Train robots to self-certify their safe operation Nature (IF 40.137) Pub Date : Valentin Robu, David Flynn, David Lane
Train robots to self-certify their safe operation Train robots to self-certify their safe operation, Published online: 16 January 2018; doi:10.1038/d41586-018-00646-w Train robots to self-certify their safe operation
Support for US postdocs is growing slowly Nature (IF 40.137) Pub Date :
Support for US postdocs is growing slowly Support for US postdocs is growing slowly, Published online: 16 January 2018; doi:10.1038/d41586-018-00559-8 Report from National Postdoctoral Association highlights progress and pain points.
The dark side of light: how artificial lighting is harming the natural world Nature (IF 40.137) Pub Date : Aisling Irwin
The dark side of light: how artificial lighting is harming the natural world The dark side of light: how artificial lighting is harming the natural world , Published online: 16 January 2018; doi:10.1038/d41586-018-00665-7 The world is lit at night like never before, and ecologists are assessing the damage.
Fixing statistics is more than a technical issue Nature (IF 40.137) Pub Date : Andrea Saltelli, Philip Stark
Fixing statistics is more than a technical issue Fixing statistics is more than a technical issue, Published online: 16 January 2018; doi:10.1038/d41586-018-00647-9 Fixing statistics is more than a technical issue
The evolution of attraction, rare brains and how to hack time: Books in brief Nature (IF 40.137) Pub Date : Barbara Kiser
The evolution of attraction, rare brains and how to hack time: Books in brief The evolution of attraction, rare brains and how to hack time: Books in brief, Published online: 16 January 2018; doi:10.1038/d41586-018-00581-w Barbara Kiser reviews five of the week’s best science picks.
An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Ming Chen, Jiangwen Zhang, Katia Sampieri, John G. Clohessy, Lourdes Mendez, Enrique Gonzalez-Billalabeitia, Xue-Song Liu, Yu-Ru Lee, Jacqueline Fung, Jesse M. Katon, Archita Venugopal Menon, Kaitlyn A. Webster, Christopher Ng, Maria Dilia Palumbieri, Moussa S. Diolombi, Susanne B. Breitkopf, Julie Teruya-Feldstein, Sabina Signoretti, Roderick T. Bronson, John M. Asara, Mireia Castillo-Martin, Carlos Cordon-Cardo, Pier Paolo Pandolfi
Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.
Pan-genome analysis highlights the extent of genomic variation in cultivated and wild rice Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Qiang Zhao, Qi Feng, Hengyun Lu, Yan Li, Ahong Wang, Qilin Tian, Qilin Zhan, Yiqi Lu, Lei Zhang, Tao Huang, Yongchun Wang, Danlin Fan, Yan Zhao, Ziqun Wang, Congcong Zhou, Jiaying Chen, Chuanrang Zhu, Wenjun Li, Qijun Weng, Qun Xu, Zi-Xuan Wang, Xinghua Wei, Bin Han, Xuehui Huang
The rich genetic diversity in Oryza sativa and Oryza rufipogon serves as the main sources in rice breeding. Large-scale resequencing has been undertaken to discover allelic variants in rice, but much of the information for genetic variation is often lost by direct mapping of short sequence reads onto the O. sativa japonica Nipponbare reference genome. Here we constructed a pan-genome dataset of the O. sativa–O. rufipogon species complex through deep sequencing and de novo assembly of 66 divergent accessions. Intergenomic comparisons identified 23 million sequence variants in the rice genome. This catalog of sequence variations includes many known quantitative trait nucleotides and will be helpful in pinpointing new causal variants that underlie complex traits. In particular, we systemically investigated the whole set of coding genes using this pan-genome data, which revealed extensive presence and absence of variation among rice accessions. This pan-genome resource will further promote evolutionary and functional studies in rice.
Genetics of lipid metabolism in prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Ninu Poulose, Francesca Amoroso, Rebecca E. Steele, Reema Singh, Chee Wee Ong, Ian G. Mills
Genetics of lipid metabolism in prostate cancer Genetics of lipid metabolism in prostate cancer, Published online: 15 January 2018; doi:10.1038/s41588-017-0037-0 Dysregulated lipid metabolism is a prominent feature of prostate cancers. Two papers in this issue identify novel genomic drivers of lipid metabolism in prostate cancer and provide implications for the subtyping and treatment of the disease.
