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  • Identifying the pathways required for coping behaviours associated with sustained pain
    Nature (IF 41.577) Pub Date : 2018-12-10
    Tianwen Huang, Shing-Hong Lin, Nathalie M. Malewicz, Yan Zhang, Ying Zhang, Martyn Goulding, Robert H. LaMotte, Qiufu Ma
    更新日期:2018-12-10
  • Electric-field-tuned topological phase transition in ultrathin Na 3 Bi
    Nature (IF 41.577) Pub Date : 2018-12-10
    James L. Collins, Anton Tadich, Weikang Wu, Lidia C. Gomes, Joao N. B. Rodrigues, Chang Liu, Jack Hellerstedt, Hyejin Ryu, Shujie Tang, Sung-Kwan Mo, Shaffique Adam, Shengyuan A. Yang, Michael S. Fuhrer, Mark T. Edmonds
    更新日期:2018-12-10
  • SETD3 is an actin histidine methyltransferase that prevents primary dystocia
    Nature (IF 41.577) Pub Date : 2018-12-10
    Alex W. Wilkinson, Jonathan Diep, Shaobo Dai, Shuo Liu, Yaw Shin Ooi, Dan Song, Tie-Mei Li, John R. Horton, Xing Zhang, Chao Liu, Darshan V. Trivedi, Katherine M. Ruppel, José G. Vilches-Moure, Kerriann M. Casey, Justin Mak, Tina Cowan, Joshua E. Elias, Claude M. Nagamine, James A. Spudich, Xiaodong Cheng, Jan E. Carette, Or Gozani

    For over fifty years, the methylation of mammalian actin at histidine 73 (actin-H73me) has been known to exist1. Beyond mammals, we find that actin-H73me is conserved in several additional model animal and plant organisms. Despite the pervasiveness of H73me, its function is enigmatic, and the enzyme generating this modification is unknown. Here, we identify SETD3 (SET domain protein 3) as the physiological actin histidine 73 methyltransferase. Structural studies reveal that an extensive network of interactions clamps the actin peptide on the SETD3 surface to properly orient H73 within the catalytic pocket and to facilitate methyl transfer. H73me reduces the nucleotide exchange rate on actin monomers and modestly accelerates actin filament assembly. Mice lacking SETD3 show complete loss of actin-H73me in multiple tissues, and quantitative proteomics singles out actin-H73 as the principal physiological SETD3 substrate. SETD3-deficient female mice have severely decreased litter sizes owing to primary maternal dystocia that is refractory to ecbolic induction agents. Further, depletion of SETD3 impairs signal-induced contraction in primary human uterine smooth muscle cells. Together, our results identify the first mammalian protein histidine methyltransferase and uncover a pivotal role for SETD3 and actin-H73me in the regulation of smooth muscle contractility. Our data also support the broader hypothesis that protein histidine methylation acts as a common regulatory mechanism.

    更新日期:2018-12-10
  • Urban isolation and daytime neighborhood social composition from Twitter data [Letters (Online Only)]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Julie Vallée

    In a recent paper in PNAS, Wang et al. (1) investigate the key question of urban isolation in light of daily mobility. Urban isolation may actually be mitigated by individuals spending much of their everyday lives in neighborhoods where social composition and urban opportunities widely diverge from their home neighborhoods. From a large dataset composed of 128 million geotagged micromessages called tweets, sent by 392,000 Twitter users living in the 50 most populous American cities, the authors overcome the pervasive spatial assumption that social interactions are limited to home neighborhoods. However, they made one temporal assumption that merits further discussion. They classified neighborhoods into …

    更新日期:2018-12-08
  • Reply to Vallee: Different questions for different data [Letters (Online Only)]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Qi Wang, Nolan Edward Phillips, Mario L. Small, Robert J. Sampson

    Vallée (1) argues that “daily changes in neighborhood social composition” should be taken into account when analyzing social isolation. We agree that changes in neighborhoods’ compositions are important and have been largely omitted from research on neighborhood effects and activity spaces. We take this opportunity to clarify an issue and offer a commentary.

    更新日期:2018-12-08
  • Improving vaccines against Streptococcus pneumoniae using synthetic glycans [Medical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Paulina Kaplonek, Naeem Khan, Katrin Reppe, Benjamin Schumann, Madhu Emmadi, Marilda P. Lisboa, Fei-Fei Xu, Adam D. J. Calow, Sharavathi G. Parameswarappa, Martin Witzenrath, Claney L. Pereira, Peter H. Seeberger

    Streptococcus pneumoniae remains a deadly disease in small children and the elderly even though conjugate and polysaccharide vaccines based on isolated capsular polysaccharides (CPS) are successful. The most common serotypes that cause infection are used in vaccines around the world, but differences in geographic and demographic serotype distribution compromises protection by leading vaccines. The medicinal chemistry approach to glycoconjugate vaccine development has helped to improve the stability and immunogenicity of synthetic vaccine candidates for several serotypes leading to the induction of higher levels of specific protective antibodies. Here, we show that marketed CPS-based glycoconjugate vaccines can be improved by adding synthetic glycoconjugates representing serotypes that are not covered by existing vaccines. Combination (coformulation) of synthetic glycoconjugates with the licensed vaccines Prevnar13 (13-valent) and Synflorix (10-valent) yields improved 15- and 13-valent conjugate vaccines, respectively, in rabbits. A pentavalent semisynthetic glycoconjugate vaccine containing five serotype antigens (sPCV5) elicits antibodies with strong in vitro opsonophagocytic activity. This study illustrates that synthetic oligosaccharides can be used in coformulation with both isolated polysaccharide glycoconjugates to expand protection from existing vaccines and each other to produce precisely defined multivalent conjugated vaccines.

    更新日期:2018-12-08
  • Fluctuating selection on migrant adaptive sodium transporter alleles in coastal Arabidopsis thaliana [Plant Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Silvia Busoms, Pirita Paajanen, Sarah Marburger, Sian Bray, Xin-Yuan Huang, Charlotte Poschenrieder, Levi Yant, David E. Salt

    Stressors such as soil salinity and dehydration are major constraints on plant growth, causing worldwide crop losses. Compounding these insults, increasing climate volatility requires adaptation to fluctuating conditions. Salinity stress responses are relatively well understood in Arabidopsis thaliana, making this system suited for the rapid molecular dissection of evolutionary mechanisms. In a large-scale genomic analysis of Catalonian A. thaliana, we resequenced 77 individuals from multiple salinity gradients along the coast and integrated these data with 1,135 worldwide A. thaliana genomes for a detailed understanding of the demographic and evolutionary dynamics of naturally evolved salinity tolerance. This revealed that Catalonian varieties adapted to highly fluctuating soil salinity are not Iberian relicts but instead have immigrated to this region more recently. De novo genome assembly of three allelic variants of the high-affinity K+ transporter (HKT1;1) locus resolved structural variation between functionally distinct alleles undergoing fluctuating selection in response to seasonal changes in soil salinity. Plants harboring alleles responsible for low root expression of HKT1;1 and consequently high leaf sodium (HKT1;1HLS) were migrants that have moved specifically into areas where soil sodium levels fluctuate widely due to geography and rainfall variation. We demonstrate that the proportion of plants harboring HKT1;1HLS alleles correlates with soil sodium level over time, HKT1;1HLS-harboring plants are better adapted to intermediate levels of salinity, and the HKT1;1HLS allele clusters with high-sodium accumulator accessions worldwide. Together, our evidence suggests that HKT1;1 is under fluctuating selection in response to climate volatility and is a worldwide determinant in adaptation to saline conditions.

