显示样式:     当前期刊: PNAS    加入关注       排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • How to explain the AKT phosphorylation of downstream targets in the wake of recent findings [Letters (Online Only)]
    PNAS (IF 9.661) Pub Date : 2018-06-15
    Anil K. Agarwal

    AKT (v-Akt oncogene), a Ser/Thr protein kinase, was also identified as protein kinase B (PKB) (reviewed in ref. 1). There are three known isoforms of AKT1-3. All these AKT isoforms are highly conserved and are recruited to the plasma membrane where they bind to PIP3,4,5 via the PH-domain and are phosphorylated. While Lučić et al. (2) studied AKT1, the study is applicable to all of the AKT isoforms. Among the three AKT isoforms, AKT2 is extensively studied due to its critical role in insulin signaling (3). AKT is a central hub for cellular signal transduction, relaying information …

    更新日期:2018-06-16
  • Reply to Agarwal: Activity against nuclear substrates is not necessarily mediated by nuclear Akt [Letters (Online Only)]
    PNAS (IF 9.661) Pub Date : 2018-06-15
    Thomas A. Leonard

    The phosphorylation of Akt substrates in subcellular compartments other than the plasma membrane has previously been proposed to be mediated by the diffusion of activated Akt (1, 2). While this neatly accounts for the observation that Akt is activated by growth factors primarily at the plasma membrane, it poses problems for the cell in controlling the spatial and temporal dynamics of Akt substrate phosphorylation, since Akt would essentially be uncoupled from its activating stimulus. We recently showed that Akt activity is in fact confined to membranes enriched in either PI(3,4,5)P3 or PI(3,4)P2 (3, 4). By restricting Akt activity to the engagement …

    更新日期:2018-06-16
  • History by the numbers? [Letters (Online Only)]
    PNAS (IF 9.661) Pub Date : 2018-06-14
    Nick Tosh, John Ferguson, Cathal Seoighe

    Turchin et al.’s (1) “Global History Databank” is an exciting project. However, we are not convinced that their principal component analysis (PCA) succeeds in discriminating between competing historical hypotheses. We also have concerns about their missing data imputation strategy.

    更新日期:2018-06-15
  • Reply to Tosh et al.: Quantitative analyses of cultural evolution require engagement with historical and archaeological research [Letters (Online Only)]
    PNAS (IF 9.661) Pub Date : 2018-06-14
    Thomas E. Currie, Peter Turchin, Harvey Whitehouse, Pieter François, Kevin Feeney, Daniel Mullins, Daniel Hoyer, Christina Collins, Stephanie Grohmann, Patrick Savage, Gavin Mendel-Gleason, Edward Turner, Agathe Dupeyron, Enrico Cioni, Jenny Reddish, Jill Levine, Greine Jordan, Eva Brandl, Alice Williams, Rudolf Cesaretti, Marta Krueger, Alessandro Ceccarelli, Joe Figliulo-Rosswurm, Po-Ju Tuan, Peter Peregrine, Arkadiusz Marciniak, Johannes Preiser-Kapeller, Nikolay Kradin, Andrey Korotayev, Alessio Palmisano, David Baker, Julye Bidmead, Peter Bol, David Christian, Connie Cook, Alan Covey, Gary Feinman, Árni Daníel Júlíusson, Axel Kristinsson, John Miksic, Ruth Mostern, Cameron Petrie, Peter Rudiak-Gould, Barend ter Haar, Vesna Wallace, Victor Mair, Liye Xie, John Baines, Elizabeth Bridges, Joseph Manning, Bruce Lockhart, Amy Bogaard, Charles Spencer

    We thank Tosh et al. (1) for their interest in our research (2) but note that their analyses do not undermine the main findings of our article. Their suggestion that polity population divided by polity area should be one of the social complexity dimensions raises a number of issues. What does this ratio mean at large spatial scales, where populations are concentrated in large urban centers and much of the territory is not heavily populated? How are societies distributed across this variable and why? For example, a small-scale “simple” society could have a very high population density if it has access to a rich resource base. Tosh et al. (1) do not provide sufficient information or context to meaningfully …

    更新日期:2018-06-15
  • Payments for environmental services supported social capital while increasing land management [Sustainability Science]
    PNAS (IF 9.661) Pub Date : 2018-06-14
    Jennifer M. Alix-Garcia, Katharine R. E. Sims, Victor H. Orozco-Olvera, Laura E. Costica, Jorge David Fernández Medina, Sofía Romo Monroy

    Payments for environmental services (PES) programs incentivize landowners to protect or improve natural resources. Many conservationists fear that introducing compensation for actions previously offered voluntarily will reduce social capital (the institutions, relationships, attitudes, and values that govern human interactions), yet little rigorous research has investigated this concern. We examined the land cover management and communal social capital impacts of Mexico’s federal conservation payments program, which is a key example for other countries committed to reducing deforestation, protecting watersheds, and conserving biodiversity. We used a regression discontinuity (RD) methodology to identify causal program effects, comparing outcomes for PES participants and similar rejected applicants close to scoring cutoffs. We found that payments increased land cover management activities, such as patrolling for illegal activity, building fire breaks, controlling pests, or promoting soil conservation, by ∼50%. Importantly, increases in paid activities as a result of PES did not crowd out unpaid contributions to land management or other prosocial work. Community social capital increased by ∼8–9%, and household-level measures of trust were not affected by the program. These findings demonstrate that major environmental conditional cash transfer programs can support both land management and the attitudes and institutions underpinning prosocial behavior. Rigorous empirical research on this question can proceed only country by country because of methodological limitations, but will be an important line of inquiry as PES continues to expand worldwide.

    更新日期:2018-06-15
  • Distribution and functional analysis of the phosphopantetheinyl transferase superfamily in Actinomycetales microorganisms [Microbiology]
    PNAS (IF 9.661) Pub Date : 2018-06-14
    Jeong Ho Kim, Mamoru Komatsu, Kazuo Shin-ya, Satoshi Omura, Haruo Ikeda

    Phosphopantetheinyl transferases (PPTases) are a superfamily of essential enzymes required for the synthetic processes of many compounds including fatty acid, polyketide, and nonribosomal peptide metabolites. These enzymes activate carrier proteins in specific biosynthetic pathways via the transfer of a phosphopantetheinyl moiety to a serine residue in the conserved motif of carrier proteins. Since many Actinomycetales microorganisms produce a number of polyketide and nonribosomal peptide metabolites, the distribution of PPTase genes was investigated in these microorganisms. PPTases were found in bacterial protein databases using a hidden Markov model search with the PF01648 (4′-phosphopantetheinyl transferase superfamily) model. Actinomycetales microorganisms harbor several genes encoding AcpS-type and Sfp-type PPTases in individual genomes, many of which were associated with the biosynthetic gene cluster for polyketide or nonribosomal peptide metabolites. The properties of these PPTases were evaluated in the heterologous expression system using the biosynthetic gene clusters and genes encoding PPTases found in the present study. Sfp-type PPTases were classified into two subgroups, and although the substrate specificities of the enzymes in one subgroup were wide, the catalytic activities of enzymes in the other subgroup were low. SAV_1784 of Streptomyces avermitilis possessed the most characteristic broad-range activity against several type I polyketide synthases and nonribosomal peptide synthetases.

    更新日期:2018-06-15
  • The social code of speech prosody must be specific and generalizable [Letters (Online Only)]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Sarah Knight, Nadine Lavan, Elise Kanber, Carolyn McGettigan

    Ponsot et al. (1) used speech transformation algorithms and reverse-correlation techniques to derive pitch contours for the word “bonjour,” constituting prosodic prototypes for trustworthy and dominant speech. The use of reverse correlation is a powerful method that allows the properties of complex expressions to be inferred from listeners’ perceptual responses to randomly varying stimuli. It is an exciting development that this elegant, data-driven approach has now been applied to social traits in voices.

    更新日期:2018-06-14
  • Reply to Knight et al.: The complexity of inferences from speech prosody should be addressed using data-driven approaches [Letters (Online Only)]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Emmanuel Ponsot, Juan José Burred, Pascal Belin, Jean-Julien Aucouturier

    We are glad our proposed methodological approach (1) raises interest in the community. Knight et al. (2) make two important theoretical considerations that we would like to further develop here. The first point they raise concerns the specificity of the pitch prototype of dominance/trustworthiness: They argue one should demonstrate that these prototypes are specific (i.e., not shared by other emotional or linguistic traits). Dominance and trustworthiness, while difficult to explicitly define, are not vague concepts: As is the case for social faces in vision (3), they constitute the two principal dimensions of the social space experimentally derived for speech with two-syllable utterances (4). These traits are therefore robust …

    更新日期:2018-06-14
  • No evidence that extinction risk increases in the largest and smallest vertebrates [Letters (Online Only)]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Daniel Pincheira-Donoso, Dave J. Hodgson

    Extinction risk is widespread across the tree of life (1, 2). Therefore, a key goal of conservation biology is to identify predictors of species endangerment. The prevailing consensus that larger species are more likely to be threatened (3) was recently overturned by Ripple et al. (4), who demonstrate instead a U-shaped relationship between endangerment and body size among the world’s vertebrates—a conclusion with significant implications (5). However, we identify four problems with their conclusions. First, increases in endangerment of smaller vertebrates are heavily biased by a single class (Amphibia), which harbors the smallest tetrapods (6). Second, a U-shaped pattern found among amphibians themselves resulted from a biased subsample of this class. Third, these biases are exaggerated by improper phylogenetic analyses. Fourth, consideration of species’ geographic range sizes (GRS) alters the relationship between endangerment …

    更新日期:2018-06-14
  • Reply to Pincheira-Donoso and Hodgson: Both the largest and smallest vertebrates have elevated extinction risk [Letters (Online Only)]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    William J. Ripple, Christopher Wolf, Thomas M. Newsome, Michael Hoffmann, Aaron J. Wirsing, Douglas J. McCauley

