Science
21 Oct 2022
Volume 378 | Issue 6617
Research
Research Articles
1.Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment 
下载原文
First Author:
Shiya Cheng ①
Corresponding Author:
Melina Schuh ②
Affiliations:
Department of Meiosis, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany. ①②
Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany. ②
Abstract:
Full-grown oocytes are transcriptionally silent and must stably maintain the messenger RNAs (mRNAs) needed for oocyte meiotic maturation and early embryonic development. However, where and how mammalian oocytes store maternal mRNAs is unclear. Here, we report that mammalian oocytes accumulate mRNAs in a mitochondria-associated ribonucleoprotein domain (MARDO). MARDO assembly around mitochondria was promoted by the RNA-binding protein ZAR1 and directed by an increase in mitochondrial membrane potential during oocyte growth. MARDO foci coalesced into hydrogel-like matrices that clustered mitochondria. Maternal mRNAs stored in the MARDO were translationally repressed. Loss of ZAR1 disrupted the MARDO, dispersed mitochondria, and caused a premature loss of MARDO-localized mRNAs. Thus, a mitochondria-associated membraneless compartment controls mitochondrial distribution and regulates maternal mRNA storage, translation, and decay to ensure fertility in mammals.
2.Structure of the hepatitis C virus E1E2 glycoprotein complex 下载原文
First Author:
Alba Torrents de la Pena①
Corresponding Authors:
Kwinten Sliepen②, Rogier W. Sanders③,
Affiliations:
Department of Integrative Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. ①Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, Netherlands. ②③
Amsterdam Institute for Infection and Immunity, Infectious Diseases, 1105 AZ Amsterdam, Netherlands. ②③
Weill Medical College of Cornell University, New York, NY 10065, USA.③
Abstract:
Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in humans and afflicts more than 58 million people worldwide. The HCV envelope E1 and E2 glycoproteins are essential for viral entry and comprise the primary antigenic target for neutralizing antibody responses. The molecular mechanisms of E1E2 assembly, as well as how the E1E2 heterodimer binds broadly neutralizing antibodies, remain elusive. Here, we present the cryo–electron microscopy structure of the membrane-extracted full-length E1E2 heterodimer in complex with three broadly neutralizing antibodies—AR4A, AT1209, and IGH505—at ~3.5-angstrom resolution. We resolve the interface between the E1 and E2 ectodomains and deliver a blueprint for the rational design of vaccine immunogens and antiviral drugs.
3.Delocalized photonic deep learning on the internet’s edge 下载原文
First Author:
Alexander Sludds ①
Corresponding Authors:
Ryan Hamerly②, Dirk Englund ③
Affiliations:
Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ①②③
Physics and Informatics Laboratories, NTT Research Inc., Sunnyvale, CA 94085, USA. ②
Abstract: Advanced machine learning models are currently impossible to run on edge devices such as smart sensors and unmanned aerial vehicles owing to constraints on power, processing, and memory. We introduce an approach to machine learning inference based on delocalized analog processing across networks. In this approach, named Netcast, cloud-based “smart transceivers” stream weight data to edge devices, enabling ultraefficient photonic inference. We demonstrate image recognition at ultralow optical energy of 40 attojoules per multiply (<1 photon per multiply) at 98.8% (93%) classification accuracy. We reproduce this performance in a Boston-area field trial over 86 kilometers of deployed optical fiber, wavelength multiplexed over 3 terahertz of optical bandwidth. Netcast allows milliwatt-class edge devices with minimal memory and processing to compute at teraFLOPS rates reserved for high-power (>100 watts) cloud computers.
4.Time-restricted feeding mitigates obesity through adipocyte thermogenesis 下载原文
First Author:
Chelsea Hepler ①
Corresponding Author:
Joseph Bass ②
Affiliations:
Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. ①②
Abstract:
Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.
5.Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators 下载原文
First Author:
Karol Fiedorczuk ①
Corresponding Author:
Jue Chen ②
Affiliation:
Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065, USA. ①②
Abstract:
The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo–electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function.
REPORTS
6.An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice 下载原文
First Author:
Joni Nikkanen①
Corresponding Author:
Holly Ingraham②
Affiliations:
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94143, USA.①②
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA. ①
Abstract:
Adaptations to infectious and dietary pressures shape mammalian physiology and disease risk. How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor B cell lymphoma 6 (BCL6), which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 protein comes at a cost during conditions of dietary excess, which result in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male survival during infection, thus establishing a sex-dependent trade-off between host defense and metabolic systems. Our findings offer strong evidence that some current sex-biased diseases are rooted in ancient evolutionary trade-offs between immunity and metabolism.
7. Miniaturized spectrometers with a tunable van der Waals junction 下载原文
First / Corresponding Author:
Hoon Hahn Yoon
Affiliations:
Department of Electronics and Nanoengineering, Aalto University, Espoo 02150, Finland.
QTF Centre of Excellence, Department of Applied Physics, Aalto University, Aalto 00076, Finland.
Abstract:
Miniaturized computational spectrometers, which can obtain incident spectra using a combination of device spectral responses and reconstruction algorithms, are essential for on-chip and implantable applications. Highly sensitive spectral measurement using a single detector allows the footprints of such spectrometers to be scaled down while achieving spectral resolution approaching that of benchtop systems. We report a high-performance computational spectrometer based on a single van der Waals junction with an electrically tunable transport-mediated spectral response. We achieve high peak wavelength accuracy (∼0.36 nanometers), high spectral resolution (∼3 nanometers), broad operation bandwidth (from ∼405 to 845 nanometers), and proof-of-concept spectral imaging. Our approach provides a route toward ultraminiaturization and offers unprecedented performance in accuracy, resolution, and operation bandwidth for single-detector computational spectrometers.