Transposon-derived small RNAs triggered by miR845 mediate genome dosage response in Arabidopsis Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Filipe Borges, Jean-Sébastien Parent, Frédéric van Ex, Philip Wolff, German Martínez, Claudia Köhler, Robert A. Martienssen
Chromosome dosage has substantial effects on reproductive isolation and speciation in both plants and animals, but the underlying mechanisms are largely obscure1. Transposable elements in animals can regulate hybridity through maternal small RNA2, whereas small RNAs in plants have been postulated to regulate dosage response via neighboring imprinted genes3,4. Here we show that a highly conserved microRNA in plants, miR845, targets the tRNAMet primer-binding site (PBS) of long terminal repeat (LTR) retrotransposons in Arabidopsis pollen, and triggers the accumulation of 21–22-nucleotide (nt) small RNAs in a dose-dependent fashion via RNA polymerase IV. We show that these epigenetically activated small interfering RNAs (easiRNAs) mediate hybridization barriers between diploid seed parents and tetraploid pollen parents (the ‘triploid block’), and that natural variation for miR845 may account for ‘endosperm balance’ allowing the formation of triploid seeds. Targeting of the PBS with small RNA is a common mechanism for transposon control in mammals and plants, and provides a uniquely sensitive means to monitor chromosome dosage and imprinting in the developing seed.
Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Ralph Stadhouders, Enrique Vidal, François Serra, Bruno Di Stefano, François Le Dily, Javier Quilez, Antonio Gomez, Samuel Collombet, Clara Berenguer, Yasmina Cuartero, Jochen Hecht, Guillaume J. Filion, Miguel Beato, Marc A. Marti-Renom, Thomas Graf
Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We have recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells. Here, we used this system to integrate time-resolved changes in genome topology with gene expression, TF binding and chromatin-state dynamics. The results showed that TFs drive topological genome reorganization at multiple architectural levels, often before changes in gene expression. Removal of locus-specific topological barriers can explain why pluripotency genes are activated sequentially, instead of simultaneously, during reprogramming. Together, our results implicate genome topology as an instructive force for implementing transcriptional programs and cell fate in mammals.
Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Jingjing Chen, Ilaria Guccini, Diletta Di Mitri, Daniela Brina, Ajinkya Revandkar, Manuela Sarti, Emiliano Pasquini, Abdullah Alajati, Sandra Pinton, Marco Losa, Gianluca Civenni, Carlo V. Catapano, Jacopo Sgrignani, Andrea Cavalli, Rocco D’Antuono, John M. Asara, Andrea Morandi, Paola Chiarugi, Sara Crotti, Marco Agostini, Monica Montopoli, Ionica Masgras, Andrea Rasola, Ramon Garcia-Escudero, Nicolas Delaleu, Andrea Rinaldi, Francesco Bertoni, Johann de Bono, Arkaitz Carracedo, Andrea Alimonti
The mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus. Whereas nuclear PDC controls the expression of sterol regulatory element-binding transcription factor (SREBF)-target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated manner, thereby sustaining anabolism. Additionally, we found that PDHA1 and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1) are frequently amplified and overexpressed at both the gene and protein levels in prostate tumors. Together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy.
Paternal easiRNAs regulate parental genome dosage in Arabidopsis Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 German Martinez, Philip Wolff, Zhenxing Wang, Jordi Moreno-Romero, Juan Santos-González, Lei Liu Conze, Christopher DeFraia, R. Keith Slotkin, Claudia Köhler
The regulation of parental genome dosage is of fundamental importance in animals and plants, as exemplified by X-chromosome inactivation and dosage compensation. The ‘triploid block’ is a classic example of dosage regulation in plants that establishes a reproductive barrier between species differing in chromosome number1,2. This barrier acts in the embryo-nourishing endosperm tissue and induces the abortion of hybrid seeds through a yet unknown mechanism3. Here we show that depletion of paternal epigenetically activated small interfering RNAs (easiRNAs) bypasses the triploid block in response to increased paternal ploidy in Arabidopsis thaliana. Paternal loss of the plant-specific RNA polymerase IV suppressed easiRNA formation and rescued triploid seeds by restoring small-RNA-directed DNA methylation at transposable elements (TEs), correlating with reduced expression of paternally expressed imprinted genes (PEGs). Our data suggest that easiRNAs form a quantitative signal for paternal chromosome number and that their balanced dosage is required for post-fertilization genome stability and seed viability.