    更新日期:2018-12-08
  • Malleable folding of coiled-coils regulates kinesin-3 dimerization [Commentaries]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Jawdat Al-Bassam, Stanley Nithianantham

    Microtubules (MTs) form polarized intracellular fibers inside eukaryotic cells that organize the cytoplasm, form tracks for long-range vesicle transport, and generate forces to align and segregate chromosomes during cell division. The discovery of conventional kinesin (termed kinesin-1) over three decades ago revealed a vast superfamily dedicated to transporting a variety of intracellular cargos or generating forces in a variety of cellular functions (1). Kinesins are now organized into 14 subfamilies which share class-conserved motor domains that promote directional motility or MT dynamic polymerization/depolymerization by adenosine 3,5 triphosphate (ATP) hydrolysis-driven cyclical binding and release from the MT lattice (2, 3). The majority of kinesin subfamilies oligomerize into dimers or tetramers via coiled-coil folding of an α-helical region named the neck coil (NC), which lies in close proximity to the motor domain (4, 5). The NC dimerizes motor domains and couples their conformational changes driven by ATP hydrolysis via a connecting element termed the neck linkers (NLs) (6). Kinesins utilize these elements to couple dual-motor domains to undertake alternating steps in a persistent hand-over-hand walking mechanism along MTs (7). In the kinesin-1 subfamily, cargo-binding domains located at the opposite end of the polypeptide directly inhibit the motor domains to prevent wasteful motility and ATP hydrolysis in the absence of cargo (8).

    更新日期:2018-12-08
  • Approaching the adiabatic timescale with machine learning [Physics]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Bryce M. Henson, Dong K. Shin, Kieran F. Thomas, Jacob A. Ross, Michael R. Hush, Sean S. Hodgman, Andrew G. Truscott

    The control and manipulation of quantum systems without excitation are challenging, due to the complexities in fully modeling such systems accurately and the difficulties in controlling these inherently fragile systems experimentally. For example, while protocols to decompress Bose–Einstein condensates (BECs) faster than the adiabatic timescale (without excitation or loss) have been well developed theoretically, experimental implementations of these protocols have yet to reach speeds faster than the adiabatic timescale. In this work, we experimentally demonstrate an alternative approach based on a machine-learning algorithm which makes progress toward this goal. The algorithm is given control of the coupled decompression and transport of a metastable helium condensate, with its performance determined after each experimental iteration by measuring the excitations of the resultant BEC. After each iteration the algorithm adjusts its internal model of the system to create an improved control output for the next iteration. Given sufficient control over the decompression, the algorithm converges to a solution that sets the current speed record in relation to the adiabatic timescale, beating out other experimental realizations based on theoretical approaches. This method presents a feasible approach for implementing fast-state preparations or transformations in other quantum systems, without requiring a solution to a theoretical model of the system. Implications for fundamental physics and cooling are discussed.

    更新日期:2018-12-08
  • Combined molecular dynamics and neural network method for predicting protein antifreeze activity [Biophysics and Computational Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Daniel J. Kozuch, Frank H. Stillinger, Pablo G. Debenedetti

    Antifreeze proteins (AFPs) are a diverse class of proteins that depress the kinetically observable freezing point of water. AFPs have been of scientific interest for decades, but the lack of an accurate model for predicting AFP activity has hindered the logical design of novel antifreeze systems. To address this, we perform molecular dynamics simulation for a collection of well-studied AFPs. By analyzing both the dynamic behavior of water near the protein surface and the geometric structure of the protein, we introduce a method that automatically detects the ice binding face of AFPs. From these data, we construct a simple neural network that is capable of quantitatively predicting experimentally observed thermal hysteresis from a trio of relevant physical variables. The model’s accuracy is tested against data for 17 known AFPs and 5 non-AFP controls.

    更新日期:2018-12-08
  • MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias [Neuroscience]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Alexander S. Brown, Pratap Meera, Banu Altindag, Ravi Chopra, Emma M. Perkins, Sharan Paul, Daniel R. Scoles, Eric Tarapore, Jessica Magri, Haoran Huang, Mandy Jackson, Vikram G. Shakkottai, Thomas S. Otis, Stefan M. Pulst, Scott X. Atwood, Anthony E. Oro

    The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.

    更新日期:2018-12-08
  • Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue [Medical Sciences]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Fabio Zanini, Makeda L. Robinson, Derek Croote, Malaya Kumar Sahoo, Ana Maria Sanz, Eliana Ortiz-Lasso, Ludwig Luis Albornoz, Fernando Rosso, Jose G. Montoya, Leslie Goo, Benjamin A. Pinsky, Stephen R. Quake, Shirit Einav

    Dengue virus (DENV) infection can result in severe complications. However, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that contain DENV RNA in vivo. Accordingly, there are currently no biomarkers predictive of progression to severe dengue (SD). Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here, we applied virus-inclusive single-cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls and to characterize distinct leukocyte subtypes that harbor viral RNA (vRNA). Multiple IFN response genes, particularly MX2 in naive B cells and CD163 in CD14+ CD16+ monocytes, were up-regulated in a cell-specific manner before progression to SD. The majority of vRNA-containing cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and various antiviral genes, followed by monocytes. Bystander, non-vRNA–containing B cells also demonstrated immune activation, and IgG1 plasmablasts from two patients exhibited clonal expansions. Lastly, assembly of the DENV genome sequence revealed diversity at unexpected sites. This study presents a multifaceted molecular elucidation of natural dengue infection in humans with implications for any tissue and viral infection and proposes candidate biomarkers for prediction of SD.

    更新日期:2018-12-08
  • Rethinking pneumonia: A paradigm shift with practical utility [Commentaries]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Rishi Chanderraj, Robert P. Dickson

    We associate the founders of germ theory, Louis Pasteur and Robert Koch, with a dusty, bygone age: gray beards, sepia tones, and antiquated techniques. However, in their own time, both Pasteur and Koch were what we would now call “early adopters,” embracing and advancing the leading edge of available technology in their efforts to identify microbes. Among his many innovations, Pasteur invented anaerobic cultivation and derived a variety of selective culture media. Koch pioneered the use of solid growth media, developed the techniques of pure culture to isolate individual species, and was the first to apply oil-immersion microscopy to respiratory specimens. [Rudolph Virchow, then the revered “Pope of Medicine,” was an old-guard skeptic. When presented with Koch’s oil-immersion discoveries, he scoffed that “What I can not see with my dry lens, I do not need to see” (1).] Though rightfully celebrated for their own scientific genius, both Pasteur and Koch were beneficiaries of recent advances in technology and both propelled their field forward with their own methodological innovations.

