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  • Lineage tracing on transcriptional landscapes links state to fate during differentiation
    Science (IF 41.037) Pub Date : 2020-01-24
    Caleb Weinreb, Alejo Rodriguez-Fraticelli, Fernando D. Camargo, Allon M. Klein

    A challenge in biology is to associate molecular differences among progenitor cells with their capacity to generate mature cell types. Here, we use expressed DNA barcodes to clonally trace transcriptomes over time and applied this to study fate determination in hematopoiesis. We identify states of primed fate potential and locate them on a continuous transcriptional landscape. We identify two routes of monocyte differentiation that leave an imprint on mature cells. Yet analysis of sister cells also reveals cells to have intrinsic fate biases not detectable by single-cell RNA sequencing. Finally, we benchmark computational methods of dynamic inference from single-cell snapshots, showing that fate choice occurs earlier than is detected by state-of the-art algorithms, and that cells progress steadily through pseudotime with precise and consistent dynamics.

    更新日期:2020-01-26
  • On the correlation between telomere shortening rate and life span [Letters (Online Only)]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Ion Udroiu

    Whittemore et al. (1) find significant correlations between maximum life span (MLS) and telomere shortening rate (TSR) in mammalian and avian species. This interesting study comes to the conclusion that “critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.” An important issue, however, has not been dealt with by the authors. The use of linear regressions (those used by the authors) assumes that samples are independent, but this is not the case in interspecies studies. In fact, the samples (i.e., the values for each species) have different grades of dependency, which derive from their phylogenetic relationship (2). This is why all tests should be performed using phylogenetic corrections, like phylogenetic-independent contrast (3 …

    更新日期:2020-01-26
  • Reply to Udroiu: Interesting mathematical analysis of telomere shortening rate and life span [Letters (Online Only)]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Kurt Whittemore, Maria A. Blasco

    We appreciate Udroiu’s letter titled “On the correlation between telomere shortening rate and life span” (1). We acknowledge that our conclusion that “critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span” in our recent publication (2) may not be the full story, but this conclusion does appear to be a fairly straightforward and logical explanation for our observations. We also understand that the same data can be analyzed using many different methods. We thought it was important to keep …

    更新日期:2020-01-26
  • An ancestral anatomical and spatial bias for visually guided behavior [Letters (Online Only)]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Patrick Friedrich, Michel Thiebaut de Schotten, Stephanie J. Forkel, Martin Stacho, Henrietta Howells

    Human behavioral asymmetries are commonly studied in the context of structural cortical and connectional asymmetries. Within this framework, Sreenivasan and Sridharan (1) provide intriguing evidence of a relationship between visual asymmetries and the lateralization of superior colliculi connections—a phylogenetically older mesencephalic structure. Specifically, response facilitation for cued locations (i.e., choice bias) in the contralateral hemifield was associated with differences in the connectivity of the superior colliculus. Given that the superior colliculus has a structural homolog—the optic tectum—which can be traced across all Vertebrata, these results may have meaningful evolutionary ramifications.

    更新日期:2020-01-26
  • Reply to Friedrich et al.: Both genetic and environmental factors may contribute to laterality in mesencephalic connectivity and bias [Letters (Online Only)]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Varsha Sreenivasan, Devarajan Sridharan

    We thank Friedrich et al. (1) for their keen interest in our study (2) and for highlighting additional examples of asymmetries in visually guided behavior and brain connectivity across several vertebrate classes.

    更新日期:2020-01-26
  • Evolutionary dynamics of recent selection on cognitive abilities [Evolution]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Sara E. Miller, Andrew W. Legan, Michael T. Henshaw, Katherine L. Ostevik, Kieran Samuk, Floria M. K. Uy, Michael J. Sheehan

    Cognitive abilities can vary dramatically among species. The relative importance of social and ecological challenges in shaping cognitive evolution has been the subject of a long-running and recently renewed debate, but little work has sought to understand the selective dynamics underlying the evolution of cognitive abilities. Here, we investigate recent selection related to cognition in the paper wasp Polistes fuscatus—a wasp that has uniquely evolved visual individual recognition abilities. We generate high quality de novo genome assemblies and population genomic resources for multiple species of paper wasps and use a population genomic framework to interrogate the probable mode and tempo of cognitive evolution. Recent, strong, hard selective sweeps in P. fuscatus contain loci annotated with functions in long-term memory formation, mushroom body development, and visual processing, traits which have recently evolved in association with individual recognition. The homologous pathways are not under selection in closely related wasps that lack individual recognition. Indeed, the prevalence of candidate cognition loci within the strongest selective sweeps suggests that the evolution of cognitive abilities has been among the strongest selection pressures in P. fuscatus’ recent evolutionary history. Detailed analyses of selective sweeps containing candidate cognition loci reveal multiple cases of hard selective sweeps within the last few thousand years on de novo mutations, mainly in noncoding regions. These data provide unprecedented insight into some of the processes by which cognition evolves.

    更新日期:2020-01-26
  • ECM1 is an essential factor for the determination of M1 macrophage polarization in IBD in response to LPS stimulation [Immunology and Inflammation]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Yaguang Zhang, Xuezhen Li, Zhongguang Luo, Liyan Ma, Songling Zhu, Zhishuo Wang, Jing Wen, Shipeng Cheng, Wangpeng Gu, Qiaoshi Lian, Xinhao Zhao, Weiguo Fan, Zhiyang Ling, Jing Ye, Songguo Zheng, Dangsheng Li, Hongyan Wang, Jie Liu, Bing Sun

    Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Here, we uncover a function of extracellular matrix protein 1 (ECM1) in promoting the pathogenesis of human and mouse IBD. ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment. A mechanistic study showed that ECM1 can regulate M1 macrophage polarization through the granulocyte-macrophage colony-stimulating factor/STAT5 signaling pathway. Pathological changes in mice with dextran sodium sulfate-induced IBD were alleviated by the specific knockout of the ECM1 gene in macrophages. Taken together, our findings show that ECM1 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.

    更新日期:2020-01-26
  • QnAs with Roger J. Davis
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Sandeep Ravindran

    The human body’s response to stress can contribute to metabolic dysfunction, inflammation, and cancer. Roger J. Davis has spent his career elucidating the mechanisms underlying such stress responses. A professor of molecular medicine at the University of Massachusetts Medical School at Worcester, Davis was elected to the National Academy of Sciences in 2018. His landmark work on stress-activated signaling includes deciphering the mechanisms of action and function of the first human stress-activated MAP kinase, the cJun NH2-terminal kinase (JNK), which is implicated in various disease processes. In his Inaugural Article (1), Davis and his colleagues investigated the role of IL-6–mediated signaling in chronic low-grade inflammation, which can lead to metabolic syndrome. He recently spoke to PNAS about his findings.

    更新日期:2020-01-26
  • Pseudomonas aeruginosa lasR mutant fitness in microoxia is supported by an Anr-regulated oxygen-binding hemerythrin [Microbiology]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Michelle E. Clay, John H. Hammond, Fangfang Zhong, Xiaolei Chen, Caitlin H. Kowalski, Alexandra J. Lee, Monique S. Porter, Thomas H. Hampton, Casey S. Greene, Ekaterina V. Pletneva, Deborah A. Hogan

    Pseudomonas aeruginosa strains with loss-of-function mutations in the transcription factor LasR are frequently encountered in the clinic and the environment. Among the characteristics common to LasR-defective (LasR−) strains is increased activity of the transcription factor Anr, relative to their LasR+ counterparts, in low-oxygen conditions. One of the Anr-regulated genes found to be highly induced in LasR− strains was PA14_42860 (PA1673), which we named mhr for microoxic hemerythrin. Purified P. aeruginosa Mhr protein contained the predicted di-iron center and bound molecular oxygen with an apparent Kd of ∼1 µM. Both Anr and Mhr were necessary for fitness in lasR+ and lasR mutant strains in colony biofilms grown in microoxic conditions, and the effects were more striking in the lasR mutant. Among genes in the Anr regulon, mhr was most closely coregulated with the Anr-controlled high-affinity cytochrome c oxidase genes. In the absence of high-affinity cytochrome c oxidases, deletion of mhr no longer caused a fitness disadvantage, suggesting that Mhr works in concert with microoxic respiration. We demonstrate that Anr and Mhr contribute to LasR− strain fitness even in biofilms grown in normoxic conditions. Furthermore, metabolomics data indicate that, in a lasR mutant, expression of Anr-regulated mhr leads to differences in metabolism in cells grown on lysogeny broth or artificial sputum medium. We propose that increased Anr activity leads to higher levels of the oxygen-binding protein Mhr, which confers an advantage to lasR mutants in microoxic conditions.

