by inhibitors of the Sec61 lateral gate. These findings elucidate the mechanism of an intramembrane chaperone and suggest a new framework for multipass membrane protein biogenesis at the endoplasmic reticulum.
19.Substrate-driven assembly of a translocon for multipass membrane proteins下载原文
First Author:
Arunkumar Sundaram①
Corresponding Author:
Robert J. Keenan②
Affiliations:
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA①②
Abstract:
Most membrane proteins are synthesized on endoplasmic reticulum (ER)-bound ribosomes docked at the translocon, a heterogeneous ensemble of transmembrane factors operating on the nascent chain. How the translocon coordinates the actions of these factors to accommodate its different substrates is not well understood. Here we define the composition, function and assembly of a translocon specialized for multipass membrane protein biogenesis. This ‘multipass translocon’ is distinguished by three components that selectively bind the ribosome–Sec61 complex during multipass protein synthesis: the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back of Sec61 (BOS) complexes. Analysis of insertion intermediates reveals how features of the nascent chain trigger multipass translocon assembly. Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability. These results establish the mechanism by which nascent multipass proteins selectively recruit the multipass translocon to facilitate their biogenesis. More broadly, they define the ER translocon as a dynamic assembly whose subunit composition adjusts co-translationally to accommodate the biosynthetic needs of its diverse range of substrates.
20.Non-canonical β-adrenergic activation of ERK at endosomes下载原文
First Author:
Yonghoon Kwon①
Corresponding Author:
Jin Zhang②
Affiliations:
Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA①②
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA②
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA②
Abstract:
G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)—a master regulator of cell proliferation and survival. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood. Here we investigated how spatially organized β2-adrenergic receptor (β2AR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors, we show that β2AR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gαs and requires ligand-stimulated β2AR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gαs, RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal β2AR and Gαs signalling blunted nuclear ERK activity,MYCgene expression and cell proliferation. These results reveal a non-canonical mechanism for the spatial regulation of ERK through GPCR signalling and identify a functionally important endosomal signalling axis.
21.Bestrophin-2 and glutamine synthetase form a complex for glutamate release下载原文
First Author:
Aaron P. Owji①
Corresponding Author:
Yu Zhang②
Affiliations:
Department of Ophthalmology, Columbia University, New York, NY, USA①
Department of Pharmacology, Columbia University, New York, NY, USA①②
Abstract:
Bestrophin-2 (BEST2) is a member of the bestrophin family of calcium-activated anion channels that has a critical role in ocular physiology. Here we uncover a directional permeability of BEST2 to glutamate that heavily favours glutamate exit, identify glutamine synthetase (GS) as a binding partner of BEST2 in the ciliary body of the eye, and solve the structure of the BEST2–GS complex. BEST2 reduces cytosolic GS activity by tethering GS to the cell membrane. GS extends the ion conducting pathway of BEST2 through its central cavity and inhibits BEST2 channel function in the absence of intracellular glutamate, but sensitizes BEST2 to intracellular glutamate, which promotes the opening of BEST2 and thus relieves the inhibitory effect of GS. We demonstrate the physiological role of BEST2 in conducting chloride and glutamate and the influence of GS in non-pigmented ciliary epithelial cells. Together, our results reveal a novel mechanism of glutamate release through BEST2–GS.