Reconstructing an African haploid genome from the 18th century Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Anuradha Jagadeesan, Ellen D. Gunnarsdóttir, S. Sunna Ebenesersdóttir, Valdis B. Guðmundsdóttir, Elisabet Linda Thordardottir, Margrét S. Einarsdóttir, Hákon Jónsson, Jean-Michel Dugoujon, Cesar Fortes-Lima, Florence Migot-Nabias, Achille Massougbodji, Gil Bellis, Luisa Pereira, Gísli Másson, Augustine Kong, Kári Stefánsson, Agnar Helgason
A genome is a mosaic of chromosome fragments from ancestors who existed some arbitrary number of generations earlier. Here, we reconstruct the genome of Hans Jonatan (HJ), born in the Caribbean in 1784 to an enslaved African mother and European father. HJ migrated to Iceland in 1802, married and had two children. We genotyped 182 of his 788 descendants using single-nucleotide polymorphism (SNP) chips and whole-genome sequenced (WGS) 20 of them. Using these data, we reconstructed 38% of HJ’s maternal genome and inferred that his mother was from the region spanned by Benin, Nigeria and Cameroon.
Transient Scute activation via a self-stimulatory loop directs enteroendocrine cell pair specification from self-renewing intestinal stem cells Nat. Cell. Biol. (IF 20.06) Pub Date : 2018-01-15 Jun Chen, Na Xu, Chenhui Wang, Pin Huang, Huanwei Huang, Zhen Jin, Zhongsheng Yu, Tao Cai, Renjie Jiao, Rongwen Xi
The process through which multiple types of cell-lineage-restricted progenitor cells are specified from multipotent stem cells is unclear. Here we show that, in intestinal stem cell lineages in adult Drosophila, in which the Delta-Notch-signalling-guided progenitor cell differentiation into enterocytes is the default mode, the specification of enteroendocrine cells (EEs) is initiated by transient Scute activation in a process driven by transcriptional self-stimulation combined with a negative feedback regulation between Scute and Notch targets. Scute activation induces asymmetric intestinal stem cell divisions that generate EE progenitor cells. The mitosis-inducing and fate-inducing activities of Scute guide each EE progenitor cell to divide exactly once prior to its terminal differentiation, yielding a pair of EEs. The transient expression of a fate inducer therefore specifies both type and numbers of committed progenitor cells originating from stem cells, which could represent a general mechanism used for diversifying committed progenitor cells from multipotent stem cells.
Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos Nat. Cell. Biol. (IF 20.06) Pub Date : 2018-01-15 Vasileios I. Floros, Angela Pyle, Sabine Dietmann, Wei Wei, Walfred W. C. Tang, Naoko Irie, Brendan Payne, Antonio Capalbo, Laila Noli, Jonathan Coxhead, Gavin Hudson, Moira Crosier, Henrik Strahl, Yacoub Khalaf, Mitinori Saitou, Dusko Ilic, M. Azim Surani, Patrick F. Chinnery
Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear1,2. Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single-cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in late PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller’s ratchet. Mutations escaping this mechanism will show shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.
Myosin-Va is required for preciliary vesicle transportation to the mother centriole during ciliogenesis Nat. Cell. Biol. (IF 20.06) Pub Date : 2018-01-15 Chien-Ting Wu, Hsin-Yi Chen, Tang K. Tang
Primary cilia play essential roles in signal transduction and development. The docking of preciliary vesicles at the distal appendages of a mother centriole is an initial/critical step of ciliogenesis, but the mechanisms are unclear. Here, we demonstrate that myosin-Va mediates the transportation of preciliary vesicles to the mother centriole and reveal the underlying mechanism. We also show that the myosin-Va-mediated transportation of preciliary vesicles is the earliest event that defines the onset of ciliogenesis. Depletion of myosin-Va significantly inhibits the attachment of preciliary vesicles to the distal appendages of the mother centriole and decreases cilia assembly. Myosin-Va functions upstream of EHD1- and Rab11-mediated ciliary vesicle formation. Importantly, dynein mediates myosin-Va-associated preciliary vesicle transportation to the pericentrosomal region along microtubules, while myosin-Va mediates preciliary vesicle transportation from the pericentrosomal region to the distal appendages of the mother centriole via the Arp2/3-associated branched actin network.