    更新日期:2020-01-26
  • EPA’s proposed transparency rule: Factors to consider, many; planets to live on, one [Editorials]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    David B. Allison, Harvey V. Fineberg

    So reads a T-shirt sold by the American Statistical Association. This pithy quip encapsulates a fundamental principle of science: Scientists rely on evidence rather than authority. Indeed, “doubt has been considered essential to science since long before the scientific method was established in the 17th century” (1). Scientists seek reasons for why something should be believed as true, and those reasons involve data, the methods used to collect those data, and the logic connecting those data to conclusions. All other things being equal, absent the opportunity to fully inspect the data, methods, and logical connections of a study, scientists are less able to judge the validity of conclusions or the truth of propositions drawn from a study. As many of us heard from our middle school mathematics teachers, it is important to “show all your work.” Generating and evaluating the scientific evidence to form conclusions about the truth of a proposition is fundamental to the work of science.

    更新日期:2020-01-26
  • Dysregulation of TLR9 in neonates leads to fatal inflammatory disease driven by IFN-{gamma} [Immunology and Inflammation]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Alison G. Stanbery, Zachary R. Newman, Gregory M. Barton

    Recognition of self-nucleic acids by innate immune receptors can lead to the development of autoimmune and/or autoinflammatory diseases. Elucidating mechanisms associated with dysregulated activation of specific receptors may identify new disease correlates and enable more effective therapies. Here we describe an aggressive in vivo model of Toll-like receptor (TLR) 9 dysregulation, based on bypassing the compartmentalized activation of TLR9 in endosomes, and use it to uncover unique aspects of TLR9-driven disease. By inducing TLR9 dysregulation at different stages of life, we show that while dysregulation in adult mice causes a mild systemic autoinflammatory disease, dysregulation of TLR9 early in life drives a severe inflammatory disease resulting in neonatal fatality. The neonatal disease includes some hallmarks of macrophage activation syndrome but is much more severe than previously described models. Unlike TLR7-mediated disease, which requires type I interferon (IFN) receptor signaling, TLR9-driven fatality is dependent on IFN-γ receptor signaling. NK cells are likely key sources of IFN-γ in this model. We identify populations of macrophages and Ly6Chi monocytes in neonates that express high levels of TLR9 and low levels of TLR7, which may explain why TLR9 dysregulation is particularly consequential early in life, while symptoms of TLR7 dysregulation take longer to manifest. Overall, this study demonstrates that inappropriate TLR9 responses can drive a severe autoinflammatory disease under homeostatic conditions and highlights differences in the diseases resulting from inappropriate activation of TLR9 and TLR7.

    更新日期:2020-01-26
  • Uncertainty in learning, choice, and visual fixation [Psychological and Cognitive Sciences]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Hrvoje Stojić, Jacob L. Orquin, Peter Dayan, Raymond J. Dolan, Maarten Speekenbrink

    Uncertainty plays a critical role in reinforcement learning and decision making. However, exactly how it influences behavior remains unclear. Multiarmed-bandit tasks offer an ideal test bed, since computational tools such as approximate Kalman filters can closely characterize the interplay between trial-by-trial values, uncertainty, learning, and choice. To gain additional insight into learning and choice processes, we obtained data from subjects’ overt allocation of gaze. The estimated value and estimation uncertainty of options influenced what subjects looked at before choosing; these same quantities also influenced choice, as additionally did fixation itself. A momentary measure of uncertainty in the form of absolute prediction errors determined how long participants looked at the obtained outcomes. These findings affirm the importance of uncertainty in multiple facets of behavior and help delineate its effects on decision making.

    更新日期:2020-01-26
  • Theory of the strange metal Sr3Ru2O7 [Physics]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Connie H. Mousatov, Erez Berg, Sean A. Hartnoll

    The bilayer perovskite Sr3Ru2O7 has been widely studied as a canonical strange metal. It exhibits T-linear resistivity and a T log(1/T) electronic specific heat in a field-tuned quantum critical fan. Criticality is known to occur in “hot” Fermi pockets with a high density of states close to the Fermi energy. We show that while these hot pockets occupy a small fraction of the Brillouin zone, they are responsible for the anomalous transport and thermodynamics of the material. Specifically, a scattering process in which two electrons from the large, “cold” Fermi surfaces scatter into one hot and one cold electron renders the ostensibly noncritical cold fermions a marginal Fermi liquid. From this fact the transport and thermodynamic phase diagram is reproduced in detail. Finally, we show that the same scattering mechanism into hot electrons that are instead localized near a 2D van Hove singularity explains the anomalous transport observed in strained Sr2RuO4.

    更新日期:2020-01-26
  • Combinatorial protein-protein interactions on a polymerizing scaffold [Biophysics and Computational Biology]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Andrés Ortiz-Muñoz, Héctor F. Medina-Abarca, Walter Fontana

    Scaffold proteins organize cellular processes by bringing signaling molecules into interaction, sometimes by forming large signalosomes. Several of these scaffolds are known to polymerize. Their assemblies should therefore not be understood as stoichiometric aggregates, but as combinatorial ensembles. We analyze the combinatorial interaction of ligands loaded on polymeric scaffolds, in both a continuum and discrete setting, and compare it with multivalent scaffolds with fixed number of binding sites. The quantity of interest is the abundance of ligand interaction possibilities—the catalytic potential Q—in a configurational mixture. Upon increasing scaffold abundance, scaffolding systems are known to first increase opportunities for ligand interaction and then to shut them down as ligands become isolated on distinct scaffolds. The polymerizing system stands out in that the dependency of Q on protomer concentration switches from being dominated by a first order to a second order term within a range determined by the polymerization affinity. This behavior boosts Q beyond that of any multivalent scaffold system. In addition, the subsequent drop-off is considerably mitigated in that Q decreases with half the power in protomer concentration than for any multivalent scaffold. We explain this behavior in terms of how the concentration profile of the polymer-length distribution adjusts to changes in protomer concentration and affinity. The discrete case turns out to be similar, but the behavior can be exaggerated at small protomer numbers because of a maximal polymer size, analogous to finite-size effects in bond percolation on a lattice.

    更新日期:2020-01-26
  • Selectivity filter modalities and rapid inactivation of the hERG1 channel [Chemistry]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Williams E. Miranda, Kevin R. DeMarco, Jiqing Guo, Henry J. Duff, Igor Vorobyov, Colleen E. Clancy, Sergei Yu. Noskov

    The human ether-á-go-go–related gene (hERG1) channel conducts small outward K+ currents that are critical for cardiomyocyte membrane repolarization. The gain-of-function mutation N629D at the outer mouth of the selectivity filter (SF) disrupts inactivation and K+-selective transport in hERG1, leading to arrhythmogenic phenotypes associated with long-QT syndrome. Here, we combined computational electrophysiology with Markov state model analysis to investigate how SF-level gating modalities control selective cation transport in wild-type (WT) and mutant (N629D) hERG1 variants. Starting from the recently reported cryogenic electron microscopy (cryo-EM) open-state channel structure, multiple microseconds-long molecular-dynamics (MD) trajectories were generated using different cation configurations at the filter, voltages, electrolyte concentrations, and force-field parameters. Most of the K+ permeation events observed in hERG1-WT simulations occurred at microsecond timescales, influenced by the spontaneous dehydration/rehydration dynamics at the filter. The SF region displayed conductive, constricted, occluded, and dilated states, in qualitative agreement with the well-documented flickering conductance of hERG1. In line with mutagenesis studies, these gating modalities resulted from dynamic interaction networks involving residues from the SF, outer-mouth vestibule, P-helices, and S5–P segments. We found that N629D mutation significantly stabilizes the SF in a state that is permeable to both K+ and Na+, which is reminiscent of the SF in the nonselective bacterial NaK channel. Increasing the external K+ concentration induced “WT-like” SF dynamics in N629D, in qualitative agreement with the recovery of flickering currents in experiments. Overall, our findings provide an understanding of the molecular mechanisms controlling selective transport in K+ channels with a nonconventional SF sequence.