    更新日期:2018-12-08
  • Role of gene body methylation in acclimatization and adaptation in a basal metazoan [Genetics]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Groves Dixon, Yi Liao, Line K. Bay, Mikhail V. Matz

    Gene body methylation (GBM) has been hypothesized to modulate responses to environmental change, including transgenerational plasticity, but the evidence thus far has been lacking. Here we show that coral fragments reciprocally transplanted between two distant reefs respond predominantly by increase or decrease in genome-wide GBM disparity: The range of methylation levels between lowly and highly methylated genes becomes either wider or narrower. Remarkably, at a broad functional level this simple adjustment correlated very well with gene expression change, reflecting a shifting balance between expressions of environmentally responsive and housekeeping genes. In our experiment, corals in a lower-quality habitat up-regulated genes involved in environmental responses, while corals in a higher-quality habitat invested more in housekeeping genes. Transplanted fragments showing closer GBM match to local corals attained higher fitness characteristics, which supports GBM’s role in acclimatization. Fixed differences in GBM between populations did not align with plastic GBM changes and were mostly observed in genes with elevated FST, which suggests that they arose predominantly through genetic divergence. However, we cannot completely rule out transgenerational inheritance of acquired GBM states.

    更新日期:2018-12-08
  • Profiling proliferative cells and their progeny in damaged murine hearts [Cell Biology]
    PNAS (IF 9.504) Pub Date : 2018-12-07
    Kai Kretzschmar, Yorick Post, Marie Bannier-Hélaouët, Andrea Mattiotti, Jarno Drost, Onur Basak, Vivian S. W. Li, Maaike van den Born, Quinn D. Gunst, Danielle Versteeg, Lieneke Kooijman, Stefan van der Elst, Johan H. van Es, Eva van Rooij, Maurice J. B. van den Hoff, Hans Clevers

    The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

    更新日期:2018-12-08
  • Duxbling Stem Cells Meet Tumorigenesis
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Beat W. Schäfer
    更新日期:2018-12-07
  • Human Intestinal Organoids Maintain Self-Renewal Capacity and Cellular Diversity in Niche-Inspired Culture Condition
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Masayuki Fujii, Mami Matano, Kohta Toshimitsu, Ai Takano, Yohei Mikami, Shingo Nishikori, Shinya Sugimoto, Toshiro Sato
    更新日期:2018-12-07
  • Esrrb Unlocks Silenced Enhancers for Reprogramming to Naive Pluripotency
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Kenjiro Adachi, Wolfgang Kopp, Guangming Wu, Sandra Heising, Boris Greber, Martin Stehling, Marcos J. Araúzo-Bravo, Stefan T. Boerno, Bernd Timmermann, Martin Vingron, Hans R. Schöler
    更新日期:2018-12-07
  • Getting Past HSC Security: Cyclosporine H Gives Lentiviruses an Entry Pass
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Daniel E. Bauer, Sung-Yun Pai

    In this issue ofCell Stem Cell,Petrillo et al. (2018)improve lentiviral transduction of hematopoietic stem cells (HSCs) by using cyclosporine H to relieve viral entry restriction by interferon-induced transmembrane protein 3 (IFITM3). This finding promises to enhance the efficiency ofex vivotherapeutic gene transfer and gene editing of HSCs.

    更新日期:2018-12-07
  • Does Adult Neurogenesis Persist in the Human Hippocampus?
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Mercedes F. Paredes, Shawn F. Sorrells, Arantxa Cebrian-Silla, Kadellyn Sandoval, Dashi Qi, Kevin W. Kelley, David James, Simone Mayer, Julia Chang, Kurtis I. Auguste, Edward F. Chang, Antonio J. Gutierrez Martin, Arnold R. Kriegstein, Gary W. Mathern, Michael C. Oldham, Eric J. Huang, Jose Manuel Garcia-Verdugo, Zhengang Yang, Arturo Alvarez-Buylla

    Whether new neurons are added to the human brain in childhood or adulthood is of widespread interest. Our recent observations suggest that newborn neurons in the adult human hippocampus (HP) are absent or very rare (Sorrells et al., 2018). A subsequent study proposes that large numbers of new neurons continue to be produced in the adult human HP (Boldrini et al., 2018Boldrini M.Fulmore C.A.Tartt A.N.Simeon L.R.Pavlova I.Poposka V.Rosoklija G.B.Stankov A.Arango V.Dwork A.J.et al.Human hippocampal neurogenesis persists throughout aging.Cell Stem Cell.2018;22:589-599.e5AbstractFull TextFull Text PDFPubMedScopus (49)Google Scholar). This has stimulated discussion and re-appraisal of this topic. Human studies have intractable caveats, making it important to interpret both positive and negative observations, including our own work, with a critical lens. A recent minireview (Kempermann et al., 2018Kempermann G.Gage F.H.Aigner L.Song H.Curtis M.A.Thuret S.Kuhn H.G.Jessberger S.Frankland P.W.Cameron H.A.et al.Human adult neurogenesis: evidence and remaining questions.Cell Stem Cell.2018;23:25-30AbstractFull TextFull Text PDFScopus (0)Google Scholar) attempts to offer a perspective on the field and discusses the challenges of working with human tissue. Yet it fails to critically evaluate the evidence for adult human hippocampal neurogenesis and how, for example, halogenated thymidine analogs or carbon 14 (14C) birthdating are susceptible to false positives or sample processing effects (Extended Discussion inSorrells et al., 2018Sorrells S.F.Paredes M.F.Cebrian-Silla A.Sandoval K.Qi D.Kelley K.W.James D.Mayer S.Chang J.Auguste K.I.et al.Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.Nature.2018;555:377-381CrossrefPubMedScopus (79)Google Scholar). Human Hippocampal Neurogenesis Persists throughout AgingBoldrini et al.Cell Stem CellApril 05, 2018In BriefFull-TextPDFHuman Adult Neurogenesis: Evidence and Remaining QuestionsKempermann et al.Cell Stem CellApril 19, 2018In BriefIn BriefFull-TextPDFConsiderations for Assessing the Extent of Hippocampal Neurogenesis in the Adult and Aging Human BrainTartt et al.Cell Stem CellDecember 06, 2018In BriefIn BriefFull-TextPDF

    更新日期:2018-12-07
  • 更新日期:2018-12-07
  • Restoring Fertility with Human Induced Pluripotent Stem Cells: Are We There Yet?
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Joanna J. Gell, Amander T. Clark
    更新日期:2018-12-07
  • Histone Demethylases KDM4B and KDM6B Promote Osteogenic Differentiation of Human MSCs
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Ling Ye, Zhipeng Fan, Bo Yu, Jia Chang, Khalid Al Hezaimi, Xuedong Zhou, No-Hee Park, Cun-Yu Wang
    更新日期:2018-12-07
  • Transcription Factors Drive Tet2-Mediated Enhancer Demethylation to Reprogram Cell Fate
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Jose Luis Sardina, Samuel Collombet, Tian V. Tian, Antonio Gómez, Bruno Di Stefano, Clara Berenguer, Justin Brumbaugh, Ralph Stadhouders, Carolina Segura-Morales, Marta Gut, Ivo G. Gut, Simon Heath, Sergi Aranda, Luciano Di Croce, Konrad Hochedlinger, Denis Thieffry, Thomas Graf
    更新日期:2018-12-07
  • Considerations for Assessing the Extent of Hippocampal Neurogenesis in the Adult and Aging Human Brain
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Alexandria N. Tartt, Camille A. Fulmore, Yan Liu, Gorazd B. Rosoklija, Andrew J. Dwork, Victoria Arango, René Hen, J. John Mann, Maura Boldrini