8. Disease outbreaks select for mate choice and coat color in wolves 下载原文
First/ Corresponding Author:
Sarah Cubaynes
Affiliation:
CEFE, University of Montpellier, CNRS, EPHE-PSL University, IRD, 34090 Montpellier, France.
Abstract:
We know much about pathogen evolution and the emergence of new disease strains, but less about host resistance and how it is signaled to other individuals and subsequently maintained. The cline in frequency of black-coated wolves (Canis lupus) across North America is hypothesized to result from a relationship with canine distemper virus (CDV) outbreaks. We tested this hypothesis using cross-sectional data from wolf populations across North America that vary in the prevalence of CDV and the allele that makes coats black, longitudinal data from Yellowstone National Park, and modeling. We found that the frequency of CDV outbreaks generates fluctuating selection that results in heterozygote advantage that in turn affects the frequency of the black allele, optimal mating behavior, and black wolf cline across the continent.
9. Deep cis-regulatory homology of the butterfly wing pattern ground plan 下载原文
First / Corresponding Author:
Anyi Mazo-Vargas
Affiliation:
Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY, USA.
Department of Biological Sciences, The George Washington University, Washington, DC, USA.
Abstract:
Butterfly wing patterns derive from a deeply conserved developmental ground plan yet are diverse and evolve rapidly. It is poorly understood how gene regulatory architectures can accommodate both deep homology and adaptive change. To address this, we characterized the cis-regulatory evolution of the color pattern gene WntA in nymphalid butterflies. Comparative assay for transposase-accessible chromatin using sequencing (ATAC-seq) and in vivo deletions spanning 46 cis-regulatory elements across five species revealed deep homology of ground plan–determining sequences, except in monarch butterflies. Furthermore, noncoding deletions displayed both positive and negative regulatory effects that were often broad in nature. Our results provide little support for models predicting rapid enhancer turnover and suggest that deeply ancestral, multifunctional noncoding elements can underlie rapidly evolving trait systems.
10. Highly flexible and superhydrophobic MOF nanosheet membrane for ultrafast alcohol-water separation 下载原文
First Author:
Li-Hao Xu ①
Corresponding Author:
Ying-Nan Feng②
Affiliation:
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, P.R. China. ①②
Abstract:
High-performance pervaporation membranes have potential in industrial separation applications, but overcoming the permeability-selectivity trade-off is a challenge. We report a strategy to create highly flexible metal-organic framework nanosheet (MOF-NS) membranes with a faveolate structure on polymer substrates for alcohol-water separation. The controlled growth followed by a surface-coating method effectively produced flexible and defect-free superhydrophobic MOF-NS membranes. The reversible deformation of the flexible MOF-NS and the vertical interlamellar pathways were captured with electron microscopy. Molecular simulations confirmed the structure and revealed transport mechanism. The ultrafast transport channels in MOF-NS exhibited an ultrahigh flux and a separation factor of 8.9 in the pervaporation of 5 weight % ethanol-water at 40°C, which can be used for biofuel recovery. MOF-NS and polydimethylsiloxane synergistically contribute to the separation performance.
11. Spillover benefits from the world’s largest fully protected MPA 下载原文
First Author:
Sarah Medoff①
Corresponding Author:
John Lynham②
Affiliations:
Cooperative Institute for Marine and Atmospheric Research, School of Ocean and Earth Science and Technology, University of Hawai’i at Mānoa, Honolulu, HI, USA. ①
Department of Economics and UHERO, University of Hawai’i at Mānoa, Honolulu, HI, USA. ②
Abstract:
Previous research has cast doubt on the potential for marine protected areas (MPAs) to provide refuge and fishery spillover benefits for migratory species as most MPAs are small relative to the geographic range of these species. We test for evidence of spillover benefits accruing from the world’s largest fully protected MPA, Papahānaumokuākea Marine National Monument. Using species-specific data collected by independent fishery observers, we examine changes in catch rates for individual vessels near to and far from the MPA before and after its expansion in 2016. We find evidence of spillover benefits for yellowfin (Thunnus albacares) and bigeye tuna (Thunnus obesus).
12. MTCH2 is a mitochondrial outer membrane protein insertase 下载原文
First Author:
Alina Guna①
Corresponding Author:
Jonathan S. Weissman ②
Affiliaitons:
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.①
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. ②
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. ②
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. ②
Abstract:
In the mitochondrial outer membrane, α-helical transmembrane proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPR screens, we identified mitochondrial carrier homolog 2 (MTCH2), and its paralog MTCH1, and showed that it is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, and multipass proteins, but not outer membrane β-barrel proteins. Purified MTCH2 was sufficient to mediate insertion into reconstituted proteoliposomes. Functional and mutational studies suggested that MTCH2 has evolved from a solute carrier transporter. MTCH2 uses membrane-embedded hydrophilic residues to function as a gatekeeper for the outer membrane, controlling mislocalization of TAs into the endoplasmic reticulum and modulating the sensitivity of leukemia cells to apoptosis. Our identification of MTCH2 as an insertase provides a mechanistic explanation for the diverse phenotypes and disease states associated with MTCH2 dysfunction.