    Pincheira-Donoso and Hodgson (1) discuss vertebrate endangerment patterns in their response to our recent article (2). They reassessed our conclusion of a bimodal body size distribution of endangerment for all vertebrates but did so using only data on body mass for amphibians. In our study, we collectively analyzed patterns of endangerment across six classes of vertebrates. Contrasting patterns specific to amphibians with results that pertain to all vertebrates fails to compare like to like and as such is perhaps an exercise of unclear value. Pincheira-Donoso and Hodgson (1) suggest that our vertebrate model is inadequate because “increases in endangerment of smaller vertebrates are heavily biased by a single class (Amphibia) . . . ” We investigated this potential bias by refitting our vertebrate model without amphibians …

    更新日期:2018-06-14
  • Squeezing and stick-slip friction behaviors of lubricants in boundary lubrication [Applied Physical Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Rong-Guang Xu, Yongsheng Leng

    The fundamental questions of how lubricant molecules organize into a layered structure under nanometers confinement and what is the interplay between layering and friction are still not well answered in the field of nanotribology. While the phase transition of lubricants during a squeeze-out process under compression is a long-standing controversial debate (i.e., liquid-like to solid-like phase transition versus amorphous glass-like transition), recent different interpretations to the stick–slip friction of lubricants in boundary lubrication present new challenges in this field. We carry out molecular dynamics simulations of a model lubricant film (cyclohexane) confined between molecularly smooth surfaces (mica)––a prototypical model system studied in surface force apparatus or surface force balance experiments. Through fully atomistic simulations, we find that repulsive force between two solid surfaces starts at about seven lubricant layers (n = 7) and the lubricant film undergoes a sudden liquid-like to solid-like phase transition at n < 6 monolayers thickness. Shear of solidified lubricant films at three- or four-monolayer thickness results in stick–slip friction. The sliding friction simulation shows that instead of shear melting of the film during the slip of the surface, boundary slips at solid–lubricant interfaces happen, while the solidified structure of the lubricant film is well maintained during repeated stick–slip friction cycles. Moreover, no dilation of the lubricant film during the slip is observed, which is surprisingly consistent with recent surface force balance experimental measurements.

    更新日期:2018-06-14
  • Combinatorial drug discovery in nanoliter droplets [Engineering]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Anthony Kulesa, Jared Kehe, Juan E. Hurtado, Prianca Tawde, Paul C. Blainey

    Combinatorial drug treatment strategies perturb biological networks synergistically to achieve therapeutic effects and represent major opportunities to develop advanced treatments across a variety of human disease areas. However, the discovery of new combinatorial treatments is challenged by the sheer scale of combinatorial chemical space. Here, we report a high-throughput system for nanoliter-scale phenotypic screening that formulates a chemical library in nanoliter droplet emulsions and automates the construction of chemical combinations en masse using parallel droplet processing. We applied this system to predict synergy between more than 4,000 investigational and approved drugs and a panel of 10 antibiotics against Escherichia coli, a model gram-negative pathogen. We found a range of drugs not previously indicated for infectious disease that synergize with antibiotics. Our validated hits include drugs that synergize with the antibiotics vancomycin, erythromycin, and novobiocin, which are used against gram-positive bacteria but are not effective by themselves to resolve gram-negative infections.

    更新日期:2018-06-14
  • Auxin methylation is required for differential growth in Arabidopsis [Plant Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Mohamad Abbas, Jorge Hernández-García, Stephan Pollmann, Sophia L. Samodelov, Martina Kolb, Jiří Friml, Ulrich Z. Hammes, Matias D. Zurbriggen, Miguel A. Blázquez, David Alabadí

    Asymmetric auxin distribution is instrumental for the differential growth that causes organ bending on tropic stimuli and curvatures during plant development. Local differences in auxin concentrations are achieved mainly by polarized cellular distribution of PIN auxin transporters, but whether other mechanisms involving auxin homeostasis are also relevant for the formation of auxin gradients is not clear. Here we show that auxin methylation is required for asymmetric auxin distribution across the hypocotyl, particularly during its response to gravity. We found that loss-of-function mutants in Arabidopsis IAA CARBOXYL METHYLTRANSFERASE1 (IAMT1) prematurely unfold the apical hook, and that their hypocotyls are impaired in gravitropic reorientation. This defect is linked to an auxin-dependent increase in PIN gene expression, leading to an increased polar auxin transport and lack of asymmetric distribution of PIN3 in the iamt1 mutant. Gravitropic reorientation in the iamt1 mutant could be restored with either endodermis-specific expression of IAMT1 or partial inhibition of polar auxin transport, which also results in normal PIN gene expression levels. We propose that IAA methylation is necessary in gravity-sensing cells to restrict polar auxin transport within the range of auxin levels that allow for differential responses.

    更新日期:2018-06-14
  • Conformational control and DNA-binding mechanism of the metazoan origin recognition complex [Biochemistry]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Franziska Bleichert, Alexander Leitner, Ruedi Aebersold, Michael R. Botchan, James M. Berger

    In eukaryotes, the heterohexameric origin recognition complex (ORC) coordinates replication onset by facilitating the recruitment and loading of the minichromosome maintenance 2–7 (Mcm2–7) replicative helicase onto DNA to license origins. Drosophila ORC can adopt an autoinhibited configuration that is predicted to prevent Mcm2–7 loading; how the complex is activated and whether other ORC homologs can assume this state are not known. Using chemical cross-linking and mass spectrometry, biochemical assays, and electron microscopy (EM), we show that the autoinhibited state of Drosophila ORC is populated in solution, and that human ORC can also adopt this form. ATP binding to ORC supports a transition from the autoinhibited state to an active configuration, enabling the nucleotide-dependent association of ORC with both DNA and Cdc6. An unstructured N-terminal region adjacent to the conserved ATPase domain of Orc1 is shown to be required for high-affinity ORC–DNA interactions, but not for activation. ORC optimally binds DNA duplexes longer than the predicted footprint of the ORC ATPases associated with a variety of cellular activities (AAA+) and winged-helix (WH) folds; cryo-EM analysis of Drosophila ORC bound to DNA and Cdc6 indicates that ORC contacts DNA outside of its central core region, bending the DNA away from its central DNA-binding channel. Our findings indicate that ORC autoinhibition may be common to metazoans and that ORC–Cdc6 remodels origin DNA before Mcm2–7 recruitment and loading.

    更新日期:2018-06-14
  • Diffusiophoresis of charged colloidal particles in the limit of very high salinity [Engineering]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Dennis C. Prieve, Stephanie M. Malone, Aditya S. Khair, Robert F. Stout, Mazen Y. Kanj

    Diffusiophoresis is the migration of a colloidal particle through a viscous fluid, caused by a gradient in concentration of some molecular solute; a long-range physical interaction between the particle and solute molecules is required. In the case of a charged particle and an ionic solute (e.g., table salt, NaCl), previous studies have predicted and experimentally verified the speed for very low salt concentrations at which the salt solution behaves ideally. The current study presents a study of diffusiophoresis at much higher salt concentrations (approaching the solubility limit). At such large salt concentrations, electrostatic interactions are almost completely screened, thus eliminating the long-range interaction required for diffusiophoresis; moreover, the high volume fraction occupied by ions makes the solution highly nonideal. Diffusiophoretic speeds were found to be measurable, albeit much smaller than for the same gradient at low salt concentrations.

    更新日期:2018-06-14
  • How to better focus waves by considering symmetry and information loss [Applied Physical Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Kai Lou, Steve Granick, François Amblard

    We amend the general belief that waves with extended spherical wavefront focus at their center of curvature. Instead, when the spherical symmetry of waves is broken by propagating them through a finite aperture along an average direction, the forward/backward symmetry is broken and the focal volume shifts its center backward along that direction. The extent of this focal shift increases as smaller apertures are used, up to the point that the nominal focal plane is out of focus. Furthermore, the loss of axial symmetry with noncircular apertures causes distinct focal shifts in distinct axial planes, and the resulting astigmatism possibly degrades the axial focusing resolution. Using experiments and simulations, focal shift with noncircular apertures is described for classical and temporal focusing. The usefulness of these conclusions to improve imaging resolution is demonstrated in a high-resolution optical microscopy application, namely line-temporal focusing microscopy. These conclusions follow from fundamental symmetries of the wave geometry and matter for an increasing number of emerging optical techniques. This work offers a general framework and strategy to understand and improve virtually any wave-based application whose efficacy depends on optimal focusing and may be helpful when information is transmitted by waves in applications from electromagnetic communications, to biological and astronomical imaging, to lithography and even warfare.

    更新日期:2018-06-14
  • A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase [Medical Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-13
    Kristian K. Kristensen, Søren Roi Midtgaard, Simon Mysling, Oleg Kovrov, Lars Bo Hansen, Nicholas Skar-Gislinge, Anne P. Beigneux, Birthe B. Kragelund, Gunilla Olivecrona, Stephen G. Young, Thomas J. D. Jørgensen, Loren G. Fong, Michael Ploug

    The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein lipase (LPL) and GPIHBP1, a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen. In the absence of GPIHBP1, LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia). The N-terminal domain of GPIHBP1, an intrinsically disordered region (IDR) rich in acidic residues, is important for stabilizing LPL’s catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding. Here, we define several important properties of GPIHBP1’s IDR. First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1–LPL interactions and the ability of GPIHBP1 to protect LPL against ANGPTL4-catalyzed unfolding. Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1–LPL encounter via electrostatic steering, increasing the association rate constant (kon) for LPL binding by >250-fold. Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1. In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1. Fourth, we found that GPIHBP1’s IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome. Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1’s ability to preserve LPL structure and activity.