    Adult hippocampal neurogenesis (AHN) is implicated in brain adaptations and disease pathogenesis. A seminal study showed adult-born neurons in the subgranular zone (SGZ) of the dentate gyrus (DG) in cancer patients 58–72 years of age, detecting bromodeoxyuridine co-localization with neuronal markers (Eriksson et al., 1998). Subsequently, human AHN was reported using immunohistochemistry targeting markers expressed by neuronal cells at different maturational stages,in situhybridization (ISH), and14C decay-defined neuronal age (Spalding et al., 2013Spalding K.L.Bergmann O.Alkass K.Bernard S.Salehpour M.Huttner H.B.Boström E.Westerlund I.Vial C.Buchholz B.A.et al.Dynamics of hippocampal neurogenesis in adult humans.Cell.2013;153:1219-1227AbstractFull TextFull Text PDFPubMedScopus (690)Google Scholar). Detection of AHN markers is dependent on methodological approaches such as brain tissue processing and fixation, postmortem interval, and other factors affecting tissue antigenicity and preservation of proteins and mRNAs (Kempermann et al., 2018Kempermann G.Gage F.H.Aigner L.Song H.Curtis M.A.Thuret S.Kuhn H.G.Jessberger S.Frankland P.W.Cameron H.A.et al.Human adult neurogenesis: evidence and remaining questions.Cell Stem Cell.2018;23:25-30AbstractFull TextFull Text PDFScopus (0)Google Scholar). This discussion intends to clarify the divergent findings between our group (Boldrini et al., 2018Boldrini M.Fulmore C.A.Tartt A.N.Simeon L.R.Pavlova I.Poposka V.Rosoklija G.B.Stankov A.Arango V.Dwork A.J.et al.Human hippocampal neurogenesis persists throughout aging.Cell Stem Cell.2018;22:589-599.e5AbstractFull TextFull Text PDFPubMedScopus (49)Google Scholar) and the Alvarez-Buylla group (Sorrells et al., 2018Sorrells S.F.Paredes M.F.Cebrian-Silla A.Sandoval K.Qi D.Kelley K.W.James D.Mayer S.Chang J.Auguste K.I.et al.Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.Nature.2018;555:377-381CrossrefPubMedScopus (79)Google Scholar,Paredes et al., 2018Paredes M.F.Sorrells S.F.Cebrian-Silla A.Sandoval K.Qi D.Kelley K.W.James D.Mayer S.Chang J.Auguste K.I.et al.Does adult neurogenesis persist in the human hippocampus?.Cell Stem Cell.2018;23(this issue):780-781Google Scholar) and elucidate key factors surrounding conflicting conclusions. Human Hippocampal Neurogenesis Persists throughout AgingBoldrini et al.Cell Stem CellApril 05, 2018In BriefFull-TextPDFHuman Adult Neurogenesis: Evidence and Remaining QuestionsKempermann et al.Cell Stem CellApril 19, 2018In BriefIn BriefFull-TextPDFDoes Adult Neurogenesis Persist in the Human Hippocampus?Paredes et al.Cell Stem CellDecember 06, 2018In BriefIn BriefFull-TextPDF

    更新日期:2018-12-07
  • Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis
    Cell Stem Cell (IF 23.29) Pub Date : 2018-12-06
    Zhigang Cai, Jonathan J. Kotzin, Baskar Ramdas, Sisi Chen, Sai Nelanuthala, Lakshmi Reddy Palam, Ruchi Pandey, Raghuveer Singh Mali, Yan Liu, Mark R. Kelley, George Sandusky, Morvarid Mohseni, Adam Williams, Jorge Henao-Mejia, Reuben Kapur
    更新日期:2018-12-07
  • Emergence and Spread of Basal Lineages of Yersinia pestis during the Neolithic Decline
    Cell (IF 31.398) Pub Date : 2018-12-06
    Nicolás Rascovan, Karl-Göran Sjögren, Kristian Kristiansen, Rasmus Nielsen, Eske Willerslev, Christelle Desnues, Simon Rasmussen
    更新日期:2018-12-07
  • The Human RNA-Binding Proteome and Its Dynamics during Translational Arrest
    Cell (IF 31.398) Pub Date : 2018-12-06
    Jakob Trendel, Thomas Schwarzl, Rastislav Horos, Ananth Prakash, Alex Bateman, Matthias W. Hentze, Jeroen Krijgsveld
    更新日期:2018-12-07
  • Engineering Epigenetic Regulation Using Synthetic Read-Write Modules
    Cell (IF 31.398) Pub Date : 2018-12-06
    Minhee Park, Nikit Patel, Albert J. Keung, Ahmad S. Khalil
    更新日期:2018-12-07
  • Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment
    Cell (IF 31.398) Pub Date : 2018-12-06
    Erin M. Gibson, Surya Nagaraja, Alfonso Ocampo, Lydia T. Tam, Lauren S. Wood, Praveen N. Pallegar, Jacob J. Greene, Anna C. Geraghty, Andrea K. Goldstein, Lijun Ni, Pamelyn J. Woo, Ben A. Barres, Shane Liddelow, Hannes Vogel, Michelle Monje
    更新日期:2018-12-07
  • Unveiling the Role of the Most Impactful Cardiovascular Risk Locus through Haplotype Editing
    Cell (IF 31.398) Pub Date : 
    Valentina Lo Sardo, Pavel Chubukov, William Ferguson, Aditya Kumar, Evan L. Teng, Michael Duran, Lei Zhang, Gregory Cost, Adam J. Engler, Fyodor Urnov, Eric J. Topol, Ali Torkamani, Kristin K. Baldwin
    更新日期:2018-12-07
  • News at a glance
    Science (IF 41.058) Pub Date : 2018-12-07
    American Association for the Advancement of Science

    In science news around the world, Brazil withdraws its offer to host the 2019 United Nations Climate Change Conference, signaling a shift in the country's stance on global warming. OSIRIS-REx, NASA's asteroid sample return mission, arrives at its target, a half-kilometer-wide asteroid called Bennu, in search of clues to the solar system's formation. Astrophysicist and science communicator Neil deGrasse Tyson comes under investigation because of sexual misconduct allegations from three women. Italy's health minister, whose party campaigned against vaccinations, fires 30 experts serving on the National Health Council, sparking fears that she could replace them with vaccine skeptics. The U.S. National Oceanic and Atmospheric Administration agrees to allow oil exploration off the Atlantic coast using seismic surveys whose loud blasts of sound have been shown elsewhere to injure or disrupt dolphins and whales. Measles cases worldwide rise 31% in 2017 compared with 2016.

    更新日期:2018-12-07
  • What now for human genome editing?
    Science (IF 41.058) Pub Date : 2018-12-07
    Jon Cohen

    In the wake of He Jiankui's shocking announcement that his lab created the first germline-edited babies, the scientific community has done great soul searching about how this happened—and how they might prevent others from using CRISPR again to edit embryos and then implant them in women. He's own behavior has been thoroughly scrutinized, and researchers who met with him before he described the details of his work last week at a Hong Kong, China, meeting said he seemed defiant and even unaware of the importance of sharing his data at the gathering. Although many countries already prohibit and even outlaw germline editing of embryos, there's a push to create an international body that can evaluate any future proposals, and there's widespread agreement that technology is not yet mature enough to do this for any reason. What's more, questions still remain about whether any medical conditions justify germline editing as another alternative exists: preimplantation genetic diagnosis (PGD) used during in vitro fertilization. Others counter that PGD has its own limitations, and that germline editing could meet important, unmet medical needs.