EXD2 governs germ stem cell homeostasis and lifespan by promoting mitoribosome integrity and translation Nat. Cell. Biol. (IF 20.06) Pub Date : 2018-01-15 Joana Silva, Suvi Aivio, Philip A. Knobel, Laura J. Bailey, Andreu Casali, Maria Vinaixa, Isabel Garcia-Cao, Étienne Coyaud, Alexis A. Jourdain, Pablo Pérez-Ferreros, Ana M. Rojas, Albert Antolin-Fontes, Sara Samino-Gené, Brian Raught, Acaimo González-Reyes, Lluís Ribas de Pouplana, Aidan J. Doherty, Oscar Yanes, Travis H. Stracker
Mitochondria are subcellular organelles that are critical for meeting the bioenergetic and biosynthetic needs of the cell. Mitochondrial function relies on genes and RNA species encoded both in the nucleus and mitochondria, and on their coordinated translation, import and respiratory complex assembly. Here, we characterize EXD2 (exonuclease 3′–5′ domain-containing 2), a nuclear-encoded gene, and show that it is targeted to the mitochondria and prevents the aberrant association of messenger RNAs with the mitochondrial ribosome. Loss of EXD2 results in defective mitochondrial translation, impaired respiration, reduced ATP production, increased reactive oxygen species and widespread metabolic abnormalities. Depletion of the Drosophila melanogaster EXD2 orthologue (CG6744) causes developmental delays and premature female germline stem cell attrition, reduced fecundity and a dramatic extension of lifespan that is reversed with an antioxidant diet. Our results define a conserved role for EXD2 in mitochondrial translation that influences development and ageing.
Dual gene activation and knockout screen reveals directional dependencies in genetic networks Nat. Biotechnol. (IF 41.667) Pub Date : 2018-01-15 Michael Boettcher, Ruilin Tian, James A Blau, Evan Markegard, Ryan T Wagner, David Wu, Xiulei Mo, Anne Biton, Noah Zaitlen, Haian Fu, Frank McCormick, Martin Kampmann, Michael T McManus
Understanding the direction of information flow is essential for characterizing how genetic networks affect phenotypes. However, methods to find genetic interactions largely fail to reveal directional dependencies. We combine two orthogonal Cas9 proteins from Streptococcus pyogenes and Staphylococcus aureus to carry out a dual screen in which one gene is activated while a second gene is deleted in the same cell. We analyze the quantitative effects of activation and knockout to calculate genetic interaction and directionality scores for each gene pair. Based on the results from over 100,000 perturbed gene pairs, we reconstruct a directional dependency network for human K562 leukemia cells and demonstrate how our approach allows the determination of directionality in activating genetic interactions. Our interaction network connects previously uncharacterized genes to well-studied pathways and identifies targets relevant for therapeutic intervention.
Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells Nat. Biotechnol. (IF 41.667) Pub Date : 2018-01-15 Alexander S Cheung, David K Y Zhang, Sandeep T Koshy, David J Mooney
Therapeutic ex vivo T-cell expansion is limited by low rates and T-cell products of limited functionality. Here we describe a system that mimics natural antigen-presenting cells (APCs) and consists of a fluid lipid bilayer supported by mesoporous silica micro-rods. The lipid bilayer presents membrane-bound cues for T-cell receptor stimulation and costimulation, while the micro-rods enable sustained release of soluble paracrine cues. Using anti-CD3, anti-CD28, and interleukin-2, we show that the APC-mimetic scaffolds (APC-ms) promote two- to tenfold greater polyclonal expansion of primary mouse and human T cells compared with commercial expansion beads (Dynabeads). The efficiency of expansion depends on the density of stimulatory cues and the amount of material in the starting culture. Following a single stimulation, APC-ms enables antigen-specific expansion of rare cytotoxic T-cell subpopulations at a greater magnitude than autologous monocyte-derived dendritic cells after 2 weeks. APC-ms support over fivefold greater expansion of restimulated CD19 CAR-T cells than Dynabeads, with similar efficacy in a xenograft lymphoma model.
Visualizing detailed postdoctoral employment trends using a new career outcome taxonomy Nat. Biotechnol. (IF 41.667) Pub Date : 2018-01-15 Hong Xu, Richard S T Gilliam, Shyamal D Peddada, Gregory M Buchold, Tammy R L Collins
Visualizing detailed postdoctoral employment trends using a new career outcome taxonomy Visualizing detailed postdoctoral employment trends using a new career outcome taxonomy, Published online: 15 January 2018; doi:10.1038/nbt.4059 A standard taxonomy and visualization methods can provide postdoctoral scholars with tools to critically evaluate their career prospects.