    更新日期:2018-06-14
  • Correction for Zhu et al., CSI1, PATROL1, and exocyst complex cooperate in delivery of cellulose synthase complexes to the plasma membrane [Correction]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    National Academy of Sciences

    PLANT BIOLOGY Correction for “CSI1, PATROL1, and exocyst complex cooperate in delivery of cellulose synthase complexes to the plasma membrane,” by Xiaoyu Zhu, Shundai Li, …

    更新日期:2018-06-13
  • Correction for Spence et al., Revealing the specificity of regulatory T cells in murine autoimmune diabetes [Correction]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    National Academy of Sciences

    IMMUNOLOGY AND INFLAMMATION Correction for “Revealing the specificity of regulatory T cells in murine autoimmune diabetes,” by Allyson Spence, Whitney Purtha, Janice Tam, Shen Dong, Youmin Kim, Chia-Hsin Ju, Teague Sterling, Maki Nakayama, William H. Robinson, Jeffrey A. Bluestone, Mark S. Anderson, and Qizhi Tang, which was first published April 30, 2018; 10.1073/pnas.1715590115 (Proc Natl Acad …

    更新日期:2018-06-13
  • Limiting global-mean temperature increase to 1.5-2 {degrees}C could reduce the incidence and spatial spread of dengue fever in Latin America [Sustainability Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Felipe J. Colón-González, Ian Harris, Timothy J. Osborn, Christine Steiner São Bernardo, Carlos A. Peres, Paul R. Hunter, Iain R. Lake

    The Paris Climate Agreement aims to hold global-mean temperature well below 2 °C and to pursue efforts to limit it to 1.5 °C above preindustrial levels. While it is recognized that there are benefits for human health in limiting global warming to 1.5 °C, the magnitude with which those societal benefits will be accrued remains unquantified. Crucial to public health preparedness and response is the understanding and quantification of such impacts at different levels of warming. Using dengue in Latin America as a study case, a climate-driven dengue generalized additive mixed model was developed to predict global warming impacts using five different global circulation models, all scaled to represent multiple global-mean temperature assumptions. We show that policies to limit global warming to 2 °C could reduce dengue cases by about 2.8 (0.8–7.4) million cases per year by the end of the century compared with a no-policy scenario that warms by 3.7 °C. Limiting warming further to 1.5 °C produces an additional drop in cases of about 0.5 (0.2–1.1) million per year. Furthermore, we found that by limiting global warming we can limit the expansion of the disease toward areas where incidence is currently low. We anticipate our study to be a starting point for more comprehensive studies incorporating socioeconomic scenarios and how they may further impact dengue incidence. Our results demonstrate that although future climate change may amplify dengue transmission in the region, impacts may be avoided by constraining the level of warming.

    更新日期:2018-06-13
  • Patterns of everyday activities across social contexts [Social Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Giacomo Vagni, Benjamin Cornwell

    Social-scientific theory and research give rise to conflicting expectations regarding the extent to which individuals’ everyday lives in modern society follow predictable patterns of behavior. Much previous research has addressed this issue implicitly by documenting widespread trends in patterns of “time use” or “time allocation,” including trends in time devoted to paid work, unpaid work, and leisure. This study expands on this research by examining common patterns with respect to not how much time individuals spend on certain everyday activities (e.g., leisure), but rather how those activities are sequenced throughout the day. Using sequence methods and cluster analysis, we analyze a large collection of harmonized time diaries from the Multinational Time Use Study (MTUS), including diaries from 23 countries and dating back to 1961. Our analysis of these diaries reveals eight common everyday sequence patterns—including different paid work, unpaid work, and leisure clusters. This same set of patterns reappears in a generally similar distribution across the different countries and time periods that are included in the MTUS sequence data. This study has implications for how analysts study time diary data and raises important questions about the causes and consequences of individuals’ experiences with particular behavioral sequences.

    更新日期:2018-06-13
  • Implications of Zika virus and congenital Zika syndrome for the number of live births in Brazil [Social Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Marcia C. Castro, Qiuyi C. Han, Lucas R. Carvalho, Cesar G. Victora, Giovanny V. A. França

    An increase in microcephaly, associated with an epidemic of Zika virus (ZIKV) in Brazil, prompted the World Health Organization to declare a Public Health Emergency of International Concern in February 2016. While knowledge on biological and epidemiological aspects of ZIKV has advanced, demographic impacts remain poorly understood. This study uses time-series analysis to assess the impact of ZIKV on births. Data on births, fetal deaths, and hospitalizations due to abortion complications for Brazilian states, from 2010 to 2016, were used. Forecasts for September 2015 to December 2016 showed that 119,095 fewer births than expected were observed, particularly after April 2016 (a reduction significant at 0.05), demonstrating a link between publicity associated with the ZIKV epidemic and the decline in births. No significant changes were observed in fetal death rates. Although no significant increases in hospitalizations were forecasted, after the ZIKV outbreak hospitalizations happened earlier in the gestational period in most states. We argue that postponement of pregnancy and an increase in abortions may have contributed to the decline in births. Also, it is likely that an increase in safe abortions happened, albeit selective by socioeconomic status. Thus, the ZIKV epidemic resulted in a generation of congenital Zika syndrome (CZS) babies that reflect and exacerbate regional and social inequalities. Since ZIKV transmission has declined, it is unlikely that reductions in births will continue. However, the possibility of a new epidemic is real. There is a need to address gaps in reproductive health and rights, and to understand CZS risk to better inform conception decisions.

    更新日期:2018-06-13
  • Face recognition accuracy of forensic examiners, superrecognizers, and face recognition algorithms [Psychological and Cognitive Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    P. Jonathon Phillips, Amy N. Yates, Ying Hu, Carina A. Hahn, Eilidh Noyes, Kelsey Jackson, Jacqueline G. Cavazos, Géraldine Jeckeln, Rajeev Ranjan, Swami Sankaranarayanan, Jun-Cheng Chen, Carlos D. Castillo, Rama Chellappa, David White, Alice J. O’Toole

    Achieving the upper limits of face identification accuracy in forensic applications can minimize errors that have profound social and personal consequences. Although forensic examiners identify faces in these applications, systematic tests of their accuracy are rare. How can we achieve the most accurate face identification: using people and/or machines working alone or in collaboration? In a comprehensive comparison of face identification by humans and computers, we found that forensic facial examiners, facial reviewers, and superrecognizers were more accurate than fingerprint examiners and students on a challenging face identification test. Individual performance on the test varied widely. On the same test, four deep convolutional neural networks (DCNNs), developed between 2015 and 2017, identified faces within the range of human accuracy. Accuracy of the algorithms increased steadily over time, with the most recent DCNN scoring above the median of the forensic facial examiners. Using crowd-sourcing methods, we fused the judgments of multiple forensic facial examiners by averaging their rating-based identity judgments. Accuracy was substantially better for fused judgments than for individuals working alone. Fusion also served to stabilize performance, boosting the scores of lower-performing individuals and decreasing variability. Single forensic facial examiners fused with the best algorithm were more accurate than the combination of two examiners. Therefore, collaboration among humans and between humans and machines offers tangible benefits to face identification accuracy in important applications. These results offer an evidence-based roadmap for achieving the most accurate face identification possible.

    更新日期:2018-06-13
  • Functional diversification of Arabidopsis SEC1-related SM proteins in cytokinetic and secretory membrane fusion [Plant Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Matthias Karnahl, Misoon Park, Cornelia Krause, Ulrike Hiller, Ulrike Mayer, York-Dieter Stierhof, Gerd Jürgens

    Sec1/Munc18 (SM) proteins contribute to membrane fusion by interacting with Qa-SNAREs or nascent trans-SNARE complexes. Gymnosperms and the basal angiosperm Amborella have only a single SEC1 gene related to the KEULE gene in Arabidopsis. However, the genomes of most angiosperms including Arabidopsis encode three SEC1-related SM proteins of which only KEULE has been functionally characterized as interacting with the cytokinesis-specific Qa-SNARE KNOLLE during cell-plate formation. Here we analyze the closest paralog of KEULE named SEC1B. In contrast to the cytokinesis defects of keule mutants, sec1b mutants are homozygous viable. However, the keule sec1b double mutant was nearly gametophytically lethal, displaying collapsed pollen grains, which suggests substantial overlap between SEC1B and KEULE functions in secretion-dependent growth. SEC1B had a strong preference for interaction with the evolutionarily ancient Qa-SNARE SYP132 involved in secretion and cytokinesis, whereas KEULE interacted with both KNOLLE and SYP132. This differential interaction with Qa-SNAREs is likely conferred by domains 1 and 2a of the two SM proteins. Comparative analysis of all four possible combinations of the relevant SEC1 Qa-SNARE double mutants revealed that in cytokinesis, the interaction of SEC1B with KNOLLE plays no role, whereas the interaction of KEULE with KNOLLE is prevalent and functionally as important as the interactions of both SEC1B and KEU with SYP132 together. Our results suggest that functional diversification of the two SEC1-related SM proteins during angiosperm evolution resulted in enhanced interaction of SEC1B with Qa-SNARE SYP132, and thus a predominant role of SEC1B in secretion.

    更新日期:2018-06-13
  • Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning [Neuroscience]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Balázs A. Györffy, Judit Kun, György Török, Éva Bulyáki, Zsolt Borhegyi, Péter Gulyássy, Viktor Kis, Péter Szocsics, András Micsonai, János Matkó, László Drahos, Gábor Juhász, Katalin A. Kékesi, József Kardos

    C1q, a member of the immune complement cascade, is implicated in the selective pruning of synapses by microglial phagocytosis. C1q-mediated synapse elimination has been shown to occur during brain development, while increased activation and complement-dependent synapse loss is observed in neurodegenerative diseases. However, the molecular mechanisms underlying C1q-controlled synaptic pruning are mostly unknown. This study addresses distortions in the synaptic proteome leading to C1q-tagged synapses. Our data demonstrated the preferential localization of C1q to the presynapse. Proteomic investigation and pathway analysis of C1q-tagged synaptosomes revealed the presence of apoptotic-like processes in C1q-tagged synapses, which was confirmed experimentally with apoptosis markers. Moreover, the induction of synaptic apoptotic-like mechanisms in a model of sensory deprivation-induced synaptic depression led to elevated C1q levels. Our results unveiled that C1q label-based synaptic pruning is triggered by and directly linked to apoptotic-like processes in the synaptic compartment.