    更新日期:2018-12-07
  • For China, a CRISPR first goes too far
    Science (IF 41.058) Pub Date : 2018-12-07
    Dennis Normile

    The report of the live birth of twin baby girls with genetically engineered genomes caused an uproar around the world. Some of the criticism focused on China's allegedly permissive research ethics. Chinese scientists resent that characterization, but the incident has set off debate within the country over its regulation of biomedical research. The researcher, He Jiankui of the Southern University of Science and Technology in Shenzhen, China, allegedly violated a provision in a regulation that came into effect in 2003, long before gene editing became a common research tool. China's scientists and ethicists are now calling for new or revised regulations. But some researchers fear a backlash provoked by one group that deliberately ignored existing regulations could result in new rules that will burden even ethical scientists.

    更新日期:2018-12-07
  • Uncertainty boosts Brexit jitters for U.K. scientists
    Science (IF 41.058) Pub Date : 2018-12-07
    Erik Stokstad

    U.K. scientists dreading the country's impending departure from the European Union, known as Brexit, now face possible outcomes ranging from undesirable to potentially disastrous. On 11 December, Parliament will vote on a withdrawal agreement that lays out the terms of a costly but smooth departure from the European Union, starting in March 2019. If the agreement is rejected, the United Kingdom could crash out instead, triggering chaos at the border, food shortages, and economic hardship. A no-deal exit would also immediately void many research agreements. Regardless of how the United Kingdom departs, it will have to negotiate new science agreements with the European Union and come up with a new EU immigration policy. A long-awaited government white paper on immigration is expected to be published this month. Two and a half years after the divisive popular referendum that launched the Brexit process, some scientists hold out hope for a reprieve: A growing number of politicians are agitating for a second referendum that might reverse the first one.

    更新日期:2018-12-07
  • Universal flu vaccine is ‘an alchemist's dream’
    Science (IF 41.058) Pub Date : 2018-12-07
    Jon Cohen

    The ever-mutating influenza virus means the vaccine must constantly be changed. What's more, the so-called seasonal vaccine isn't particularly effective, with only 20% to 60% of people who receive it dodging illness because their immune systems have been properly trained. At an unusual meeting last month in Nashville, leading flu researchers met to discuss the obstacles to making a "universal" flu vaccine that works against the majority of strains that infect humans and lasts for years, if not a lifetime. One problem is that the seasonal vaccines aim to trigger antibodies against the top part, or head, of the hemagglutinin protein—one of two proteins that stud the surface of the virus. But that portion mutates frequently, and studies have shown that antibodies against the other surface protein, neuraminidase, better correlate with protection. Many experimental vaccines have attempted to exploit the fact that the bottom part of the hemagglutinin protein does not change much from strain to strain, but those preparations haven't proved potent enough. There's also a problem called imprinting, in which the first flu virus or vaccine a child receives can influence how they respond to all other flu infections for life. The meeting goers discussed many novel approaches to move the field forward.

    更新日期:2018-12-07
  • Demotion dismays researchers at storied Danish museum
    Science (IF 41.058) Pub Date : 2018-12-07
    Gretchen Vogel

    Over the past decade, the 40 researchers at the Natural History Museum of Denmark in Copenhagen have published more than 100 papers in Nature and Science, putting it among the world's top research museums. But budget pressures are forcing a reorganization that will split museum research from curation and outreach, dismaying the museum's scientists. Several of the most prominent group leaders say they may leave. Last month, the university announced that, as of 1 January 2019, the museum will be downsized, becoming a unit within the biology department. Roughly half of the 40 researchers will remain part of that unit; they will give up some of their research to focus on curation and outreach. The other half will become full faculty within the biology department—including the geologists and astrophysicists. These scientists will lose their affiliation with the museum and replace their curatorial roles with increased teaching duties. Researchers say divorcing the scientists' dual roles will curtail the fruitful way that curation pollinates research.

    更新日期:2018-12-07
  • Taking aim
    Science (IF 41.058) Pub Date : 2018-12-07
    Meredith Wadman

    Rebecca Cunningham of the University of Michigan in Ann Arbor became acquainted with guns at a tender age: When she was 5 years old, her mother kicked out her violent husband, who had beaten her and threatened to kill her. And she bought a gun. Today, Cunningham, who once watched her mother tuck that pistol in her purse as she headed to the shooting range, is directing the largest gun research grant that the U.S. National Institutes of Health (NIH) has awarded in at least 30 years. With $4.9 million from NIH's child health institute and a team of 27 researchers at 12 institutions, she is on a mission to jump-start gun injury research on a population as vulnerable as she once was: U.S. children and teenagers, for whom guns are the second-leading cause of death.

    更新日期:2018-12-07
  • Barrier(less) islands
    Science (IF 41.058) Pub Date : 2018-12-07
    Bart Kahr, Michael D. Ward

    Crystal nuclei—the minute collections of molecules needed to spark crystal growth—are small, short-lived, and generally unobserved. Classical nucleation theory, a model for the earliest stages of crystallization, is an accounting of the free-energy debits for creating an interface between crystals and the medium from which they grow, and the free energy credits for enlarging the interior of the crystal (1, 2). On page 1135 of this issue, Chen et al. (3) report the growth of one-dimensional (1D) peptide crystals in rows on crystalline substrates, which subsequently assemble laterally row by row into films (and ultimately 2D arrays) (see the figure). Growth rates along and perpendicular to the rows, measured by scanning probe microscopy, support the absence of an activation barrier that typically must be surmounted to overcome the surface energy. This unexpected challenge to the classical nucleation theory arises from high-resolution imaging that captures kinetic measurements for very small molecular aggregates (4). No matter the sophistication of our models, looking ever more closely at growing crystals often reveals unanticipated mechanisms (5).

    更新日期:2018-12-07
  • Climate change and marine mass extinction
    Science (IF 41.058) Pub Date : 2018-12-07
    Lee Kump

    Voluminous emissions of carbon dioxide to the atmosphere, rapid global warming, and a decline in biodiversity—the storyline is modern, but the setting is ancient: The end of the Permian Period, some 252 million years ago. For the end-Permian, the result was catastrophic: the greatest loss of plant and animal life in Earth history (1). Understanding the details of how this mass extinction played out is thus crucial to its use as an analog for our future. On page 1130 of this issue, Penn et al. (2) add an intriguing clue: The extinction was most severe at high latitudes. Using a state-of-the-art climate model that was interpreted in terms of physiological stress, the authors further identify the killer as hypoxia, which was brought on by warm temperatures and ocean deoxygenation.