Molecular pathways to nonbiting mosquitoes PNAS (IF 9.661) Pub Date : 2018-01-12 Peter A. Armbruster
Mosquitoes are often referred to as the deadliest animals on Earth because of the devastating pathogens they are able to transmit when females bite and then feed on blood from human hosts (male mosquitoes don’t bite). In 2015 alone there were an estimated 212 million cases of malaria, resulting in 429,000 deaths (1). Approximately one-third of Earth’s population is considered at risk for infection by the dengue virus (2). Furthermore, the rapid emergence and global spread of mosquito-borne viruses, such as West Nile, Zika, and chikungunya, are of increasing public health concern (3,4). Because effective vaccines and drug therapies are not available for the majority of these mosquito-borne pathogens, efforts to reduce disease transmission have traditionally focused on suppressing or eliminating the mosquito vector, usually by reducing larval habitats (source reduction) or applying insecticides. However, the effectiveness of these traditional approaches is limited by the proliferation of man-made habitats (e.g., discarded tires and cisterns), the rapid geographic spread of vector species associated with human commerce and travel, and the evolution of insecticide resistance. Novel approaches to control are desperately needed. Recently, a variety of exciting strategies to disrupt disease transmission have emerged based on genetic modification of vectors or infection of vectors with bacterial symbionts (5,6). These strategies seek to either suppress vector populations to sufficiently low numbers that pathogen transmission cannot be sustained (population suppression), or to introduce and spread genetic modifications or bacterial symbiont infections through natural populations so the mosquitoes are incapable of transmitting pathogens (population replacement). Current population replacement strategies focus on preventing the mosquito from transmitting a pathogen once it has already taken a bite and ingested blood. In PNAS, Bradshaw et al. (7) establish the foundation of an intriguing alternative approach based on the potent logic that mosquitoes that don’t …
Greening up the mountain PNAS (IF 9.661) Pub Date : 2018-01-12 V. Vandvik, A. H. Halbritter, R. J. Telford
The progression of key plant life-history events, such as spring leaf-out and flowering, along bioclimatic gradients in elevation and latitude is one of the more conspicuous patterns in nature, and, as such, it has served as a source of opportunity, industry, inspiration, and wonder for farmers, natural scientists, and artists alike (1⇓–3). For example, in many regions across the world, transhumance, traditional land-use practices that involve the seasonal movement of people and their livestock between fixed summer and winter pastures, has developed to exploit such phenological gradients across the landscape (2,4,5). These phenological patterns are tightly linked to temperature, leading to the formulation of bioclimatic “laws” about phenology (6). Advancing spring phenologies were also among the first clear empirical examples of biotic responses to a warming climate (7,8).
Large genomic insertion at the Shh locus results in hammer toes through enhancer adoption PNAS (IF 9.661) Pub Date : 2018-01-12 Christina Paliou, Guillaume Andrey
Enhancers arecis-regulatory elements which control the expression of genes in a defined spatiotemporal pattern, enabling the normal morphogenesis of organs and structures during embryogenesis. Enhancers control their target genes independently of their orientation or distance through chromosomal looping and are thought to evolve through various mutational mechanisms (1). A critical biological process that leads to the acquisition of new gene expression domains as well as pathological outcomes is termed “enhancer adoption,” whereby a gene is regulated by an enhancer that is not normally its own (2). Enhancer adoption can derive from the insertion of transposable elements (TEs) with regulatory capacities or genomic structural variants (SVs). In particular, many studies have demonstrated the importance of SVs, including deletions, inversions, duplications, and translocations, with regard to 3D genome organization, gene regulation, and disease (3⇓–5). Recent advances in genome engineering and in sequencing technologies have contributed to a deeper understanding of the molecular mechanisms behind genomic rearrangements and their role in evolution and pathology. Therefore, researchers have seized the opportunity to reinterpret old mouse alleles obtained by spontaneous mutations like X-irradiation-induced phocomelia,Hemimelic extra toes(Hx),Ulnaless, and so on, in the light of modern molecular tools (6⇓–8). In PNAS, Mouri et al. (10) set out to reanalyze a mouse mutant with syndactyly and interdigital webbing, known as Hammer toe (Hm), first described in 1964 (9). The authors found that a genomic insertion of an interdigital regulatory region in the vicinity of the geneSonic hedgehog(Shh) results in its ectopic expression and theHmphenotype. The authors use chromatin technologies and CRISPR/Cas9 genetic engineering to dissect the regulatory function of …
Predicting tipping points in complex environmental systems PNAS (IF 9.661) Pub Date : 2018-01-11 John C. Moore