    更新日期:2018-06-13
  • Navigation of brain networks [Neuroscience]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Caio Seguin, Martijn P. van den Heuvel, Andrew Zalesky

    Understanding the mechanisms of neural communication in large-scale brain networks remains a major goal in neuroscience. We investigated whether navigation is a parsimonious routing model for connectomics. Navigating a network involves progressing to the next node that is closest in distance to a desired destination. We developed a measure to quantify navigation efficiency and found that connectomes in a range of mammalian species (human, mouse, and macaque) can be successfully navigated with near-optimal efficiency (>80% of optimal efficiency for typical connection densities). Rewiring network topology or repositioning network nodes resulted in 45–60% reductions in navigation performance. We found that the human connectome cannot be progressively randomized or clusterized to result in topologies with substantially improved navigation performance (>5%), suggesting a topological balance between regularity and randomness that is conducive to efficient navigation. Navigation was also found to (i) promote a resource-efficient distribution of the information traffic load, potentially relieving communication bottlenecks, and (ii) explain significant variation in functional connectivity. Unlike commonly studied communication strategies in connectomics, navigation does not mandate assumptions about global knowledge of network topology. We conclude that the topology and geometry of brain networks are conducive to efficient decentralized communication.

    更新日期:2018-06-13
  • Increase in chemokine CXCL1 by ER{beta} ligand treatment is a key mediator in promoting axon myelination [Neuroscience]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Hawra Karim, Sung Hoon Kim, Andrew S. Lapato, Norio Yasui, John A. Katzenellenbogen, Seema K. Tiwari-Woodruff

    Estrogen receptor β (ERβ) ligands promote remyelination in mouse models of multiple sclerosis. Recent work using experimental autoimmune encephalomyelitis (EAE) has shown that ERβ ligands induce axon remyelination, but impact peripheral inflammation to varying degrees. To identify if ERβ ligands initiate a common immune mechanism in remyelination, central and peripheral immunity and pathology in mice given ERβ ligands at peak EAE were assessed. All ERβ ligands induced differential expression of cytokines and chemokines, but increased levels of CXCL1 in the periphery and in astrocytes. Oligodendrocyte CXCR2 binds CXCL1 and has been implicated in normal myelination. In addition, despite extensive immune cell accumulation in the CNS, all ERβ ligands promoted extensive remyelination in mice at peak EAE. This finding highlights a component of the mechanism by which ERβ ligands mediate remyelination. Hence, interplay between the immune system and central nervous system may be responsible for the remyelinating effects of ERβ ligands. Our findings of potential neuroprotective benefits arising from the presence of CXCL1 could have implications for improved therapies for multiple sclerosis.

    更新日期:2018-06-13
  • Selection of Plasmodium falciparum cytochrome B mutants by putative PfNDH2 inhibitors [Microbiology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Kristin D. Lane, Jianbing Mu, Jinghua Lu, Sean T. Windle, Anna Liu, Peter D. Sun, Thomas E. Wellems

    Malaria control is threatened by a limited pipeline of effective pharmaceuticals against drug-resistant strains of Plasmodium falciparum. Components of the mitochondrial electron transport chain (ETC) are attractive targets for drug development, owing to exploitable differences between the parasite and human ETC. Disruption of ETC function interferes with metabolic processes including de novo pyrimidine synthesis, essential for nucleic acid replication. We investigated the effects of ETC inhibitor selection on two distinct P. falciparum clones, Dd2 and 106/1. Compounds CK-2-68 and RYL-552, substituted quinolones reported to block P. falciparum NADH dehydrogenase 2 (PfNDH2; a type II NADH:quinone oxidoreductase), unexpectedly selected mutations at the quinol oxidation (Qo) pocket of P. falciparum cytochrome B (PfCytB). Selection experiments with atovaquone (ATQ) on 106/1 parasites yielded highly resistant PfCytB Y268S mutants seen in clinical infections that fail ATQ-proguanil treatment. In contrast, ATQ pressure on Dd2 yielded moderately resistant parasites carrying a PfCytB M133I or K272R mutation. Strikingly, all ATQ-selected mutants demonstrated little change or slight increase of sensitivity to CK-2-68 or RYL-552. Molecular docking studies demonstrated binding of all three ETC inhibitors to the Qo pocket of PfCytB, where Y268 forms strong van der Waals interactions with the hydroxynaphthoquinone ring of ATQ but not the quinolone ring of CK-2-68 or RYL-552. Our results suggest that combinations of suitable ETC inhibitors may be able to subvert or delay the development of P. falciparum drug resistance.

    更新日期:2018-06-13
  • Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes [Medical Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Julie P. Saiki, Hongbin Cao, Lauren D. Van Wassenhove, Vignesh Viswanathan, Joshua Bloomstein, Dhanya K. Nambiar, Aaron J. Mattingly, Dadi Jiang, Che-Hong Chen, Matthew C. Stevens, Amanda L. Simmons, Hyun Shin Park, Rie von Eyben, Eric T. Kool, Davud Sirjani, Sarah M. Knox, Quynh Thu Le, Daria Mochly-Rosen

    Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated Aldh3a1−/− adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands. To identify a safe ALDH3A1 activator for potential clinical testing, we screened a traditional Chinese medicine library and isolated d-limonene, commonly used as a food-flavoring agent, as a single constituent activator. ALDH3A1 activation by d-limonene significantly reduced aldehyde accumulation in SSPCs and whole embryonic glands, increased sphere-forming ability, decreased apoptosis, and improved submandibular gland structure and function in vivo after radiation. A phase 0 study in patients with salivary gland tumors showed effective delivery of d-limonene into human salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy.

    更新日期:2018-06-13
  • Geometric hydrodynamics via Madelung transform [Mathematics]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Boris Khesin, Gerard Misiolek, Klas Modin

    We introduce a geometric framework to study Newton’s equations on infinite-dimensional configuration spaces of diffeomorphisms and smooth probability densities. It turns out that several important partial differential equations of hydrodynamical origin can be described in this framework in a natural way. In particular, the Madelung transform between the Schrödinger equation and Newton’s equations is a symplectomorphism of the corresponding phase spaces. Furthermore, the Madelung transform turns out to be a Kähler map when the space of densities is equipped with the Fisher–Rao information metric. We describe several dynamical applications of these results.

    更新日期:2018-06-13
  • Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies [Immunology and Inflammation]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Ilona Baraniak, Barbara Kropff, Lyn Ambrose, Megan McIntosh, Gary R. McLean, Sylvie Pichon, Claire Atkinson, Richard S. B. Milne, Michael Mach, Paul D. Griffiths, Matthew B. Reeves

    Human cytomegalovirus (HCMV) is an important pathogen in transplant patients and in congenital infection. Previously, we demonstrated that vaccination with a recombinant viral glycoprotein B (gB)/MF59 adjuvant formulation before solid organ transplant reduced viral load parameters post transplant. Reduced posttransplant viremia was directly correlated with antibody titers against gB consistent with a humoral response against gB being important. Here we show that sera from the vaccinated seronegative patients displayed little evidence of a neutralizing antibody response against cell-free HCMV in vitro. Additionally, sera from seronegative vaccine recipients had minimal effect on the replication of a strain of HCMV engineered to be cell-associated in a viral spread assay. Furthermore, although natural infection can induce antibody-dependent cellular cytotoxicity (ADCC) responses, serological analysis of seronegative vaccinees again presented no evidence of a substantial ADCC-promoting antibody response being generated de novo. Finally, analyses for responses against major antigenic domains of gB following vaccination were variable, and their pattern was distinct compared with natural infection. Taken together, these data argue that the protective effect elicited by the gB vaccine is via a mechanism of action in seronegative vaccinees that cannot be explained by neutralization or the induction of ADCC. More generally, these data, which are derived from a human challenge model that demonstrated that the gB vaccine is protective, highlight the need for more sophisticated analyses of new HCMV vaccines over and above the quantification of an ability to induce potent neutralizing antibody responses in vitro.

    更新日期:2018-06-13
  • HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions [Immunology and Inflammation]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Cody S. Nelson, Tori Huffman, Jennifer A. Jenks, Eduardo Cisneros de la Rosa, Guanhua Xie, Nathan Vandergrift, Robert F. Pass, Justin Pollara, Sallie R. Permar

    Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating ∼50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.

    更新日期:2018-06-13
  • CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy [Genetics]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Yoshikatsu Hosoda, Munemitsu Yoshikawa, Masahiro Miyake, Yasuharu Tabara, Jeeyun Ahn, Se Joon Woo, Shigeru Honda, Yoichi Sakurada, Chieko Shiragami, Hideo Nakanishi, Akio Oishi, Sotaro Ooto, Akiko Miki, Nagahama Study Group, Tomohiro Iida, Hiroyuki Iijima, Makoto Nakamura, Chiea Chuen Khor, Tien Yin Wong, Kyuyoung Song, Kyu Hyung Park, Ryo Yamada, Fumihiko Matsuda, Akitaka Tsujikawa, Kenji Yamashiro

    Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10−10 and 6.75 × 10−8, respectively). Case–control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10−5 and 5.14 × 10−5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.