    更新日期:2018-12-07
  • Bioenergetics through thick and thin
    Science (IF 41.058) Pub Date : 2018-12-07
    Eric A. Schon

    The cells in all biological systems are composed of a limited number of molecular constituents, mainly proteins, nucleic acids, carbohydrates, and lipids. Of these, lipids tend to receive the shortest shrift, as they are typically considered to be merely the building blocks of membranes that provide a scaffold in which the “important” molecules, such as enzymes or signaling proteins, reside. In recent years, and with the advent of advanced lipidomics techniques, we have learned that “a lipid is a lipid is a lipid” is simply not true, and that the lipid composition of membranes can have profound effects on the behavior and activity of its resident macromolecules. For example, some lipids, such as members of the phosphatidylinositol family, are important signaling molecules. However, what is less appreciated is that the physical composition of lipid membranes can have profound effects on cellular behavior as well. On page 1186 of this issue, Budin et al. (1) use the Gram-negative bacterium Escherichia coli and the budding yeast Saccharomyces cerevisiae as model systems to show that the fluidity of a membrane, as determined by its lipid composition, can have huge effects on the efficiency of aerobic energy production (respiration) by the highly hydrophobic, membrane-embedded, oxidative phosphorylation (OxPhos) system.

    更新日期:2018-12-07
  • Semiconducting polymer blends that exhibit stable charge transport at high temperatures
    Science (IF 41.058) Pub Date : 2018-12-07
    Aristide Gumyusenge, Dung T. Tran, Xuyi Luo, Gregory M. Pitch, Yan Zhao, Kaelon A. Jenkins, Tim J. Dunn, Alexander L. Ayzner, Brett M. Savoie, Jianguo Mei

    Although high-temperature operation (i.e., beyond 150°C) is of great interest for many electronics applications, achieving stable carrier mobilities for organic semiconductors at elevated temperatures is fundamentally challenging. We report a general strategy to make thermally stable high-temperature semiconducting polymer blends, composed of interpenetrating semicrystalline conjugated polymers and high glass-transition temperature insulating matrices. When properly engineered, such polymer blends display a temperature-insensitive charge transport behavior with hole mobility exceeding 2.0 cm2/V·s across a wide temperature range from room temperature up to 220°C in thin-film transistors.

    更新日期:2018-12-07
  • Building two-dimensional materials one row at a time: Avoiding the nucleation barrier
    Science (IF 41.058) Pub Date : 2018-12-07
    Jiajun Chen, Enbo Zhu, Juan Liu, Shuai Zhang, Zhaoyang Lin, Xiangfeng Duan, Hendrik Heinz, Yu Huang, James J. De Yoreo

    Assembly of two-dimensional (2D) molecular arrays on surfaces produces a wide range of architectural motifs exhibiting unique properties, but little attention has been given to the mechanism by which they nucleate. Using peptides selected for their binding affinity to molybdenum disulfide, we investigated nucleation of 2D arrays by molecularly resolved in situ atomic force microscopy and compared our results to molecular dynamics simulations. The arrays assembled one row at a time, and the nuclei were ordered from the earliest stages and formed without a free energy barrier or a critical size. The results verify long-standing but unproven predictions of classical nucleation theory in one dimension while revealing key interactions underlying 2D assembly.

    更新日期:2018-12-07
  • A general reinforcement learning algorithm that masters chess, shogi, and Go through self-play
    Science (IF 41.058) Pub Date : 2018-12-07
    David Silver, Thomas Hubert, Julian Schrittwieser, Ioannis Antonoglou, Matthew Lai, Arthur Guez, Marc Lanctot, Laurent Sifre, Dharshan Kumaran, Thore Graepel, Timothy Lillicrap, Karen Simonyan, Demis Hassabis

    The game of chess is the longest-studied domain in the history of artificial intelligence. The strongest programs are based on a combination of sophisticated search techniques, domain-specific adaptations, and handcrafted evaluation functions that have been refined by human experts over several decades. By contrast, the AlphaGo Zero program recently achieved superhuman performance in the game of Go by reinforcement learning from self-play. In this paper, we generalize this approach into a single AlphaZero algorithm that can achieve superhuman performance in many challenging games. Starting from random play and given no domain knowledge except the game rules, AlphaZero convincingly defeated a world champion program in the games of chess and shogi (Japanese chess), as well as Go.

    更新日期:2018-12-07
  • Room-temperature cycling of metal fluoride electrodes: Liquid electrolytes for high-energy fluoride ion cells
    Science (IF 41.058) Pub Date : 2018-12-07
    Victoria K. Davis, Christopher M. Bates, Kaoru Omichi, Brett M. Savoie, Nebojša Momčilović, Qingmin Xu, William J. Wolf, Michael A. Webb, Keith J. Billings, Nam Hawn Chou, Selim Alayoglu, Ryan K. McKenney, Isabelle M. Darolles, Nanditha G. Nair, Adrian Hightower, Daniel Rosenberg, Musahid Ahmed, Christopher J. Brooks, Thomas F. Miller, Robert H. Grubbs, Simon C. Jones

    Fluoride ion batteries are potential “next-generation” electrochemical storage devices that offer high energy density. At present, such batteries are limited to operation at high temperatures because suitable fluoride ion–conducting electrolytes are known only in the solid state. We report a liquid fluoride ion–conducting electrolyte with high ionic conductivity, wide operating voltage, and robust chemical stability based on dry tetraalkylammonium fluoride salts in ether solvents. Pairing this liquid electrolyte with a copper–lanthanum trifluoride (Cu@LaF3) core-shell cathode, we demonstrate reversible fluorination and defluorination reactions in a fluoride ion electrochemical cell cycled at room temperature. Fluoride ion–mediated electrochemistry offers a pathway toward developing capacities beyond that of lithium ion technology.

    更新日期:2018-12-07
  • A valley valve and electron beam splitter
    Science (IF 41.058) Pub Date : 2018-12-07
    Jing Li, Rui-Xing Zhang, Zhenxi Yin, Jianxiao Zhang, Kenji Watanabe, Takashi Taniguchi, Chaoxing Liu, Jun Zhu

    Developing alternative paradigms of electronics beyond silicon technology requires the exploration of fundamentally new physical mechanisms, such as the valley-specific phenomena in hexagonal two-dimensional materials. We realize ballistic valley Hall kink states in bilayer graphene and demonstrate gate-controlled current transmission in a four-kink router device. The operations of a waveguide, a valve, and a tunable electron beam splitter are demonstrated. The valley valve exploits the valley-momentum locking of the kink states and reaches an on/off ratio of 8 at zero magnetic field. A magnetic field enables a full-range tunable coherent beam splitter. These results pave a path to building a scalable, coherent quantum transportation network based on the kink states.

    更新日期:2018-12-07
  • Photonic crystals for nano-light in moiré graphene superlattices
    Science (IF 41.058) Pub Date : 2018-12-07
    S. S. Sunku, G. X. Ni, B. Y. Jiang, H. Yoo, A. Sternbach, A. S. McLeod, T. Stauber, L. Xiong, T. Taniguchi, K. Watanabe, P. Kim, M. M. Fogler, D. N. Basov

    Graphene is an atomically thin plasmonic medium that supports highly confined plasmon polaritons, or nano-light, with very low loss. Electronic properties of graphene can be drastically altered when it is laid upon another graphene layer, resulting in a moiré superlattice. The relative twist angle between the two layers is a key tuning parameter of the interlayer coupling in thus-obtained twisted bilayer graphene (TBG). We studied the propagation of plasmon polaritons in TBG by infrared nano-imaging. We discovered that the atomic reconstruction occurring at small twist angles transforms the TBG into a natural plasmon photonic crystal for propagating nano-light. This discovery points to a pathway for controlling nano-light by exploiting quantum properties of graphene and other atomically layered van der Waals materials, eliminating the need for arduous top-down nanofabrication.