    更新日期:2020-01-26
  • Allosteric activation of MALT1 by its ubiquitin-binding Ig3 domain [Immunology and Inflammation]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Rebekka Schairer, Gareth Hall, Ming Zhang, Richard Cowan, Roberta Baravalle, Frederick W. Muskett, Peter J. Coombs, Chido Mpamhanga, Lisa R. Hale, Barbara Saxty, Justyna Iwaszkiewicz, Chantal Décaillet, Mai Perroud, Mark D. Carr, Margot Thome

    The catalytic activity of the protease MALT1 is required for adaptive immune responses and regulatory T (Treg)-cell development, while dysregulated MALT1 activity can lead to lymphoma. MALT1 activation requires its monoubiquitination on lysine 644 (K644) within the Ig3 domain, localized adjacent to the protease domain. The molecular requirements for MALT1 monoubiquitination and the mechanism by which monoubiquitination activates MALT1 had remained elusive. Here, we show that the Ig3 domain interacts directly with ubiquitin and that an intact Ig3-ubiquitin interaction surface is required for the conjugation of ubiquitin to K644. Moreover, by generating constitutively active MALT1 mutants that overcome the need for monoubiquitination, we reveal an allosteric communication between the ubiquitination site K644, the Ig3-protease interaction surface, and the active site of the protease domain. Finally, we show that MALT1 mutants that alter the Ig3-ubiquitin interface impact the biological response of T cells. Thus, ubiquitin binding by the Ig3 domain promotes MALT1 activation by an allosteric mechanism that is essential for its biological function.

    更新日期:2020-01-26
  • Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging [Genetics]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Ying-Chen Claire Hou, Hung-Chun Yu, Rick Martin, Elizabeth T. Cirulli, Natalie M. Schenker-Ahmed, Michael Hicks, Isaac V. Cohen, Thomas J. Jönsson, Robyn Heister, Lori Napier, Christine Leon Swisher, Saints Dominguez, Haibao Tang, Weizhong Li, Bradley A. Perkins, Jaime Barea, Christina Rybak, Emily Smith, Keegan Duchicela, Michael Doney, Pamila Brar, Nathaniel Hernandez, Ewen F. Kirkness, Andrew M. Kahn, J. Craig Venter, David S. Karow, C. Thomas Caskey

    Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.

    更新日期:2020-01-26
  • Reassessing enzyme kinetics: Considering protease-as-substrate interactions in proteolytic networks [Systems Biology]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Meghan C. Ferrall-Fairbanks, Chris A. Kieslich, Manu O. Platt

    Enzymes are catalysts in biochemical reactions that, by definition, increase rates of reactions without being altered or destroyed. However, when that enzyme is a protease, a subclass of enzymes that hydrolyze other proteins, and that protease is in a multiprotease system, protease-as-substrate dynamics must be included, challenging assumptions of enzyme inertness, shifting kinetic predictions of that system. Protease-on-protease inactivating hydrolysis can alter predicted protease concentrations used to determine pharmaceutical dosing strategies. Cysteine cathepsins are proteases capable of cathepsin cannibalism, where one cathepsin hydrolyzes another with substrate present, and misunderstanding of these dynamics may cause miscalculations of multiple proteases working in one proteolytic network of interactions occurring in a defined compartment. Once rates for individual protease-on-protease binding and catalysis are determined, proteolytic network dynamics can be explored using computational models of cooperative/competitive degradation by multiple proteases in one system, while simultaneously incorporating substrate cleavage. During parameter optimization, it was revealed that additional distraction reactions, where inactivated proteases become competitive inhibitors to remaining, active proteases, occurred, introducing another network reaction node. Taken together, improved predictions of substrate degradation in a multiple protease network were achieved after including reaction terms of autodigestion, inactivation, cannibalism, and distraction, altering kinetic considerations from other enzymatic systems, since enzyme can be lost to proteolytic degradation. We compiled and encoded these dynamics into an online platform (https://plattlab.shinyapps.io/catKLS/) for individual users to test hypotheses of specific perturbations to multiple cathepsins, substrates, and inhibitors, and predict shifts in proteolytic network reactions and system dynamics.

    更新日期:2020-01-26
  • Regulation of adipose tissue inflammation by interleukin 6 [Immunology and Inflammation]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Myoung Sook Han, Alexis White, Rachel J. Perry, Joao-Paulo Camporez, Juan Hidalgo, Gerald I. Shulman, Roger J. Davis

    Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear. We tested the role of specific cells using a mouse model with conditional expression of the Il6 gene. We found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. These opposite actions were associated with a switch of IL6 signaling from a canonical mode (myeloid cells) to a noncanonical trans-signaling mode (adipocytes and muscle) with increased expression of the ADAM10/17 metalloprotease that promotes trans-signaling by the soluble IL6 receptor α. Collectively, these data demonstrate that the source of IL6 production plays a major role in the physiological regulation of metabolism.

    更新日期:2020-01-26
  • Conformational changes upon gating of KirBac1.1 into an open-activated state revealed by solid-state NMR and functional assays [Biophysics and Computational Biology]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Reza Amani, Collin G. Borcik, Nazmul H. Khan, Derek B. Versteeg, Maryam Yekefallah, Hoa Q. Do, Heather R. Coats, Benjamin J. Wylie

    The conformational changes required for activation and K+ conduction in inward-rectifier K+ (Kir) channels are still debated. These structural changes are brought about by lipid binding. It is unclear how this process relates to fast gating or if the intracellular and extracellular regions of the protein are coupled. Here, we examine the structural details of KirBac1.1 reconstituted into both POPC and an activating lipid mixture of 3:2 POPC:POPG (wt/wt). KirBac1.1 is a prokaryotic Kir channel that shares homology with human Kir channels. We establish that KirBac1.1 is in a constitutively active state in POPC:POPG bilayers through the use of real-time fluorescence quenching assays and Förster resonance energy transfer (FRET) distance measurements. Multidimensional solid-state NMR (SSNMR) spectroscopy experiments reveal two different conformers within the transmembrane regions of the protein in this activating lipid environment, which are distinct from the conformation of the channel in POPC bilayers. The differences between these three distinct channel states highlight conformational changes associated with an open activation gate and suggest a unique allosteric pathway that ties the selectivity filter to the activation gate through interactions between both transmembrane helices, the turret, selectivity filter loop, and the pore helix. We also identify specific residues involved in this conformational exchange that are highly conserved among human Kir channels.

    更新日期:2020-01-26
  • Fast-freezing kinetics inside a droplet impacting on a cold surface [Applied Physical Sciences]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Pallav Kant, Robin B. J. Koldeweij, Kirsten Harth, Michiel A. J. van Limbeek, Detlef Lohse

    Freezing or solidification of impacting droplets is omnipresent in nature and technology, be it a rain droplet falling on a supercooled surface; in inkjet printing, where often molten wax is used; in additive manufacturing or metal-production processes; or in extreme ultraviolet lithography (EUV) for the chip production, where molten tin is used to generate the EUV radiation. For many of these industrial applications, a detailed understanding of the solidification process is essential. Here, by adopting an optical technique in the context of freezing—namely, total-internal reflection (TIR)—we elucidate the freezing kinetics during the solidification of a droplet while it impacts on an undercooled surface. We show that at sufficiently high undercooling, a peculiar freezing morphology exists that involves sequential advection of frozen fronts from the center of the droplet to its boundaries. This phenomenon is examined by combining elements of classical nucleation theory to the large-scale hydrodynamics on the droplet scale, bringing together two subfields which traditionally have been quite separated. Furthermore, we report a self-peeling phenomenon of a frozen splat that is driven by the existence of a transient crystalline state during solidification.