    更新日期:2018-06-13
  • Experimental evidence for delayed contingent cooperation among wild dwarf mongooses [Evolution]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Julie M. Kern, Andrew N. Radford

    Many animals participate in biological markets, with strong evidence existing for immediate cooperative trades. In particular, grooming is often exchanged for itself or other commodities, such as coalitionary support or access to food and mates. More contentious is the possibility that nonhuman animals can rely on memories of recent events, providing contingent cooperation even when there is a temporal delay between two cooperative acts. Here we provide experimental evidence of delayed cross-commodity grooming exchange in wild dwarf mongooses (Helogale parvula). First, we use natural observations and social-network analyses to demonstrate a positive link between grooming and sentinel behavior (acting as a raised guard). Group members who contributed more to sentinel behavior received more grooming and had a better social-network position. We then used a field-based playback experiment to test a causal link between contributions to sentinel behavior and grooming received later in the day. During 3-h trial sessions, the perceived sentinel contributions of a focal individual were either up-regulated (playback of its surveillance calls, which are given naturally during sentinel bouts) or unmanipulated (playback of its foraging close calls as a control). On returning to the sleeping refuge at the end of the day, focal individuals received more grooming following surveillance-call playback than control-call playback and more grooming than a matched individual whose sentinel contributions were not up-regulated. We believe our study therefore provides experimental evidence of delayed contingent cooperation in a wild nonprimate species.

    更新日期:2018-06-13
  • Comprehensive phylogeny of ray-finned fishes (Actinopterygii) based on transcriptomic and genomic data [Evolution]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Lily C. Hughes, Guillermo Ortí, Yu Huang, Ying Sun, Carole C. Baldwin, Andrew W. Thompson, Dahiana Arcila, Ricardo Betancur-R., Chenhong Li, Leandro Becker, Nicolás Bellora, Xiaomeng Zhao, Xiaofeng Li, Min Wang, Chao Fang, Bing Xie, Zhuocheng Zhou, Hai Huang, Songlin Chen, Byrappa Venkatesh, Qiong Shi

    Our understanding of phylogenetic relationships among bony fishes has been transformed by analysis of a small number of genes, but uncertainty remains around critical nodes. Genome-scale inferences so far have sampled a limited number of taxa and genes. Here we leveraged 144 genomes and 159 transcriptomes to investigate fish evolution with an unparalleled scale of data: >0.5 Mb from 1,105 orthologous exon sequences from 303 species, representing 66 out of 72 ray-finned fish orders. We apply phylogenetic tests designed to trace the effect of whole-genome duplication events on gene trees and find paralogy-free loci using a bioinformatics approach. Genome-wide data support the structure of the fish phylogeny, and hypothesis-testing procedures appropriate for phylogenomic datasets using explicit gene genealogy interrogation settle some long-standing uncertainties, such as the branching order at the base of the teleosts and among early euteleosts, and the sister lineage to the acanthomorph and percomorph radiations. Comprehensive fossil calibrations date the origin of all major fish lineages before the end of the Cretaceous.

    更新日期:2018-06-13
  • Dynamic regimes of electrified liquid filaments [Engineering]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Tiantian Kong, Howard A. Stone, Liqiu Wang, Ho Cheung Shum

    We investigate the dynamics of an electrified liquid filament in a nozzle-to-substrate configuration with a close separation. The interplay between compressive viscous and electrostatic stresses dictates previously undocumented transitions between dynamic regimes of “jetting,” “coiling,” and “whipping.” In particular, the onsets of both coiling and whipping instabilities are significantly influenced by the minimum radius along the liquid filament. Using a low-interfacial-tension system, we unravel the physics behind the transitions between jetting, coiling, and whipping of an electrified filament for a range of liquid properties and geometric parameters. Our results enrich the overall physical picture of the electrically forced jets, and provide insights for the emerging high-resolution instability-assisted printing of materials such as folded assemblies and scaffolds.

    更新日期:2018-06-13
  • Global signal of top-down control of terrestrial plant communities by herbivores [Ecology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Shihong Jia, Xugao Wang, Zuoqiang Yuan, Fei Lin, Ji Ye, Zhanqing Hao, Matthew Scott Luskin

    The theory of “top-down” ecological regulation predicts that herbivory suppresses plant abundance, biomass, and survival but increases diversity through the disproportionate consumption of dominant species, which inhibits competitive exclusion. To date, these outcomes have been clear in aquatic ecosystems but not on land. We explicate this discrepancy using a meta-analysis of experimental results from 123 native animal exclusions in natural terrestrial ecosystems (623 pairwise comparisons). Consistent with top-down predictions, we found that herbivores significantly reduced plant abundance, biomass, survival, and reproduction (all P < 0.01) and increased species evenness but not richness (P = 0.06 and P = 0.59, respectively). However, when examining patterns in the strength of top-down effects, with few exceptions, we were unable to detect significantly different effect sizes among biomes, based on local site characteristics (climate or productivity) or study characteristics (study duration or exclosure size). The positive effects on diversity were only significant in studies excluding large animals or located in temperate grasslands. The results demonstrate that top-down regulation by herbivores is a pervasive process shaping terrestrial plant communities at the global scale, but its strength is highly site specific and not predicted by basic site conditions. We suggest that including herbivore densities as a covariate in future exclosure studies will facilitate the discovery of unresolved macroecology trends in the strength of herbivore–plant interactions.

    更新日期:2018-06-13
  • Empirical evidence for stability of the 405-kiloyear Jupiter-Venus eccentricity cycle over hundreds of millions of years [Earth, Atmospheric, and Planetary Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Dennis V. Kent, Paul E. Olsen, Cornelia Rasmussen, Christopher Lepre, Roland Mundil, Randall B. Irmis, George E. Gehrels, Dominique Giesler, John W. Geissman, William G. Parker

    The Newark–Hartford astrochronostratigraphic polarity timescale (APTS) was developed using a theoretically constant 405-kiloyear eccentricity cycle linked to gravitational interactions with Jupiter–Venus as a tuning target and provides a major timing calibration for about 30 million years of Late Triassic and earliest Jurassic time. While the 405-ky cycle is both unimodal and the most metronomic of the major orbital cycles thought to pace Earth’s climate in numerical solutions, there has been little empirical confirmation of that behavior, especially back before the limits of orbital solutions at about 50 million years before present. Moreover, the APTS is anchored only at its younger end by U–Pb zircon dates at 201.6 million years before present and could even be missing a number of 405-ky cycles. To test the validity of the dangling APTS and orbital periodicities, we recovered a diagnostic magnetic polarity sequence in the volcaniclastic-bearing Chinle Formation in a scientific drill core from Petrified Forest National Park (Arizona) that provides an unambiguous correlation to the APTS. New high precision U–Pb detrital zircon dates from the core are indistinguishable from ages predicted by the APTS back to 215 million years before present. The agreement shows that the APTS is continuous and supports a stable 405-kiloyear cycle well beyond theoretical solutions. The validated Newark–Hartford APTS can be used as a robust framework to help differentiate provinciality from global temporal patterns in the ecological rise of early dinosaurs in the Late Triassic, amongst other problems.

    更新日期:2018-06-13
  • A molecular perspective for global modeling of upper atmospheric NH3 from freezing clouds [Earth, Atmospheric, and Planetary Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Cui Ge, Chongqin Zhu, Joseph S. Francisco, Xiao Cheng Zeng, Jun Wang

    Ammonia plays a key role in the neutralization of atmospheric acids such as sulfate and nitrates. A few in situ observations have supported the theory that gas-phase NH3 concentrations should decrease sharply with altitude and be extremely low in the upper troposphere and lower stratosphere (UTLS). This theory, however, seems inconsistent with recent satellite measurements and is also not supported by the aircraft data showing highly or fully neutralized sulfate aerosol particles by ammonium in the UTLS in many parts of the world. Here we reveal the contributions of deep convective clouds to NH3 in the UTLS by using integrated cross-scale modeling, which includes molecular dynamic simulations, a global chemistry transport model, and satellite and aircraft measurements. We show that the NH3 dissolved in liquid cloud droplets is prone to being released into the UTLS upon freezing during deep convection. Because NH3 emission is not regulated in most countries and its future increase is likely persistent from agricultural growth and the warmer climate, the effect of NH3 on composition and phase of aerosol particles in the UTLS can be significant, which in turn can affect cirrus cloud formation, radiation, and the budgets of NOx and O3.

    更新日期:2018-06-13
  • {beta}-Catenin-dependent mechanotransduction dates back to the common ancestor of Cnidaria and Bilateria [Developmental Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Ekaterina Pukhlyakova, Andrew J. Aman, Kareem Elsayad, Ulrich Technau

    Although the genetic regulation of cellular differentiation processes is well established, recent studies have revealed the role of mechanotransduction on a variety of biological processes, including regulation of gene expression. However, it remains unclear how universal and widespread mechanotransduction is in embryonic development of animals. Here, we investigate mechanosensitive gene expression during gastrulation of the starlet sea anemone Nematostella vectensis, a cnidarian model organism. We show that the blastoporal marker gene brachyury is down-regulated by blocking myosin II-dependent gastrulation movements. Brachyury expression can be restored by applying external mechanical force. Using CRISPR/Cas9 and morpholino antisense technology, we also show that mechanotransduction leading to brachyury expression is β-catenin dependent, similar to recent findings in fish and Drosophila [Brunet T, et al. (2013) Nat Commun 4:1–15]. Finally, we demonstrate that prolonged application of mechanical stress on the embryo leads to ectopic brachyury expression. Thus, our data indicate that β-catenin–dependent mechanotransduction is an ancient gene regulatory mechanism, which was present in the common ancestor of cnidarians and bilaterians, at least 600 million years ago.