    更新日期:2018-12-07
  • Salmonella persisters undermine host immune defenses during antibiotic treatment
    Science (IF 41.058) Pub Date : 2018-12-07
    Daphne A. C. Stapels, Peter W. S. Hill, Alexander J. Westermann, Robert A. Fisher, Teresa L. Thurston, Antoine-Emmanuel Saliba, Isabelle Blommestein, Jörg Vogel, Sophie Helaine

    Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of Salmonella species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that Salmonella persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the Salmonella pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing Salmonella cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.

    更新日期:2018-12-07
  • Quantifying the contribution of recessive coding variation to developmental disorders
    Science (IF 41.058) Pub Date : 2018-12-07
    Hilary C. Martin, Wendy D. Jones, Rebecca McIntyre, Gabriela Sanchez-Andrade, Mark Sanderson, James D. Stephenson, Carla P. Jones, Juliet Handsaker, Giuseppe Gallone, Michaela Bruntraeger, Jeremy F. McRae, Elena Prigmore, Patrick Short, Mari Niemi, Joanna Kaplanis, Elizabeth J. Radford, Nadia Akawi, Meena Balasubramanian, John Dean, Rachel Horton, Alice Hulbert, Diana S. Johnson, Katie Johnson, Dhavendra Kumar, Sally Ann Lynch, Sarju G. Mehta, Jenny Morton, Michael J. Parker, Miranda Splitt, Peter D. Turnpenny, Pradeep C. Vasudevan, Michael Wright, Andrew Bassett, Sebastian S. Gerety, Caroline F. Wright, David R. FitzPatrick, Helen V. Firth, Matthew E. Hurles, Jeffrey C. Barrett, on behalf of the Deciphering Developmental Disorders Study

    We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

    更新日期:2018-12-07
  • A mechanistic classification of clinical phenotypes in neuroblastoma
    Science (IF 41.058) Pub Date : 2018-12-07
    Sandra Ackermann, Maria Cartolano, Barbara Hero, Anne Welte, Yvonne Kahlert, Andrea Roderwieser, Christoph Bartenhagen, Esther Walter, Judith Gecht, Laura Kerschke, Ruth Volland, Roopika Menon, Johannes M. Heuckmann, Moritz Gartlgruber, Sabine Hartlieb, Kai-Oliver Henrich, Konstantin Okonechnikov, Janine Altmüller, Peter Nürnberg, Steve Lefever, Bram de Wilde, Frederik Sand, Fakhera Ikram, Carolina Rosswog, Janina Fischer, Jessica Theissen, Falk Hertwig, Aatur D. Singhi, Thorsten Simon, Wenzel Vogel, Sven Perner, Barbara Krug, Matthias Schmidt, Sven Rahmann, Viktor Achter, Ulrich Lang, Christian Vokuhl, Monika Ortmann, Reinhard Büttner, Angelika Eggert, Frank Speleman, Roderick J. O’Sullivan, Roman K. Thomas, Frank Berthold, Jo Vandesompele, Alexander Schramm, Frank Westermann, Johannes H. Schulte, Martin Peifer, Matthias Fischer

    Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance–negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.

    更新日期:2018-12-07
  • LZTR1 is a regulator of RAS ubiquitination and signaling
    Science (IF 41.058) Pub Date : 2018-12-07
    Johannes W. Bigenzahn, Giovanna M. Collu, Felix Kartnig, Melanie Pieraks, Gregory I. Vladimer, Leonhard X. Heinz, Vitaly Sedlyarov, Fiorella Schischlik, Astrid Fauster, Manuele Rebsamen, Katja Parapatics, Vincent A. Blomen, André C. Müller, Georg E. Winter, Robert Kralovics, Thijn R. Brummelkamp, Marek Mlodzik, Giulio Superti-Furga

    In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (LZTR1) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because LZTR1 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for LZTR1 involvement in a variety of inherited and acquired human disorders.

    更新日期:2018-12-07
  • Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination
    Science (IF 41.058) Pub Date : 2018-12-07
    M. Steklov, S. Pandolfi, M. F. Baietti, A. Batiuk, P. Carai, P. Najm, M. Zhang, H. Jang, F. Renzi, Y. Cai, L. Abbasi Asbagh, T. Pastor, M. De Troyer, M. Simicek, E. Radaelli, H. Brems, E. Legius, J. Tavernier, K. Gevaert, F. Impens, L. Messiaen, R. Nussinov, S. Heymans, S. Eyckerman, A. A. Sablina

    The leucine zipper–like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.

    更新日期:2018-12-07
  • A DNA methylation reader complex that enhances gene transcription
    Science (IF 41.058) Pub Date : 2018-12-07
    C. Jake Harris, Marion Scheibe, Somsakul Pop Wongpalee, Wanlu Liu, Evan M. Cornett, Robert M. Vaughan, Xueqin Li, Wei Chen, Yan Xue, Zhenhui Zhong, Linda Yen, William D. Barshop, Shima Rayatpisheh, Javier Gallego-Bartolome, Martin Groth, Zonghua Wang, James A. Wohlschlegel, Jiamu Du, Scott B. Rothbart, Falk Butter, Steven E. Jacobsen

    DNA methylation generally functions as a repressive transcriptional signal, but it is also known to activate gene expression. In either case, the downstream factors remain largely unknown. By using comparative interactomics, we isolated proteins in Arabidopsis thaliana that associate with methylated DNA. Two SU(VAR)3-9 homologs, the transcriptional antisilencing factor SUVH1, and SUVH3, were among the methyl reader candidates. SUVH1 and SUVH3 bound methylated DNA in vitro, were associated with euchromatic methylation in vivo, and formed a complex with two DNAJ domain-containing homologs, DNAJ1 and DNAJ2. Ectopic recruitment of DNAJ1 enhanced gene transcription in plants, yeast, and mammals. Thus, the SUVH proteins bind to methylated DNA and recruit the DNAJ proteins to enhance proximal gene expression, thereby counteracting the repressive effects of transposon insertion near genes.

    更新日期:2018-12-07
  • Viscous control of cellular respiration by membrane lipid composition
    Science (IF 41.058) Pub Date : 2018-12-07
    Itay Budin, Tristan de Rond, Yan Chen, Leanne Jade G. Chan, Christopher J. Petzold, Jay D. Keasling

    Lipid composition determines the physical properties of biological membranes and can vary substantially between and within organisms. We describe a specific role for the viscosity of energy-transducing membranes in cellular respiration. Engineering of fatty acid biosynthesis in Escherichia coli allowed us to titrate inner membrane viscosity across a 10-fold range by controlling the abundance of unsaturated or branched lipids. These fluidizing lipids tightly controlled respiratory metabolism, an effect that can be explained with a quantitative model of the electron transport chain (ETC) that features diffusion-coupled reactions between enzymes and electron carriers (quinones). Lipid unsaturation also modulated mitochondrial respiration in engineered budding yeast strains. Thus, diffusion in the ETC may serve as an evolutionary constraint for lipid composition in respiratory membranes.