Ecologists have long recognized that ecosystems can exist and function in one state within predictable bounds for extended periods of time and then abruptly shift to an alternate state (1⇓⇓⇓–5). Desertification of grasslands, shrub expansion in the Arctic, the eutrophication of lakes, ocean acidification, the formation of marine dead zones, and the degradation of coral reefs represent real and potential ecological regime shifts marked by a tipping point or threshold in one or more external drivers or controlling variables within the system that when breached causes a major change in the system’s structure, function, or dynamics (6⇓⇓–9). Large or incremental alterations in climate, land use, biodiversity (invasive species or the overexploitation of species), and biogeochemical cycles represent external and internal drivers that when pushed too far cross thresholds that can could lead to regime shifts (Fig. 1). Seeing the tipping point after the fact and ascribing mechanisms to the change is one thing; predicting them using empirical data has been a challenge. The difficulty in predicting tipping points stems from the large number of species and interactions (high dimensionality) within ecological systems, the stochastic nature of the systems and their drivers, and the uncertainty and importance of initial conditions that the nonlinear nature of the systems introduce to outcomes. In PNAS, Jiang et al. (10) confront these issues using a dimension-reduction framework that uses empirical data from 59 complex multidimensional plant–pollinator mutualistic networks, some of which contain scores of species and interactions, to develop simpler 2D models for studying and predicting tipping points.
Toward a unifying theory of biodiversity PNAS (IF 9.661) Pub Date : 2018-01-11 Marten Scheffer, Egbert H. van Nes, Remi Vergnon
Ecologists have long agreed that to coexist species must be sufficiently different (1,2). This worldview was challenged when Stephen Hubbell published his neutral theory of biodiversity showing that species that are essentially equal should also be able to evade competitive exclusion (3). Although this neutral theory inspired a fresh look at biodiversity, it also met resistance as it seemed to violate the deeply held belief that all species are fundamentally different. Interestingly, a harmonious combination of niche differentiation and neutrality can emerge naturally in simulated communities, thus suggesting a way of unifying the niche and neutral view (4). A peculiar prediction of this theory of emergent neutrality is that species should be distributed over niche space in a lumpy way, a pattern that is indeed often observed in nature (5⇓⇓⇓–9). In this view the lumps correspond to niches, while species within lumps are essentially more of the same, reflecting two alternative ways for species to coexist: being sufficiently different or being sufficiently similar (Fig. 1). A study in PNAS now lends important support to this unifying theory by showing its compatibility with Tilman’s widely embraced theory of competition for resources (10).
Partitioning aggression PNAS (IF 9.661) Pub Date : 2018-01-11 Martin Daly
Have aggression and violence been ramped up in human evolution or dialed down? This sounds like a question that empirical research might have settled long ago, but it remains strangely contentious. In PNAS, Richard Wrangham (1) proposes that debates persist because too many evolutionary anthropologists mistakenly conceive of aggression as unitary and that a well-established distinction between “proactive” and “reactive” aggression holds the key to a resolution.
Future of nonnucleoside reverse transcriptase inhibitors PNAS (IF 9.661) Pub Date : 2018-01-11 Nicolas Sluis-Cremer
The nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are small molecules that bind to HIV-1 RT at a site distinct from the DNA polymerase active site of the enzyme and block retroviral reverse transcription via an allosteric mechanism of action (1). Nevirapine (NVP) was the first NNRTI approved in 1996 by the US Food and Drug Administration for the treatment of HIV-1 infection, followed by delavirdine in 1997, efavirenz (EFV) in 1998, etravirine (ETV) in 2008, and rilpivirine (RPV) in 2011. For almost 20 y NNRTIs served as the cornerstone of combination antiretroviral therapy (cART). Indeed, most first-line cART included one NNRTI (typically NVP, EFV, or RPV) in combination with two nucleoside/nucleotide RT inhibitors. Just last month, RPV and the integrase inhibitor dolutegravir were approved as the first once-daily, single-pill, two-drug regimen for the maintenance treatment of virologically suppressed HIV-1 infection. ETV can be included in salvage cART for the treatment of HIV-1–infected ART-experienced individuals, including those with prior NNRTI exposure. NNRTIs have also been used to prevent HIV-1 infection. NVP has been used to prevent mother-to-child transmission (2 …
Linked networks for learning and expressing location-specific threat PNAS (IF 9.661) Pub Date : 2018-01-11 Benjamin Suarez-Jimenez, James A. Bisby, Aidan J. Horner, John A. King, Daniel S. Pine, Neil Burgess
Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were “picked.” Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or “bee sting”); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC–hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula–hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula–dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders.