    更新日期:2018-06-13
  • Unimolecular reaction of acetone oxide and its reaction with water in the atmosphere [Chemistry]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Bo Long, Junwei Lucas Bao, Donald G. Truhlar

    Criegee intermediates (i.e., carbonyl oxides with two radical sites) are known to be important atmospheric reagents; however, our knowledge of their reaction kinetics is still limited. Although experimental methods have been developed to directly measure the reaction rate constants of stabilized Criegee intermediates, the experimental results cover limited temperature ranges and do not completely agree well with one another. Here we investigate the unimolecular reaction of acetone oxide [(CH3)2COO] and its bimolecular reaction with H2O to obtain rate constants with quantitative accuracy comparable to experimental accuracy. We do this by using CCSDT(Q)/CBS//CCSD(T)-F12a/DZ-F12 benchmark results to select and validate exchange-correlation functionals, which are then used for direct dynamics calculations by variational transition state theory with small-curvature tunneling and torsional and high-frequency anharmonicity. We find that tunneling is very significant in the unimolecular reaction of (CH3)2COO and its bimolecular reaction with H2O. We show that the atmospheric lifetimes of (CH3)2COO depend on temperature and that the unimolecular reaction of (CH3)2COO is the dominant decay mode above 240 K, while the (CH3)2COO + SO2 reaction can compete with the corresponding unimolecular reaction below 240 K when the SO2 concentration is 9 × 1010 molecules per cubic centimeter. We also find that experimental results may not be sufficiently accurate for the unimolecular reaction of (CH3)2COO above 310 K. Not only does the present investigation provide insights into the decay of (CH3)2COO in the atmosphere, but it also provides an illustration of how to use theoretical methods to predict quantitative rate constants of medium-sized Criegee intermediates.

    更新日期:2018-06-13
  • The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells [Cell Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Katharina Leithner, Alexander Triebl, Martin Trötzmüller, Barbara Hinteregger, Petra Leko, Beatrix I. Wieser, Gabriele Grasmann, Alexandra L. Bertsch, Thomas Züllig, Elvira Stacher, Alessandro Valli, Ruth Prassl, Andrea Olschewski, Adrian L. Harris, Harald C. Köfeler, Horst Olschewski, Andelko Hrzenjak

    Cancer cells are reprogrammed to consume large amounts of glucose to support anabolic biosynthetic pathways. However, blood perfusion and consequently the supply with glucose are frequently inadequate in solid cancers. PEPCK-M (PCK2), the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK), has been shown by us and others to be functionally expressed and to mediate gluconeogenesis, the reverse pathway of glycolysis, in different cancer cells. Serine and ribose synthesis have been identified as downstream pathways fed by PEPCK in cancer cells. Here, we report that PEPCK-M–dependent glycerol phosphate formation from noncarbohydrate precursors (glyceroneogenesis) occurs in starved lung cancer cells and supports de novo glycerophospholipid synthesis. Using stable isotope-labeled glutamine and lactate, we show that PEPCK-M generates phosphoenolpyruvate and 3-phosphoglycerate, which are at least partially converted to glycerol phosphate and incorporated into glycerophospholipids (GPL) under glucose and serum starvation. This pathway is required to maintain levels of GPL, especially phosphatidylethanolamine (PE), as shown by stable shRNA-mediated silencing of PEPCK-M in H23 lung cancer cells. PEPCK-M shRNA led to reduced colony formation after starvation, and the effect was partially reversed by the addition of dioleyl-PE. Furthermore, PEPCK-M silencing abrogated cancer growth in a lung cancer cell xenograft model. In conclusion, glycerol phosphate formation for de novo GPL synthesis via glyceroneogenesis is a newly characterized anabolic pathway in cancer cells mediated by PEPCK-M under conditions of severe nutrient deprivation.

    更新日期:2018-06-13
  • TAp73 contributes to the oxidative stress response by regulating protein synthesis [Cell Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Alberto Marini, Barak Rotblat, Thomas Sbarrato, Maria Victoria Niklison-Chirou, John R. P. Knight, Kate Dudek, Carolyn Jones, Martin Bushell, Richard A. Knight, Ivano Amelio, Anne E. Willis, Gerry Melino

    TAp73 is a transcription factor that plays key roles in brain development, aging, and cancer. At the cellular level, TAp73 is a critical homeostasis-maintaining factor, particularly following oxidative stress. Although major studies focused on TAp73 transcriptional activities have indicated a contribution of TAp73 to cellular metabolism, the mechanisms underlying its role in redox homeostasis have not been completely elucidated. Here we show that TAp73 contributes to the oxidative stress response by participating in the control of protein synthesis. Regulation of mRNA translation occupies a central position in cellular homeostasis during the stress response, often by reducing global rates of protein synthesis and promoting translation of specific mRNAs. TAp73 depletion results in aberrant ribosomal RNA (rRNA) processing and impaired protein synthesis. In particular, polysomal profiles show that TAp73 promotes the integration of mRNAs that encode rRNA-processing factors in polysomes, supporting their translation. Concurrently, TAp73 depletion causes increased sensitivity to oxidative stress that correlates with reduced ATP levels, hyperactivation of AMPK, and translational defects. TAp73 is important for maintaining active translation of mitochondrial transcripts in response to oxidative stress, thus promoting mitochondrial activity. Our results indicate that TAp73 contributes to redox homeostasis by affecting the translational machinery, facilitating the translation of specific mitochondrial transcripts. This study identifies a mechanism by which TAp73 contributes to the oxidative stress response and describes a completely unexpected role for TAp73 in regulating protein synthesis.

    更新日期:2018-06-13
  • Inner Workings: Microscopy lights up stem cells in action [Cell Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Carolyn Beans

    As developmental and cell biologist Valentina Greco stood on a stage in Philadelphia last December, candid time-lapse shots of some of the body’s most elusive cells flashed behind her in quick succession. These stem cells, photographed in a living mouse, were caught in the acts of dividing, differentiating, and interacting with neighbors. Such videos are more than just captivating cellular cinema—they could reveal key details about how stem cells work.

    更新日期:2018-06-13
  • An intermediate along the recovery stroke of myosin VI revealed by X-ray crystallography and molecular dynamics [Biophysics and Computational Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Florian Blanc, Tatiana Isabet, Hannah Benisty, H. Lee Sweeney, Marco Cecchini, Anne Houdusse

    Myosins form a class of actin-based, ATPase motor proteins that mediate important cellular functions such as cargo transport and cell motility. Their functional cycle involves two large-scale swings of the lever arm: the force-generating powerstroke, which takes place on actin, and the recovery stroke during which the lever arm is reprimed into an armed configuration. Previous analyses of the prerecovery (postrigor) and postrecovery (prepowerstroke) states predicted that closure of switch II in the ATP binding site precedes the movement of the converter and the lever arm. Here, we report on a crystal structure of myosin VI, called pretransition state (PTS), which was solved at 2.2 Å resolution. Structural analysis and all-atom molecular dynamics simulations are consistent with PTS being an intermediate along the recovery stroke, where the Relay/SH1 elements adopt a postrecovery conformation, and switch II remains open. In this state, the converter appears to be largely uncoupled from the motor domain and explores an ensemble of partially reprimed configurations through extensive, reversible fluctuations. Moreover, we found that the free energy cost of hydrogen-bonding switch II to ATP is lowered by more than 10 kcal/mol compared with the prerecovery state. These results support the conclusion that closing of switch II does not initiate the recovery stroke transition in myosin VI. Rather, they suggest a mechanism in which lever arm repriming would be mostly driven by thermal fluctuations and eventually stabilized by the switch II interaction with the nucleotide in a ratchet-like fashion.

    更新日期:2018-06-13
  • How electrostatic networks modulate specificity and stability of collagen [Biophysics and Computational Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Hongning Zheng, Cheng Lu, Jun Lan, Shilong Fan, Vikas Nanda, Fei Xu

    One-quarter of the 28 types of natural collagen exist as heterotrimers. The oligomerization state of collagen affects the structure and mechanics of the extracellular matrix, providing essential cues to modulate biological and pathological processes. A lack of high-resolution structural information limits our mechanistic understanding of collagen heterospecific self-assembly. Here, the 1.77-Å resolution structure of a synthetic heterotrimer demonstrates the balance of intermolecular electrostatics and hydrogen bonding that affects collagen stability and heterospecificity of assembly. Atomistic simulations and mutagenesis based on the solved structure are used to explore the contributions of specific interactions to energetics. A predictive model of collagen stability and specificity is developed for engineering novel collagen structures.

    更新日期:2018-06-13
  • Convergent evolution of tertiary structure in rhodopsin visual proteins from vertebrates and box jellyfish [Biophysics and Computational Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Elliot Gerrard, Eshita Mutt, Takashi Nagata, Mitsumasa Koyanagi, Tilman Flock, Elena Lesca, Gebhard F. X. Schertler, Akihisa Terakita, Xavier Deupi, Robert J. Lucas

    Box jellyfish and vertebrates are separated by >500 million years of evolution yet have structurally analogous lens eyes that employ rhodopsin photopigments for vision. All opsins possess a negatively charged residue—the counterion—to maintain visible-light sensitivity and facilitate photoisomerization of their retinaldehyde chromophore. In vertebrate rhodopsins, the molecular evolution of the counterion position—from a highly conserved distal location in the second extracellular loop (E181) to a proximal location in the third transmembrane helix (E113)—is established as a key driver of higher fidelity photoreception. Here, we use computational biology and heterologous action spectroscopy to determine whether the appearance of the advanced visual apparatus in box jellyfish was also accompanied by changes in the opsin tertiary structure. We found that the counterion in an opsin from the lens eye of the box jellyfish Carybdea rastonii (JellyOp) has also moved to a unique proximal location within the transmembrane bundle—E94 in TM2. Furthermore, we reveal that this Schiff base/counterion system includes an additional positive charge—R186—that has coevolved with E94 to functionally separate E94 and E181 in the chromophore-binding pocket of JellyOp. By engineering this pocket—neutralizing R186 and E94, or swapping E94 with the vertebrate counterion E113—we can recreate versions of the invertebrate and vertebrate counterion systems, respectively, supporting a relatively similar overall architecture in this region of animal opsins. In summary, our data establish the third only counterion site in animal opsins and reveal convergent evolution of tertiary structure in opsins from distantly related species with advanced visual systems.