    更新日期:2020-01-26
  • Selective reduction of CO to acetaldehyde with CuAg electrocatalysts [Engineering]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Lei Wang, Drew C. Higgins, Yongfei Ji, Carlos G. Morales-Guio, Karen Chan, Christopher Hahn, Thomas F. Jaramillo

    Electrochemical CO reduction can serve as a sequential step in the transformation of CO2 into multicarbon fuels and chemicals. In this study, we provide insights on how to steer selectivity for CO reduction almost exclusively toward a single multicarbon oxygenate by carefully controlling the catalyst composition and its surrounding reaction conditions. Under alkaline reaction conditions, we demonstrate that planar CuAg electrodes can reduce CO to acetaldehyde with over 50% Faradaic efficiency and over 90% selectivity on a carbon basis at a modest electrode potential of −0.536 V vs. the reversible hydrogen electrode. The Faradaic efficiency to acetaldehyde was further enhanced to 70% by increasing the roughness factor of the CuAg electrode. Density functional theory calculations indicate that Ag ad-atoms on Cu weaken the binding energy of the reduced acetaldehyde intermediate and inhibit its further reduction to ethanol, demonstrating that the improved selectivity to acetaldehyde is due to the electronic effect from Ag incorporation. These findings will aid in the design of catalysts that are able to guide complex reaction networks and achieve high selectivity for the desired product.

    更新日期:2020-01-26
  • Reciprocity and behavioral heterogeneity govern the stability of social networks [Psychological and Cognitive Sciences]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Roslyn Dakin, T. Brandt Ryder

    The dynamics of social networks can determine the transmission of information, the spread of diseases, and the evolution of behavior. Despite this broad importance, a general framework for predicting social network stability has not been proposed. Here we present longitudinal data on the social dynamics of a cooperative bird species, the wire-tailed manakin, to evaluate the potential causes of temporal network stability. We find that when partners interact less frequently and when social connectedness increases, the network is subsequently less stable. Social connectivity was also negatively associated with the temporal persistence of coalition partnerships on an annual timescale. This negative association between connectivity and stability was surprising, especially given that individual manakins who were more connected also had more stable partnerships. This apparent paradox arises from a within-individual behavioral trade-off between partnership quantity and quality. Crucially, this trade-off is easily masked by behavioral variation among individuals. Using a simulation, we show that these results are explained by a simple model that combines among-individual behavioral heterogeneity and reciprocity within the network. As social networks become more connected, individuals face a trade-off between partnership quantity and maintenance. This model also demonstrates how among-individual behavioral heterogeneity, a ubiquitous feature of natural societies, can improve social stability. Together, these findings provide unifying principles that are expected to govern diverse social systems.

    更新日期:2020-01-26
  • FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis [Medical Sciences]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Kwang Il Lee, Sungwook Choi, Tokio Matsuzaki, Oscar Alvarez-Garcia, Merissa Olmer, Shawn P. Grogan, Darryl D. D’Lima, Martin K. Lotz

    The objective of this study was to examine FoxO expression and FoxO function in meniscus. In menisci from human knee joints with osteoarthritis (OA), FoxO1 and 3 expression were significantly reduced compared with normal menisci from young and old normal donors. The expression of FoxO1 and 3 was also significantly reduced in mouse menisci during aging and OA induced by surgical meniscus destabilization or mechanical overuse. Deletion of FoxO1 and combined FoxO1, 3, and 4 deletions induced abnormal postnatal meniscus development in mice and these mutant mice spontaneously displayed meniscus pathology at 6 mo. Mice with Col2Cre-mediated deletion of FoxO3 or FoxO4 had normal meniscus development but had more severe aging-related damage. In mature AcanCreERT2 mice, the deletion of FoxO1, 3, and 4 aggravated meniscus lesions in all experimental OA models. FoxO deletion suppressed autophagy and antioxidant defense genes and altered several meniscus-specific genes. Expression of these genes was modulated by adenoviral FoxO1 in cultured human meniscus cells. These results suggest that FoxO1 plays a key role in meniscus development and maturation, and both FoxO1 and 3 support homeostasis and protect against meniscus damage in response to mechanical overuse and during aging and OA.

    更新日期:2020-01-26
  • IL-4 controls activated neutrophil Fc{gamma}R2b expression and migration into inflamed ȷoints [Immunology and Inflammation]
    PNAS (IF 9.580) Pub Date : 2020-01-24
    Sudeepta Kumar Panda, Gustaf Wigerblad, Long Jiang, Yanek Jiménez-Andrade, Vaishnavi Srinivasan Iyer, Yunbing Shen, Sanjaykumar V. Boddul, André Ortlieb Guerreiro-Cacais, Bruno Raposo, Zsolt Kasza, Fredrik Wermeling

    Neutrophils are the most abundant immune cells found in actively inflamed joints of patients with rheumatoid arthritis (RA), and most animal models for RA depend on neutrophils for the induction of joint inflammation. Exogenous IL-4 and IL-13 protect mice from antibody-mediated joint inflammation, although the mechanism is not understood. Neutrophils display a very strong basal expression of STAT6, which is responsible for signaling following exposure to IL-4 and IL-13. Still, the role of IL-4 and IL-13 in neutrophil biology has not been well studied. This can be explained by the low neutrophil surface expression of the IL-4 receptor α-chain (IL-4Rα), essential for IL-4– and IL-13–induced STAT6 signaling. Here we identify that colony stimulating factor 3 (CSF3), released during acute inflammation, mediates potent STAT3-dependent neutrophil IL-4Rα up-regulation during sterile inflammatory conditions. We further demonstrate that IL-4 limits neutrophil migration to inflamed joints, and that CSF3 combined with IL-4 or IL-13 results in a prominent neutrophil up-regulation of the inhibitory Fcγ receptor (FcγR2b). Taking these data together, we demonstrate that the IL-4 and CSF3 pathways are linked and play important roles in regulating proinflammatory neutrophil behavior.

    更新日期:2020-01-26
  • Daily briefing: First evidence of how stress turns hair grey
    Nature (IF 43.070) Pub Date : 2020-01-24
    Flora Graham
    更新日期:2020-01-26
  • What you need to know about the Wuhan coronavirus
    Nature (IF 43.070) Pub Date : 2020-01-24
    Dan Fox
    更新日期:2020-01-26
  • 更新日期:2020-01-26
  • Overhaul environmental risk assessment for pesticides
    Science (IF 41.037) Pub Date : 2020-01-24
    C. J. Topping, A. Aldrich, P. Berny

    Among aspects of agricultural intensification that have been criticized for negative impacts on biodiversity (1, 2), pesticides have been linked to declines in insects, birds, and biodiversity in aquatic systems (3–5). If pesticide use is to blame, even partially, then this raises questions both about pesticide use and the regulatory procedures that are used to protect the environment (4). Environmental risk assessment (ERA) of pesticides does not account for many stressors that have intensified in recent years, such as climate change, habitat destruction, and increasing landscape homogeneity, the combination of which can aggravate effects of pesticides in nature. We describe how several assumptions underlying ERA may not hold in modern intensive agricultural landscapes, and the interaction among assumption violations may account for observed declines in biodiversity. Using European contexts to exemplify these global concerns, we review how regulatory ERA for pesticides has fallen out of step with scientific knowledge (4) and societal demands for sustainable food production and suggest systematic and recently feasible changes for regulation.