    更新日期:2018-12-07
  • Technology Feature | ChIP off the old block: Beyond chromatin immunoprecipitation
    Science (IF 41.058) Pub Date : 2018-12-07
    Charlotte Schubert

    Chromatin immunoprecipitation, now over 30 years old, modernizes to include emerging techniques such as gene editing and single-cell platforms.Read the Feature (Full-Text HTML)Read the Feature (PDF)Read New Products (PDF)

    更新日期:2018-12-07
  • Temperature-dependent hypoxia explains biogeography and severity of end-Permian marine mass extinction
    Science (IF 41.058) Pub Date : 2018-12-07
    Justin L. Penn, Curtis Deutsch, Jonathan L. Payne, Erik A. Sperling

    Rapid climate change at the end of the Permian Period (~252 million years ago) is the hypothesized trigger for the largest mass extinction in Earth’s history. We present model simulations of the Permian/Triassic climate transition that reproduce the ocean warming and oxygen (O2) loss indicated by the geologic record. The effect of these changes on animal survival is evaluated using the Metabolic Index (Φ), a measure of scope for aerobic activity governed by organismal traits sampled in diverse modern species. Modeled loss of aerobic habitat predicts lower extinction intensity in the tropics, a pattern confirmed with a spatially explicit analysis of the marine fossil record. The combined physiological stresses of ocean warming and O2 loss can account for more than half the magnitude of the “Great Dying.”

    更新日期:2018-12-07
  • Early human dispersals within the Americas
    Science (IF 41.058) Pub Date : 2018-12-07
    J. Víctor Moreno-Mayar, Lasse Vinner, Peter de Barros Damgaard, Constanza de la Fuente, Jeffrey Chan, Jeffrey P. Spence, Morten E. Allentoft, Tharsika Vimala, Fernando Racimo, Thomaz Pinotti, Simon Rasmussen, Ashot Margaryan, Miren Iraeta Orbegozo, Dorothea Mylopotamitaki, Matthew Wooller, Clement Bataille, Lorena Becerra-Valdivia, David Chivall, Daniel Comeskey, Thibaut Devièse, Donald K. Grayson, Len George, Harold Harry, Verner Alexandersen, Charlotte Primeau, Jon Erlandson, Claudia Rodrigues-Carvalho, Silvia Reis, Murilo Q. R. Bastos, Jerome Cybulski, Carlos Vullo, Flavia Morello, Miguel Vilar, Spencer Wells, Kristian Gregersen, Kasper Lykke Hansen, Niels Lynnerup, Marta Mirazón Lahr, Kurt Kjær, André Strauss, Marta Alfonso-Durruty, Antonio Salas, Hannes Schroeder, Thomas Higham, Ripan S. Malhi, Jeffrey T. Rasic, Luiz Souza, Fabricio R. Santos, Anna-Sapfo Malaspinas, Martin Sikora, Rasmus Nielsen, Yun S. Song, David J. Meltzer, Eske Willerslev

    Studies of the peopling of the Americas have focused on the timing and number of initial migrations. Less attention has been paid to the subsequent spread of people within the Americas. We sequenced 15 ancient human genomes spanning from Alaska to Patagonia; six are ≥10,000 years old (up to ~18× coverage). All are most closely related to Native Americans, including those from an Ancient Beringian individual and two morphologically distinct “Paleoamericans.” We found evidence of rapid dispersal and early diversification that included previously unknown groups as people moved south. This resulted in multiple independent, geographically uneven migrations, including one that provides clues of a Late Pleistocene Australasian genetic signal, as well as a later Mesoamerican-related expansion. These led to complex and dynamic population histories from North to South America.

    更新日期:2018-12-07
  • Animals and the zoogeochemistry of the carbon cycle
    Science (IF 41.058) Pub Date : 2018-12-07
    Oswald J. Schmitz, Christopher C. Wilmers, Shawn J. Leroux, Christopher E. Doughty, Trisha B. Atwood, Mauro Galetti, Andrew B. Davies, Scott J. Goetz

    Predicting and managing the global carbon cycle requires scientific understanding of ecosystem processes that control carbon uptake and storage. It is generally assumed that carbon cycling is sufficiently characterized in terms of uptake and exchange between ecosystem plant and soil pools and the atmosphere. We show that animals also play an important role by mediating carbon exchange between ecosystems and the atmosphere, at times turning ecosystem carbon sources into sinks, or vice versa. Animals also move across landscapes, creating a dynamism that shapes landscape-scale variation in carbon exchange and storage. Predicting and measuring carbon cycling under such dynamism is an important scientific challenge. We explain how to link analyses of spatial ecosystem functioning, animal movement, and remote sensing of animal habitats with carbon dynamics across landscapes.

    更新日期:2018-12-07
  • Open-source discovery of chemical leads for next-generation chemoprotective antimalarials
    Science (IF 41.058) Pub Date : 2018-12-07
    Yevgeniya Antonova-Koch, Stephan Meister, Matthew Abraham, Madeline R. Luth, Sabine Ottilie, Amanda K. Lukens, Tomoyo Sakata-Kato, Manu Vanaerschot, Edward Owen, Juan Carlos Jado Rodriguez, Steven P. Maher, Jaeson Calla, David Plouffe, Yang Zhong, Kaisheng Chen, Victor Chaumeau, Amy J. Conway, Case W. McNamara, Maureen Ibanez, Kerstin Gagaring, Fernando Neria Serrano, Korina Eribez, Cullin McLean Taggard, Andrea L. Cheung, Christie Lincoln, Biniam Ambachew, Melanie Rouillier, Dionicio Siegel, François Nosten, Dennis E. Kyle, Francisco-Javier Gamo, Yingyao Zhou, Manuel Llinás, David A. Fidock, Dyann F. Wirth, Jeremy Burrows, Brice Campo, Elizabeth A. Winzeler

    To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

    更新日期:2018-12-07
  • Functionally diverse type V CRISPR-Cas systems
    Science (IF 41.058) Pub Date : 2018-12-06
    Winston X. Yan, Pratyusha Hunnewell, Lauren E. Alfonse, Jason M. Carte, Elise Keston-Smith, Shanmugapriya Sothiselvam, Anthony J. Garrity, Shaorong Chong, Kira S. Makarova, Eugene V. Koonin, David R. Cheng, David A. Scott

    Type V CRISPR-Cas systems are distinguished by a single RNA-guided RuvC domain-containing effector, Cas12. Although effectors of subtypes V-A (Cas12a) and V-B (Cas12b) have been studied in detail, the distinct domain architectures and diverged RuvC sequences of uncharacterized Cas12 proteins suggest unexplored functional diversity. Here, we identify and characterize Cas12c, g, h, and i. Cas12c, h, and i demonstrate RNA-guided double-stranded (ds) DNA interference activity. Cas12i exhibits markedly different efficiencies of crRNA spacer complementary and non-complementary strand cleavage resulting in predominant dsDNA nicking. Cas12g is an RNA-guided RNase with collateral RNase and single-stranded DNase activities. Our study reveals the functional diversity emerging along different routes of type V CRISPR-Cas evolution and expands the CRISPR toolbox.

    更新日期:2018-12-07
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.
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