    更新日期:2018-06-13
  • Fluctuating hydrogen-bond networks govern anomalous electron transfer kinetics in a blue copper protein [Biophysics and Computational Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Joshua S. Kretchmer, Nicholas Boekelheide, Jeffrey J. Warren, Jay R. Winkler, Harry B. Gray, Thomas F. Miller

    We combine experimental and computational methods to address the anomalous kinetics of long-range electron transfer (ET) in mutants of Pseudomonas aeruginosa azurin. ET rates and driving forces for wild type (WT) and three N47X mutants (X = L, S, and D) of Ru(2,2′-bipyridine)2 (imidazole)(His83) azurin are reported. An enhanced ET rate for the N47L mutant suggests either an increase of the donor–acceptor (DA) electronic coupling or a decrease in the reorganization energy for the reaction. The underlying atomistic features are investigated using a recently developed nonadiabatic molecular dynamics method to simulate ET in each of the azurin mutants, revealing unexpected aspects of DA electronic coupling. In particular, WT azurin and all studied mutants exhibit more DA compression during ET (>2 Å) than previously recognized. Moreover, it is found that DA compression involves an extended network of hydrogen bonds, the fluctuations of which gate the ET reaction, such that DA compression is facilitated by transiently rupturing hydrogen bonds. It is found that the N47L mutant intrinsically disrupts this hydrogen-bond network, enabling particularly facile DA compression. This work, which reveals the surprisingly fluctional nature of ET in azurin, suggests that hydrogen-bond networks can modulate the efficiency of long-range biological ET.

    更新日期:2018-06-13
  • Heme redox potentials hold the key to reactivity differences between nitric oxide reductase and heme-copper oxidase [Biochemistry]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Ambika Bhagi-Damodaran, Julian H. Reed, Qianhong Zhu, Yelu Shi, Parisa Hosseinzadeh, Braddock A. Sandoval, Kevin A. Harnden, Shuyan Wang, Madeline R. Sponholtz, Evan N. Mirts, Sudharsan Dwaraknath, Yong Zhang, Pierre Moënne-Loccoz, Yi Lu

    Despite high structural homology between NO reductases (NORs) and heme-copper oxidases (HCOs), factors governing their reaction specificity remain to be understood. Using a myoglobin-based model of NOR (FeBMb) and tuning its heme redox potentials (E°′) to cover the native NOR range, through manipulating hydrogen bonding to the proximal histidine ligand and replacing heme b with monoformyl (MF-) or diformyl (DF-) hemes, we herein demonstrate that the E°′ holds the key to reactivity differences between NOR and HCO. Detailed electrochemical, kinetic, and vibrational spectroscopic studies, in tandem with density functional theory calculations, demonstrate a strong influence of heme E°′ on NO reduction. Decreasing E°′ from +148 to −130 mV significantly impacts electronic properties of the NOR mimics, resulting in 180- and 633-fold enhancements in NO association and heme-nitrosyl decay rates, respectively. Our results indicate that NORs exhibit finely tuned E°′ that maximizes their enzymatic efficiency and helps achieve a balance between opposite factors: fast NO binding and decay of dinitrosyl species facilitated by low E°′ and fast electron transfer facilitated by high E°′. Only when E°′ is optimally tuned in FeBMb(MF-heme) for NO binding, heme-nitrosyl decay, and electron transfer does the protein achieve multiple (>35) turnovers, previously not achieved by synthetic or enzyme-based NOR models. This also explains a long-standing question in bioenergetics of selective cross-reactivity in HCOs. Only HCOs with heme E°′ in a similar range as NORs (between −59 and 200 mV) exhibit NOR reactivity. Thus, our work demonstrates efficient tuning of E°′ in various metalloproteins for their optimal functionality.

    更新日期:2018-06-13
  • Metastable quasicrystal-induced nucleation in a bulk glass-forming liquid [Applied Physical Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Güven Kurtuldu, Karl F. Shamlaye, Jörg F. Löffler

    This study presents a unique Mg-based alloy composition in the Mg–Zn–Yb system which exhibits bulk metallic glass, metastable icosahedral quasicrystals (iQCs), and crystalline approximant phases in the as-cast condition. Microscopy revealed a smooth gradual transition from glass to QC. We also report the complete melting of a metastable eutectic phase mixture (including a QC phase), generated via suppression of the metastable-to-stable phase transition at high heating rates using fast differential scanning calorimetry (FDSC). The melting temperature and enthalpy of fusion of this phase mixture could be measured directly, which unambiguously proves its metastability in any temperature range. The kinetic pathway from liquid state to stable solid state (an approximant phase) minimizes the free-energy barrier for nucleation through an intermediate state (metastable QC phase) because of its low solid–liquid interfacial energy. At high undercooling of the liquid, where diffusion is limited, another approximant phase with near-liquid composition forms just above the glass-transition temperature. These experimental results shed light on the competition between metastable and stable crystals, and on glass formation via system frustration associated with the presence of several free-energy minima.

    更新日期:2018-06-13
  • MINFLUX monitors rapid molecular jumps with superior spatiotemporal resolution [Applied Physical Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Yvan Eilers, Haisen Ta, Klaus C. Gwosch, Francisco Balzarotti, Stefan W. Hell

    Compared with localization schemes solely based on evaluating patterns of molecular emission, the recently introduced single-molecule localization concept called MINFLUX and the fluorescence nanoscopies derived from it require up to orders of magnitude fewer emissions to attain single-digit nanometer resolution. Here, we demonstrate that the lower number of required fluorescence photons enables MINFLUX to detect molecular movements of a few nanometers at a temporal sampling of well below 1 millisecond. Using fluorophores attached to thermally fluctuating DNA strands as model systems, we demonstrate that measurement times as short as 400 microseconds suffice to localize fluorescent molecules with ∼2-nm precision. Such performance is out of reach for popular camera-based localization by centroid calculation of emission diffraction patterns. Since theoretical limits have not been reached, our results show that emerging MINFLUX nanoscopy bears great potential for dissecting the motions of individual (macro)molecules at hitherto-unattained combinations of spatial and temporal resolution.

    更新日期:2018-06-13
  • Consequences of resistance evolution in a Cas9-based sex conversion-suppression gene drive for insect pest management [Applied Biological Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Mohammad KaramiNejadRanjbar, Kolja N. Eckermann, Hassan M. M. Ahmed, Héctor M. Sánchez C., Stefan Dippel, John M. Marshall, Ernst A. Wimmer

    The use of a site-specific homing-based gene drive for insect pest control has long been discussed, but the easy design of such systems has become possible only with the recent establishment of CRISPR/Cas9 technology. In this respect, novel targets for insect pest management are provided by new discoveries regarding sex determination. Here, we present a model for a suppression gene drive designed to cause an all-male population collapse in an agricultural pest insect. To evaluate the molecular details of such a sex conversion-based suppression gene drive experimentally, we implemented this strategy in Drosophila melanogaster to serve as a safe model organism. We generated a Cas9-based homing gene-drive element targeting the transformer gene and showed its high efficiency for sex conversion from females to males. However, nonhomologous end joining increased the rate of mutagenesis at the target site, which resulted in the emergence of drive-resistant alleles and therefore curbed the gene drive. This confirms previous studies that simple homing CRISPR/Cas9 gene-drive designs will be ineffective. Nevertheless, by performing population dynamics simulations using the parameters we obtained in D. melanogaster and by adjusting the model for the agricultural pest Ceratitis capitata, we were able to identify adequate modifications that could be successfully applied for the management of wild Mediterranean fruit fly populations using our proposed sex conversion-based suppression gene-drive strategy.

    更新日期:2018-06-13
  • Fluctuating radiocarbon offsets observed in the southern Levant and implications for archaeological chronology debates [Anthropology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Sturt W. Manning, Carol Griggs, Brita Lorentzen, Christopher Bronk Ramsey, David Chivall, A. J. Timothy Jull, Todd E. Lange

    Considerable work has gone into developing high-precision radiocarbon (14C) chronologies for the southern Levant region during the Late Bronze to Iron Age/early Biblical periods (∼1200–600 BC), but there has been little consideration whether the current standard Northern Hemisphere 14C calibration curve (IntCal13) is appropriate for this region. We measured 14C ages of calendar-dated tree rings from AD 1610 to 1940 from southern Jordan to investigate contemporary 14C levels and to compare these with IntCal13. Our data reveal an average offset of ∼19 14C years, but, more interestingly, this offset seems to vary in importance through time. While relatively small, such an offset has substantial relevance to high-resolution 14C chronologies for the southern Levant, both archaeological and paleoenvironmental. For example, reconsidering two published studies, we find differences, on average, of 60% between the 95.4% probability ranges determined from IntCal13 versus those approximately allowing for the observed offset pattern. Such differences affect, and even potentially undermine, several current archaeological and historical positions and controversies.