    更新日期:2020-01-24
  • Can phase separation buffer cellular noise?
    Science (IF 41.037) Pub Date : 2020-01-24
    Joshua A. Riback, Clifford P. Brangwynne

    Scientists have long marveled at the ability of complex patterns to emerge from seemingly chaotic origins. In biology, each cell must circumvent the stochastic nature, or noise, inherent to chemical reactions and molecular diffusion. This noise introduces large fluctuations in messenger RNA (mRNA) and protein concentrations, which might be deleterious to processes such as biosynthesis, macroscale organization, and self-replication. Noise may be decreased through compartmentalization, including liquid-liquid phase separation (LLPS), a process underlying the formation of membraneless compartments (1, 2). On page 464 of this issue, Klosin et al. (3) provide evidence that LLPS can buffer noise in cells and may play a role in stabilizing various biological circuits.

    更新日期:2020-01-24
  • Support cells in the brain promote longevity
    Science (IF 41.037) Pub Date : 2020-01-24
    Jason Wayne Miklas, Anne Brunet

    Aging is a multifaceted process that results in organismal decay. At the cellular level, protein homeostasis is a key system that becomes dysregulated with age, causing the accumulation of aberrant or unfolded proteins. In a youthful individual, unfolded proteins normally trigger the unfolded protein response (UPR), which upregulates the protein clearance machinery and returns cells to a homeostatic state. The UPR is typically induced in a cell-autonomous manner. But some cells communicate protein folding stress to distal cells. For example, neurons communicate activation of the UPR to peripheral tissues to promote longevity in the worm Caenorhabditis elegans (1). On page 436 of this issue, Frakes et al. (2) show that support cells in the brain called glial cells (3) can also initiate long-range activation of the endoplasmic reticulum UPR (UPRER) in distal cells to coordinate stress resistance and longevity in C. elegans and that this occurs through neuropeptide secretion.

    更新日期:2020-01-24
  • Coherent scanning tunneling microscopy
    Science (IF 41.037) Pub Date : 2020-01-24
    Clarice D. Aiello

    The ultimate goal of any nanotechnology is to resolve and control elementary processes in matter. In general, although many spectroscopies can achieve high temporal resolution and many microscopies can achieve high spatial resolution, achieving both is difficult. On page 411 of this issue, Garg and Kern (1) improve the limits of concomitant spatial and temporal resolutions by combining scanning tunneling microscopy (STM) (2) with an ingenious phase-locking train of ultrafast optical pulses. The authors go on to demonstrate that their instrument can deconvolve femtosecond electron dynamics with nanoscale resolution. These feats are only made more interesting because the phase-locking scheme enables an imprint of the laser's (coherent) phase onto the tunneling electrons. This demonstration of “light-wave electronics” at atomic scales is unprecedented.

    更新日期:2020-01-24
  • A notorious Nazi, revealed
    Science (IF 41.037) Pub Date : 2020-01-24
    Patricia Heberer Rice

    Drawing from new sources and scholarship, historian David Marwell has written a compelling work that dispels many of the myths obscuring the identity of the infamous physician, Josef Mengele. Mengele: Unmasking the "Angel of Death" is at once a compact biography of the notorious war criminal, a detailed account of Mengele's flight to South America, and an absorbing narrative of the quest to bring him to justice.

    更新日期:2020-01-24
  • Confronting campus sexual assault
    Science (IF 41.037) Pub Date : 2020-01-24
    Claire M. Renzetti

    Sexual Citizens is one of the products of a 5-year study of undergraduates at Columbia University called the Sexual Health Initiative to Foster Transformation (SHIFT). The goal of SHIFT was to identify the social causes of campus sexual assault in order to develop more effective prevention strategies. This mixed-methods project, involving nearly 30 researchers from multiple disciplines, included a population-based survey, a 60-day daily diary study, 17 focus groups, multihour interviews, and hundreds of hours of ethnographic field observation of students socializing in various settings.

    更新日期:2020-01-24
  • Learning from the past and considering the future of chemicals in the environment
    Science (IF 41.037) Pub Date : 2020-01-24
    Andrew C. Johnson, Xiaowei Jin, Norihide Nakada, John P. Sumpter

    Knowledge of the hazards and associated risks from chemicals discharged to the environment has grown considerably over the past 40 years. This improving awareness stems from advances in our ability to measure chemicals at low environmental concentrations, recognition of a range of effects on organisms, and a worldwide growth in expertise. Environmental scientists and companies have learned from the experiences of the past; in theory, the next generation of chemicals will cause less acute toxicity and be less environmentally persistent and bioaccumulative. However, researchers still struggle to establish whether the nonlethal effects associated with some modern chemicals and substances will have serious consequences for wildlife. Obtaining the resources to address issues associated with chemicals in the environment remains a challenge.

    更新日期:2020-01-24
  • Tracking complex mixtures of chemicals in our changing environment
    Science (IF 41.037) Pub Date : 2020-01-24
    Beate I. Escher, Heather M. Stapleton, Emma L. Schymanski

    Chemicals have improved our quality of life, but the resulting environmental pollution has the potential to cause detrimental effects on humans and the environment. People and biota are chronically exposed to thousands of chemicals from various environmental sources through multiple pathways. Environmental chemists and toxicologists have moved beyond detecting and quantifying single chemicals to characterizing complex mixtures of chemicals in indoor and outdoor environments and biological matrices. We highlight analytical and bioanalytical approaches to isolating, characterizing, and tracking groups of chemicals of concern in complex matrices. Techniques that combine chemical analysis and bioassays have the potential to facilitate the identification of mixtures of chemicals that pose a combined risk.

    更新日期:2020-01-24
  • The exposome and health: Where chemistry meets biology
    Science (IF 41.037) Pub Date : 2020-01-24
    Roel Vermeulen, Emma L. Schymanski, Albert-László Barabási, Gary W. Miller

    Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The “exposome” concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.

    更新日期:2020-01-24
  • Designing for a green chemistry future
    Science (IF 41.037) Pub Date : 2020-01-24
    Julie B. Zimmerman, Paul T. Anastas, Hanno C. Erythropel, Walter Leitner

    The material basis of a sustainable society will depend on chemical products and processes that are designed following principles that make them conducive to life. Important inherent properties of molecules need to be considered from the earliest stage—the design stage—to address whether compounds and processes are depleting versus renewable, toxic versus benign, and persistent versus readily degradable. Products, feedstocks, and manufacturing processes will need to integrate the principles of green chemistry and green engineering under an expanded definition of performance that includes sustainability considerations. This transformation will require the best of the traditions of science and innovation coupled with new emerging systems thinking and systems design that begins at the molecular level and results in a positive impact on the global scale.

    更新日期:2020-01-24
  • Single-cell transcriptional diversity is a hallmark of developmental potential
    Science (IF 41.037) Pub Date : 2020-01-24
    Gunsagar S. Gulati, Shaheen S. Sikandar, Daniel J. Wesche, Anoop Manjunath, Anjan Bharadwaj, Mark J. Berger, Francisco Ilagan, Angera H. Kuo, Robert W. Hsieh, Shang Cai, Maider Zabala, Ferenc A. Scheeren, Neethan A. Lobo, Dalong Qian, Feiqiao B. Yu, Frederick M. Dirbas, Michael F. Clarke, Aaron M. Newman

    Single-cell RNA sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. However, inferring both the state and direction of differentiation is challenging. Here, we demonstrate a simple, yet robust, determinant of developmental potential—the number of expressed genes per cell—and leverage this measure of transcriptional diversity to develop a computational framework (CytoTRACE) for predicting differentiation states from scRNA-seq data. When applied to diverse tissue types and organisms, CytoTRACE outperformed previous methods and nearly 19,000 annotated gene sets for resolving 52 experimentally determined developmental trajectories. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. This study thus establishes a key RNA-based feature of developmental potential and a platform for delineation of cellular hierarchies.

    更新日期:2020-01-24
  • Attosecond coherent manipulation of electrons in tunneling microscopy
    Science (IF 41.037) Pub Date : 2020-01-24
    M. Garg, K. Kern

    Nanoelectronic devices operating in the quantum regime require coherent manipulation and control over electrons at atomic length and time scales. We demonstrate coherent control over electrons in a tunnel junction of a scanning tunneling microscope by means of precise tuning of the carrier-envelope phase of two-cycle long (<6-femtosecond) optical pulses. We explore photon and field-driven tunneling, two different regimes of interaction of optical pulses with the tunnel junction, and demonstrate a transition from one regime to the other. Our results show that it is possible to induce, track, and control electronic current at atomic scales with subfemtosecond resolution, providing a route to develop petahertz coherent nanoelectronics and microscopy.