    更新日期:2018-06-13
  • Mediator subunit MED31 is required for radial patterning of Arabidopsis roots [Plant Biology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Xiaoyue Zhang, Wenkun Zhou, Qian Chen, Mingming Fang, Shuangshuang Zheng, Ben Scheres, Chuanyou Li

    Stem cell specification in multicellular organisms relies on the precise spatiotemporal control of RNA polymerase II (Pol II)-dependent gene transcription, in which the evolutionarily conserved Mediator coactivator complex plays an essential role. In Arabidopsis thaliana, SHORTROOT (SHR) and SCARECROW (SCR) orchestrate a transcriptional program that determines the fate and asymmetrical divisions of stem cells generating the root ground tissue. The mechanism by which SHR/SCR relays context-specific regulatory signals to the Pol II general transcription machinery is unknown. Here, we report the role of Mediator in controlling the spatiotemporal transcriptional output of SHR/SCR during asymmetrical division of stem cells and ground tissue patterning. The Mediator subunit MED31 interacted with SCR but not SHR. Reduction of MED31 disrupted the spatiotemporal activation of CYCLIND6;1 (CYCD6;1), leading to defective asymmetrical division of stem cells generating ground tissue. MED31 was recruited to the promoter of CYCD6;1 in an SCR-dependent manner. MED31 was involved in the formation of a dynamic MED31/SCR/SHR ternary complex through the interface protein SCR. We demonstrate that the relative protein abundance of MED31 and SHR in different cell types regulates the dynamic formation of the ternary complex, which provides a tunable switch to strictly control the spatiotemporal transcriptional output. This study provides valuable clues to understand the mechanism by which master transcriptional regulators control organ patterning.

    更新日期:2018-06-13
  • A theta rhythm in macaque visual cortex and its attentional modulation [Neuroscience]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Georgios Spyropoulos, Conrado Arturo Bosman, Pascal Fries

    Theta rhythms govern rodent sniffing and whisking, and human language processing. Human psychophysics suggests a role for theta also in visual attention. However, little is known about theta in visual areas and its attentional modulation. We used electrocorticography (ECoG) to record local field potentials (LFPs) simultaneously from areas V1, V2, V4, and TEO of two macaque monkeys performing a selective visual attention task. We found a ≈4-Hz theta rhythm within both the V1–V2 and the V4–TEO region, and theta synchronization between them, with a predominantly feedforward directed influence. ECoG coverage of large parts of these regions revealed a surprising spatial correspondence between theta and visually induced gamma. Furthermore, gamma power was modulated with theta phase. Selective attention to the respective visual stimulus strongly reduced these theta-rhythmic processes, leading to an unusually strong attention effect for V1. Microsaccades (MSs) were partly locked to theta. However, neuronal theta rhythms tended to be even more pronounced for epochs devoid of MSs. Thus, we find an MS-independent theta rhythm specific to visually driven parts of V1–V2, which rhythmically modulates local gamma and entrains V4–TEO, and which is strongly reduced by attention. We propose that the less theta-rhythmic and thereby more continuous processing of the attended stimulus serves the exploitation of this behaviorally most relevant information. The theta-rhythmic and thereby intermittent processing of the unattended stimulus likely reflects the ecologically important exploration of less relevant sources of information.

    更新日期:2018-06-13
  • Doc2-mediated superpriming supports synaptic augmentation [Neuroscience]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Renhao Xue, David A. Ruhl, Joseph S. Briguglio, Alexander G. Figueroa, Robert A. Pearce, Edwin R. Chapman

    Various forms of synaptic plasticity underlie aspects of learning and memory. Synaptic augmentation is a form of short-term plasticity characterized by synaptic enhancement that persists for seconds following specific patterns of stimulation. The mechanisms underlying this form of plasticity are unclear but are thought to involve residual presynaptic Ca2+. Here, we report that augmentation was reduced in cultured mouse hippocampal neurons lacking the Ca2+ sensor, Doc2; other forms of short-term enhancement were unaffected. Doc2 binds Ca2+ and munc13 and translocates to the plasma membrane to drive augmentation. The underlying mechanism was not associated with changes in readily releasable pool size or Ca2+ dynamics, but rather resulted from superpriming a subset of synaptic vesicles. Hence, Doc2 forms part of the Ca2+-sensing apparatus for synaptic augmentation via a mechanism that is molecularly distinct from other forms of short-term plasticity.

    更新日期:2018-06-13
  • NT3-chitosan enables de novo regeneration and functional recovery in monkeys after spinal cord injury [Neuroscience]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Jia-Sheng Rao, Can Zhao, Aifeng Zhang, Hongmei Duan, Peng Hao, Rui-Han Wei, Junkui Shang, Wen Zhao, Zuxiang Liu, Juehua Yu, Kevin S. Fan, Zhaolong Tian, Qihua He, Wei Song, Zhaoyang Yang, Yi Eve Sun, Xiaoguang Li

    Spinal cord injury (SCI) often leads to permanent loss of motor, sensory, and autonomic functions. We have previously shown that neurotrophin3 (NT3)-loaded chitosan biodegradable material allowed for prolonged slow release of NT3 for 14 weeks under physiological conditions. Here we report that NT3-loaded chitosan, when inserted into a 1-cm gap of hemisectioned and excised adult rhesus monkey thoracic spinal cord, elicited robust axonal regeneration. Labeling of cortical motor neurons indicated motor axons in the corticospinal tract not only entered the injury site within the biomaterial but also grew across the 1-cm-long lesion area and into the distal spinal cord. Through a combination of magnetic resonance diffusion tensor imaging, functional MRI, electrophysiology, and kinematics-based quantitative walking behavioral analyses, we demonstrated that NT3-chitosan enabled robust neural regeneration accompanied by motor and sensory functional recovery. Given that monkeys and humans share similar genetics and physiology, our method is likely translatable to human SCI repair.

    更新日期:2018-06-13
  • Maturation of polycistronic mRNAs by the endoribonuclease RNase Y and its associated Y-complex in Bacillus subtilis [Microbiology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Aaron DeLoughery, Jean-Benoît Lalanne, Richard Losick, Gene-Wei Li

    Endonucleolytic cleavage within polycistronic mRNAs can lead to differential stability, and thus discordant abundance, among cotranscribed genes. RNase Y, the major endonuclease for mRNA decay in Bacillus subtilis, was originally identified for its cleavage activity toward the cggR-gapA operon, an event that differentiates the synthesis of a glycolytic enzyme from its transcriptional regulator. A three-protein Y-complex (YlbF, YmcA, and YaaT) was recently identified as also being required for this cleavage in vivo, raising the possibility that it is an accessory factor acting to regulate RNase Y. However, whether the Y-complex is broadly required for RNase Y activity is unknown. Here, we used end-enrichment RNA sequencing (Rend-seq) to globally identify operon mRNAs that undergo maturation posttranscriptionally by RNase Y and the Y-complex. We found that the Y-complex is required for the majority of RNase Y-mediated mRNA maturation events and also affects riboswitch abundance in B. subtilis. In contrast, noncoding RNA maturation by RNase Y often does not require the Y-complex. Furthermore, deletion of RNase Y has more pleiotropic effects on the transcriptome and cell growth than deletions of the Y-complex. We propose that the Y-complex is a specificity factor for RNase Y, with evidence that its role is conserved in Staphylococcus aureus.

    更新日期:2018-06-13
  • Metaproteomics method to determine carbon sources and assimilation pathways of species in microbial communities [Microbiology]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Manuel Kleiner, Xiaoli Dong, Tjorven Hinzke, Juliane Wippler, Erin Thorson, Bernhard Mayer, Marc Strous

    Measurements of stable carbon isotope ratios (δ13C) are widely used in biology to address questions regarding food sources and metabolic pathways used by organisms. The analysis of these so-called stable isotope fingerprints (SIFs) for microbes involved in biogeochemical cycling and microbiota of plants and animals has led to major discoveries in environmental microbiology. Currently, obtaining SIFs for microbial communities is challenging as the available methods either only provide low taxonomic resolution, such as the use of lipid biomarkers, or are limited in throughput, such as nanoscale secondary ion MS imaging of single cells. Here we present “direct protein-SIF” and the Calis-p software package (https://sourceforge.net/projects/calis-p/), which enable high-throughput measurements of accurate δ13C values for individual species within a microbial community. We benchmark the method using 20 pure culture microorganisms and show that the method reproducibly provides SIF values consistent with gold-standard bulk measurements performed with an isotope ratio mass spectrometer. Using mock community samples, we demonstrate that SIF values can also be obtained for individual species within a microbial community. Finally, a case study of an obligate bacteria–animal symbiosis shows that direct protein-SIF confirms previous physiological hypotheses and can provide unexpected insights into the symbionts’ metabolism. This confirms the usefulness of this approach to accurately determine δ13C values for different species in microbial community samples.

    更新日期:2018-06-13
  • KDM4B protects against obesity and metabolic dysfunction [Medical Sciences]
    PNAS (IF 9.661) Pub Date : 2018-06-12
    Yingduan Cheng, Quan Yuan, Laurent Vergnes, Xin Rong, Ji Youn Youn, Jiong Li, Yongxin Yu, Wei Liu, Hua Cai, Jiandie D. Lin, Peter Tontonoz, Christine Hong, Karen Reue, Cun-Yu Wang

    Although significant progress has been made in understanding epigenetic regulation of in vitro adipogenesis, the physiological functions of epigenetic regulators in metabolism and their roles in obesity remain largely elusive. Here, we report that KDM4B (lysine demethylase 4B) in adipose tissues plays a critical role in energy balance, oxidation, lipolysis, and thermogenesis. Loss of KDM4B in mice resulted in obesity associated with reduced energy expenditure and impaired adaptive thermogenesis. Obesity in KDM4B-deficient mice was accompanied by hyperlipidemia, insulin resistance, and pathological changes in the liver and pancreas. Adipocyte-specific deletion of Kdm4b revealed that the adipose tissues were the main sites for KDM4B antiobesity effects. KDM4B directly controlled the expression of multiple metabolic genes, including Ppargc1a and Ppara. Collectively, our studies identify KDM4B as an essential epigenetic factor for the regulation of metabolic health and maintaining normal body weight in mice. KDM4B may provide a therapeutic target for treatment of obesity.

    更新日期:2018-06-13
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
化学 • 材料 期刊列表