    更新日期:2020-01-24
  • A type Ia supernova at the heart of superluminous transient SN 2006gy
    Science (IF 41.037) Pub Date : 2020-01-24
    Anders Jerkstrand, Keiichi Maeda, Koji S. Kawabata

    Superluminous supernovae radiate up to 100 times more energy than normal supernovae. The origin of this energy and the nature of the stellar progenitors of these transients are poorly understood. We identify neutral iron lines in the spectrum of one such supernova, SN 2006gy, and show that they require a large mass of iron (≳0.3 solar masses) expanding at 1500 kilometers per second. By modeling a standard type Ia supernova hitting a shell of circumstellar material, we produce a light curve and late-time iron-dominated spectrum that match the observations of SN 2006gy. In such a scenario, common envelope evolution of a progenitor binary system can synchronize envelope ejection and supernova explosion and may explain these bright transients.

    更新日期:2020-01-24
  • Rational construction of a scalable heterostructured nanorod megalibrary
    Science (IF 41.037) Pub Date : 2020-01-24
    Benjamin C. Steimle, Julie L. Fenton, Raymond E. Schaak

    Integrating multiple materials in arbitrary arrangements within nanoparticles is a prerequisite for advancing many applications. Strategies to synthesize heterostructured nanoparticles are emerging, but they are limited in complexity, scope, and scalability. We introduce two design guidelines, based on interfacial reactivity and crystal structure relations, that enable the rational synthesis of a heterostructured nanorod megalibrary. We define synthetically feasible pathways to 65,520 distinct multicomponent metal sulfide nanorods having as many as 6 materials, 8 segments, and 11 internal interfaces by applying up to seven sequential cation-exchange reactions to copper sulfide nanorod precursors. We experimentally observe 113 individual heterostructured nanorods and demonstrate the scalable production of three samples. Previously unimaginable complexity in heterostructured nanorods is now routinely achievable with simple benchtop chemistry and standard laboratory glassware.

    更新日期:2020-01-24
  • Entanglement-based single-shot detection of a single magnon with a superconducting qubit
    Science (IF 41.037) Pub Date : 2020-01-24
    Dany Lachance-Quirion, Samuel Piotr Wolski, Yutaka Tabuchi, Shingo Kono, Koji Usami, Yasunobu Nakamura

    The recent development of hybrid systems based on superconducting circuits provides the possibility of engineering quantum sensors that exploit different degrees of freedom. Quantum magnonics, which aims to control and read out quanta of collective spin excitations in magnetically ordered systems, provides opportunities for advances in both the study of magnetism and the development of quantum technologies. Using a superconducting qubit as a quantum sensor, we report the detection of a single magnon in a millimeter-sized ferrimagnetic crystal with a quantum efficiency of up to 0.71. The detection is based on the entanglement between a magnetostatic mode and the qubit, followed by a single-shot measurement of the qubit state. This proof-of-principle experiment establishes the single-photon detector counterpart for magnonics.

    更新日期:2020-01-24
  • Visualizing H2O molecules reacting at TiO2 active sites with transmission electron microscopy
    Science (IF 41.037) Pub Date : 2020-01-24
    Wentao Yuan, Beien Zhu, Xiao-Yan Li, Thomas W. Hansen, Yang Ou, Ke Fang, Hangsheng Yang, Ze Zhang, Jakob B. Wagner, Yi Gao, Yong Wang

    Imaging a reaction taking place at the molecular level could provide direct information for understanding the catalytic reaction mechanism. We used in situ environmental transmission electron microscopy and a nanocrystalline anatase titanium dioxide (001) surface with (1 × 4) reconstruction as a catalyst, which provided highly ordered four-coordinated titanium “active rows” to realize real-time monitoring of water molecules dissociating and reacting on the catalyst surface. The twin-protrusion configuration of adsorbed water was observed. During the water–gas shift reaction, dynamic changes in these structures were visualized on these active rows at the molecular level.

    更新日期:2020-01-24
  • A two-way molecular dialogue between embryo and endosperm is required for seed development
    Science (IF 41.037) Pub Date : 2020-01-24
    N. M. Doll, S. Royek, S. Fujita, S. Okuda, S. Chamot, A. Stintzi, T. Widiez, M. Hothorn, A. Schaller, N. Geldner, G. Ingram

    The plant embryonic cuticle is a hydrophobic barrier deposited de novo by the embryo during seed development. At germination, it protects the seedling from water loss and is, thus, critical for survival. Embryonic cuticle formation is controlled by a signaling pathway involving the ABNORMAL LEAF SHAPE1 subtilase and the two GASSHO receptor-like kinases. We show that a sulfated peptide, TWISTED SEED1 (TWS1), acts as a GASSHO ligand. Cuticle surveillance depends on the action of the subtilase, which, unlike the TWS1 precursor and the GASSHO receptors, is not produced in the embryo but in the neighboring endosperm. Subtilase-mediated processing of the embryo-derived TWS1 precursor releases the active peptide, triggering GASSHO-dependent cuticle reinforcement in the embryo. Thus, a bidirectional molecular dialogue between embryo and endosperm safeguards cuticle integrity before germination.

    更新日期:2020-01-24
  • Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling in C. elegans
    Science (IF 41.037) Pub Date : 2020-01-24
    Ashley E. Frakes, Melissa G. Metcalf, Sarah U. Tronnes, Raz Bar-Ziv, Jenni Durieux, Holly K. Gildea, Nazineen Kandahari, Samira Monshietehadi, Andrew Dillin

    The ability of the nervous system to sense cellular stress and coordinate protein homeostasis is essential for organismal health. Unfortunately, stress responses that mitigate disturbances in proteostasis, such as the unfolded protein response of the endoplasmic reticulum (UPRER), become defunct with age. In this work, we expressed the constitutively active UPRER transcription factor, XBP-1s, in a subset of astrocyte-like glia, which extended the life span in Caenorhabditis elegans. Glial XBP-1s initiated a robust cell nonautonomous activation of the UPRER in distal cells and rendered animals more resistant to protein aggregation and chronic ER stress. Mutants deficient in neuropeptide processing and secretion suppressed glial cell nonautonomous induction of the UPRER and life-span extension. Thus, astrocyte-like glial cells play a role in regulating organismal ER stress resistance and longevity.

    更新日期:2020-01-24
  • A common hub for sleep and motor control in the substantia nigra
    Science (IF 41.037) Pub Date : 2020-01-24
    Danqian Liu, Weifu Li, Chenyan Ma, Weitong Zheng, Yuanyuan Yao, Chak Foon Tso, Peng Zhong, Xi Chen, Jun Ho Song, Woochul Choi, Se-Bum Paik, Hua Han, Yang Dan

    The arousal state of the brain covaries with the motor state of the animal. How these state changes are coordinated remains unclear. We discovered that sleep–wake brain states and motor behaviors are coregulated by shared neurons in the substantia nigra pars reticulata (SNr). Analysis of mouse home-cage behavior identified four states with different levels of brain arousal and motor activity: locomotion, nonlocomotor movement, quiet wakefulness, and sleep; transitions occurred not randomly but primarily between neighboring states. The glutamic acid decarboxylase 2 but not the parvalbumin subset of SNr γ-aminobutyric acid (GABA)–releasing (GABAergic) neurons was preferentially active in states of low motor activity and arousal. Their activation or inactivation biased the direction of natural behavioral transitions and promoted or suppressed sleep, respectively. These GABAergic neurons integrate wide-ranging inputs and innervate multiple arousal-promoting and motor-control circuits through extensive collateral projections.

    更新日期:2020-01-24
  • An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors
    Science (IF 41.037) Pub Date : 2020-01-24
    Katharina Reinhard, Benjamin Rengstl, Petra Oehm, Kristina Michel, Arne Billmeier, Nina Hayduk, Oliver Klein, Kathrin Kuna, Yasmina Ouchan, Stefan Wöll, Elmar Christ, David Weber, Martin Suchan, Thomas Bukur, Matthias Birtel, Veronika Jahndel, Karolina Mroz, Kathleen Hobohm, Lena Kranz, Mustafa Diken, Klaus Kühlcke, Özlem Türeci, Ugur Sahin

    Chimeric antigen receptor (CAR)–T cells have shown efficacy in patients with B cell malignancies. Yet, their application for solid tumors has challenges that include limited cancer-specific targets and nonpersistence of adoptively transferred CAR-T cells. Here, we introduce the developmentally regulated tight junction protein claudin 6 (CLDN6) as a CAR target in solid tumors and a strategy to overcome inefficient CAR-T cell stimulation in vivo. We demonstrate that a nanoparticulate RNA vaccine, designed for body-wide delivery of the CAR antigen into lymphoid compartments, stimulates adoptively transferred CAR-T cells. Presentation of the natively folded target on resident antigen-presenting cells promotes cognate and selective expansion of CAR-T cells. Improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models was achieved at subtherapeutic CAR-T cell doses.

    更新日期:2020-01-24
  • A tensile ring drives tissue flows to shape the gastrulating amniote embryo
    Science (IF 41.037) Pub Date : 2020-01-24
    Mehdi Saadaoui, Didier Rocancourt, Julian Roussel, Francis Corson, Jerome Gros

    Tissue morphogenesis is driven by local cellular deformations that are powered by contractile actomyosin networks. How localized forces are transmitted across tissues to shape them at a mesoscopic scale is still unclear. Analyzing gastrulation in entire avian embryos, we show that it is driven by the graded contraction of a large-scale supracellular actomyosin ring at the margin between the embryonic and extraembryonic territories. The propagation of these forces is enabled by a fluid-like response of the epithelial embryonic disk, which depends on cell division. A simple model of fluid motion entrained by a tensile ring quantitatively captures the vortex-like “polonaise” movements that accompany the formation of the primitive streak. The geometry of the early embryo thus arises from the transmission of active forces generated along its boundary.

    更新日期:2020-01-24
  • Total synthesis reveals atypical atropisomerism in a small-molecule natural product, tryptorubin A
    Science (IF 41.037) Pub Date : 2020-01-24
    Solomon H. Reisberg, Yang Gao, Allison S. Walker, Eric J. N. Helfrich, Jon Clardy, Phil S. Baran

    Molecular shape defines function in both biological and material settings, and chemists have developed an ever-increasing vernacular to describe these shapes. Noncanonical atropisomers—shape-defined molecules that are formally topologically trivial but are interconvertible only by complex, nonphysical multibond torsions—form a unique subset of atropisomers that differ from both canonical atropisomers (e.g., binaphthyls) and topoisomers (i.e., molecules that have identical connectivity but nonidentical molecular graphs). Small molecules, in contrast to biomacromolecules, are not expected to exhibit such ambiguous shapes. Using total synthesis, we found that the peptidic alkaloid tryptorubin A can be one of two noncanonical atropisomers. We then devised a synthetic strategy that drives the atropospecific synthesis of a noncanonical atrop-defined small molecule.

    更新日期:2020-01-24
  • Phase separation provides a mechanism to reduce noise in cells
    Science (IF 41.037) Pub Date : 2020-01-24
    A. Klosin, F. Oltsch, T. Harmon, A. Honigmann, F. Jülicher, A. A. Hyman, C. Zechner

    Expression of proteins inside cells is noisy, causing variability in protein concentration among identical cells. A central problem in cellular control is how cells cope with this inherent noise. Compartmentalization of proteins through phase separation has been suggested as a potential mechanism to reduce noise, but systematic studies to support this idea have been missing. In this study, we used a physical model that links noise in protein concentration to theory of phase separation to show that liquid droplets can effectively reduce noise. We provide experimental support for noise reduction by phase separation using engineered proteins that form liquid-like compartments in mammalian cells. Thus, phase separation can play an important role in biological signal processing and control.

    更新日期:2020-01-24
  • Chromatin accessibility dynamics in a model of human forebrain development
    Science (IF 41.037) Pub Date : 2020-01-24
    Alexandro E. Trevino, Nasa Sinnott-Armstrong, Jimena Andersen, Se-Jin Yoon, Nina Huber, Jonathan K. Pritchard, Howard Y. Chang, William J. Greenleaf, Sergiu P. Pașca

    Forebrain development is characterized by highly synchronized cellular processes, which, if perturbed, can cause disease. To chart the regulatory activity underlying these events, we generated a map of accessible chromatin in human three-dimensional forebrain organoids. To capture corticogenesis, we sampled glial and neuronal lineages from dorsal or ventral forebrain organoids over 20 months in vitro. Active chromatin regions identified in human primary brain tissue were observed in organoids at different developmental stages. We used this resource to map genetic risk for disease and to explore evolutionary conservation. Moreover, we integrated chromatin accessibility with transcriptomics to identify putative enhancer-gene linkages and transcription factors that regulate human corticogenesis. Overall, this platform brings insights into gene-regulatory dynamics at previously inaccessible stages of human forebrain development, including signatures of neuropsychiatric disorders.

    更新日期:2020-01-24
  • Quantum anomalous Hall effect in intrinsic magnetic topological insulator MnBi2Te4
    Science (IF 41.037) Pub Date : 2020-01-23
    Yujun Deng, Yijun Yu, Meng Zhu Shi, Zhongxun Guo, Zihan Xu, Jing Wang, Xian Hui Chen, Yuanbo Zhang

    In a magnetic topological insulator, nontrivial band topology conspires with magnetic order to produce exotic states of matter such as quantum anomalous Hall (QAH) insulators and axion insulators. Here, we probe quantum transport in MnBi2Te4 thin flake—a topological insulator with intrinsic magnetic order. In this layered van der Waals crystal, the ferromagnetic layers couple anti-parallel to each other; atomically thin MnBi2Te4, however, becomes ferromagnetic when the sample has an odd number of septuple layers. We observe zero-field QAH effect in a five-septuple-layer specimen at 1.4 Kelvin; an external magnetic field further raises the quantization temperature up to 6.5 Kelvin by aligning all layers ferromagnetically. The results establish MnBi2Te4 as an ideal arena for further exploring various topological phenomena with a spontaneously broken time-reversal symmetry.

    更新日期:2020-01-24
  • Polymeric sheet actuators with programmable bioinstructivity [Biophysics and Computational Biology]
    PNAS (IF 9.580) Pub Date : 2020-01-23
    Zijun Deng, Weiwei Wang, Xun Xu, Oliver E. C. Gould, Karl Kratz, Nan Ma, Andreas Lendlein

    Stem cells are capable of sensing and processing environmental inputs, converting this information to output a specific cell lineage through signaling cascades. Despite the combinatorial nature of mechanical, thermal, and biochemical signals, these stimuli have typically been decoupled and applied independently, requiring continuous regulation by controlling units. We employ a programmable polymer actuator sheet to autonomously synchronize thermal and mechanical signals applied to mesenchymal stem cells (MSCs). Using a grid on its underside, the shape change of polymer sheet, as well as cell morphology, calcium (Ca2+) influx, and focal adhesion assembly, could be visualized and quantified. This paper gives compelling evidence that the temperature sensing and mechanosensing of MSCs are interconnected via intracellular Ca2+. Up-regulated Ca2+ levels lead to a remarkable alteration of histone H3K9 acetylation and activation of osteogenic related genes. The interplay of physical, thermal, and biochemical signaling was utilized to accelerate the cell differentiation toward osteogenic lineage. The approach of programmable bioinstructivity provides a fundamental principle for functional biomaterials exhibiting multifaceted stimuli on differentiation programs. Technological impact is expected in the tissue engineering of periosteum for treating bone defects.

    更新日期:2020-01-24
  • SYNPLA, a method to identify synapses displaying plasticity after learning [Neuroscience]
    PNAS (IF 9.580) Pub Date : 2020-01-23
    Kim Dore, Yvonne Pao, Jose Soria Lopez, Sage Aronson, Huiqing Zhan, Sanchari Ghosh, Sabina Merrill, Anthony M. Zador, Roberto Malinow, Justus M. Kebschull

    Which neural circuits undergo synaptic changes when an animal learns? Although it is widely accepted that changes in synaptic strength underlie many forms of learning and memory, it remains challenging to connect changes in synaptic strength at specific neural pathways to specific behaviors and memories. Here we introduce SYNPLA (synaptic proximity ligation assay), a synapse-specific, high-throughput, and potentially brain-wide method capable of detecting circuit-specific learning-induced synaptic plasticity.

    更新日期:2020-01-24
  • Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression [Systems Biology]
    PNAS (IF 9.580) Pub Date : 2020-01-23
    Katarzyna A. Dudek, Laurence Dion-Albert, Manon Lebel, Katherine LeClair, Simon Labrecque, Ellen Tuck, Carmen Ferrer Perez, Sam A. Golden, Carol Tamminga, Gustavo Turecki, Naguib Mechawar, Scott J. Russo, Caroline Menard

    Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

    更新日期:2020-01-24
  • Structural analysis of the intrinsically disordered splicing factor Spp2 and its binding to the DEAH-box ATPase Prp2 [Biophysics and Computational Biology]
    PNAS (IF 9.580) Pub Date : 2020-01-23
    Florian Hamann, Andreas Schmitt, Filippo Favretto, Romina Hofele, Piotr Neumann, ShengQi Xiang, Henning Urlaub, Markus Zweckstetter, Ralf Ficner

    The spliceosome consists of five small RNAs and more than 100 proteins. Almost 50% of the human spliceosomal proteins were predicted to be intrinsically disordered or to contain disordered regions, among them the G-patch protein Spp2. The G-patch region of Spp2 binds to the DEAH-box ATPase Prp2, and both proteins together are essential for promoting the transition from the Bact to the catalytically active B* spliceosome. Here we show by circular dichroism and nuclear magnetic resonance (NMR) spectroscopy that Spp2 is intrinsically disordered in solution. Crystal structures of a complex consisting of Prp2-ADP and the G-patch domain of Spp2 demonstrate that the G-patch gains a defined fold when bound to Prp2. While the N-terminal region of the G-patch always folds into an α-helix in five different crystal structures, the C-terminal part is able to adopt two alternative conformations. NMR studies further revealed that the N-terminal part of the Spp2 G-patch, which is the most conserved region in different G-patch proteins, transiently samples helical conformations, possibly facilitating a conformational selection binding mechanism. The structural analysis unveils the role of conserved residues of the G-patch in the dynamic interaction mode of Spp2 with Prp2, which is vital to maintain the binding during the Prp2 domain movements needed for RNA translocation.

    更新日期:2020-01-24
  • Genome-scale transcriptional dynamics and environmental biosensing [Systems Biology]
    PNAS (IF 9.580) Pub Date : 2020-01-23
    Garrett Graham, Nicholas Csicsery, Elizabeth Stasiowski, Gregoire Thouvenin, William H. Mather, Michael Ferry, Scott Cookson, Jeff Hasty

    Genome-scale technologies have enabled mapping of the complex molecular networks that govern cellular behavior. An emerging theme in the analyses of these networks is that cells use many layers of regulatory feedback to constantly assess and precisely react to their environment. The importance of complex feedback in controlling the real-time response to external stimuli has led to a need for the next generation of cell-based technologies that enable both the collection and analysis of high-throughput temporal data. Toward this end, we have developed a microfluidic platform capable of monitoring temporal gene expression from over 2,000 promoters. By coupling the “Dynomics” platform with deep neural network (DNN) and associated explainable artificial intelligence (XAI) algorithms, we show how machine learning can be harnessed to assess patterns in transcriptional data on a genome scale and identify which genes contribute to these patterns. Furthermore, we demonstrate the utility of the Dynomics platform as a field-deployable real-time biosensor through prediction of the presence of heavy metals in urban water and mine spill samples, based on the the dynamic transcription profiles of 1,807 unique Escherichia coli promoters.

    更新日期:2020-01-24
  • ARABIDOPSIS DEHISCENCE ZONE POLYGALACTURONASE 1 (ADPG1) releases latent defense signals in stems with reduced lignin content [Plant Biology]
    PNAS (IF 9.580) Pub Date : 2020-01-23
    Lina Gallego-Giraldo, Chang Liu, Sara Pose-Albacete, Sivakumar Pattathil, Angelo Gabriel Peralta, Jenna Young, Jan Westpheling, Michael G. Hahn, Xiaolan Rao, J. Paul Knox, Barbara De Meester, Wout Boerjan, Richard A. Dixon

    There is considerable interest in engineering plant cell wall components, particularly lignin, to improve forage quality and biomass properties for processing to fuels and bioproducts. However, modifying lignin content and/or composition in transgenic plants through down-regulation of lignin biosynthetic enzymes can induce expression of defense response genes in the absence of biotic or abiotic stress. Arabidopsis thaliana lines with altered lignin through down-regulation of hydroxycinnamoyl CoA:shikimate/quinate hydroxycinnamoyl transferase (HCT) or loss of function of cinnamoyl CoA reductase 1 (CCR1) express a suite of pathogenesis-related (PR) protein genes. The plants also exhibit extensive cell wall remodeling associated with induction of multiple cell wall-degrading enzymes, a process which renders the corresponding biomass a substrate for growth of the cellulolytic thermophile Caldicellulosiruptor bescii lacking a functional pectinase gene cluster. The cell wall remodeling also results in the release of size- and charge-heterogeneous pectic oligosaccharide elicitors of PR gene expression. Genetic analysis shows that both in planta PR gene expression and release of elicitors are the result of ectopic expression in xylem of the gene ARABIDOPSIS DEHISCENCE ZONE POLYGALACTURONASE 1 (ADPG1), which is normally expressed during anther and silique dehiscence. These data highlight the importance of pectin in cell wall integrity and the value of lignin modification as a tool to interrogate the informational content of plant cell walls.

    更新日期:2020-01-24
  • Release of a disordered domain enhances HspB1 chaperone activity toward tau [Biochemistry]
    PNAS (IF 9.580) Pub Date : 2020-01-23
    Hannah E. R. Baughman, Thanh-Hau T. Pham, Chloe S. Adams, Abhinav Nath, Rachel E. Klevit

    Small heat shock proteins (sHSPs) are a class of ATP-independent molecular chaperones that play vital roles in maintaining protein solubility and preventing aberrant protein aggregation. They form highly dynamic, polydisperse oligomeric ensembles and contain long intrinsically disordered regions. Experimental challenges posed by these properties have greatly impeded our understanding of sHSP structure and mechanism of action. Here we characterize interactions between the human sHSP HspB1 (Hsp27) and microtubule-associated protein tau, which is implicated in multiple dementias, including Alzheimer’s disease. We show that tau binds both to a well-known binding groove within the structured alpha-crystallin domain (ACD) and to sites within the enigmatic, disordered N-terminal region (NTR) of HspB1. However, only interactions involving the NTR lead to productive chaperone activity, whereas ACD binding is uncorrelated with chaperone function. The tau-binding groove in the ACD also binds short hydrophobic regions within HspB1 itself, and HspB1 mutations that disrupt these intrinsic ACD–NTR interactions greatly enhance chaperone activity toward tau. This leads to a mechanism in which the release of the disordered NTR from a binding groove on the ACD enhances chaperone activity toward tau. The study advances understanding of the mechanisms by which sHSPs achieve their chaperone activity against amyloid-forming clients and how cells defend against pathological tau aggregation. Furthermore, the resulting mechanistic model points to ways in which sHSP chaperone activity may be increased, either by native factors within the cell or by therapeutic intervention.

    更新日期:2020-01-24
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