Frankenstein lives on Science (IF 37.205) Pub Date : 2018-01-12 Henk van den Belt
It was 200 years ago that Mary Shelley's Frankenstein; or, The Modern Prometheus was published. Over the decades, this gothic tale has captured the popular imagination through the numerous theater productions and films it inspired. The story is commonly taken to imply a dire warning about the dangers of scientific hubris. Just mention the name Frankenstein and laypersons think of scientists “playing God.” In the common view, the inevitable consequence of Frankenstein's alleged transgression—bestowing life on inanimate matter—was that he created a monster that would wreak havoc on his family and friends. Frankenstein's name is repeatedly invoked in debates about emerging technologies like biotech, nanotech, synthetic biology, and artificial intelligence. However, the view of Shelley's story as a cautionary tale about scientific hubris, although dominant, is only one possible interpretation. Her novel, actually, is a multilayered story full of ambivalences and much subtler than most Hollywood versions. It naturally lends itself to diverse interpretations.
News at a glance Science (IF 37.205) Pub Date : 2018-01-12 American Association for the Advancement of Science
In science news around the world, the U.S. National Football League provides $16 million for medical research on concussions and other football-related illnesses, and the World Health Organization approves a new, long-lasting vaccine for typhoid fever. China announces it will build a new research and development park in Beijing to develop artificial intelligence technologies, and South Korean universities refuse to renew their contracts with Elsevier for access to its ScienceDirect database because of a price hike. Scientists install new devices at the South Pole to measure neutrinos, and a volunteer discovers the largest prime number, containing more than 23 million digits. And the U.S. Department of the Interior decides to review certain grants to universities and nonprofit groups to ensure they align with the priorities of President Donald Trump's administration.
DOE pushes for useful quantum computing Science (IF 37.205) Pub Date : 2018-01-12 Adrian Cho
The U.S. Department of Energy (DOE) is joining the quest to develop quantum computers, devices that would exploit quantum mechanics to crack problems that overwhelm conventional computers. The initiative comes as Google and other companies race to build a quantum computer that can demonstrate "quantum supremacy" by beating classical computers on a test problem. But reaching that milestone will not mean practical uses are at hand, and the new $40 million DOE effort is intended to spur the development of useful quantum computing algorithms for its work in chemistry, materials science, nuclear physics, and particle physics. With the resources at its 17 national laboratories, DOE could play a key role in developing the machines, researchers say, although finding problems with which quantum computers can help isn't so easy.
In Pakistan, surveillance for polio reveals a paradox Science (IF 37.205) Pub Date : 2018-01-12 Leslie Roberts
Last year polio fighters could smell victory in Pakistan, which many believe will be the last country on Earth to harbor the virus. Cases dropped to an all-time low. Blood tests showed that immunity to the poliovirus had never been higher. Surely, there were not enough susceptible children to sustain transmission, and the virus would burn itself out within a year. Unsettling new findings, however, show it is far from gone. In the most extensive effort in any country to scour the environment for traces of the virus, polio workers are finding it widely across Pakistan, in places they thought it had disappeared. They are wondering "just what the hell is going on" and how worried they should be, says epidemiologist Chris Maher of the World Health Organization in Geneva, Switzerland, who runs polio operations in the eastern Mediterranean region. Does this mean the virus is more entrenched than anyone realized and is poised to resurge? Or is this how a virus behaves in its final days—persisting in the environment but not causing disease until it fades out?
Earth scientists list top priorities for space missions Science (IF 37.205) Pub Date : 2018-01-12 Paul Voosen
Earth scientists hope a new priority setting effort will help them make the most of NASA's limited budget for satellite missions that watch over the planet. The so-called decadal survey, issued in January by the National Academies of Sciences, Engineering, and Medicine, laid out the community's consensus wish list, ranging from cloud monitoring to multiwavelength imaging—and recommends a strong dose of competition to keep costs down. The report prioritizes five observations for launch, including hyperspectral imaging, clouds, atmospheric particles, and missions to chart gravity variations and tiny crustal movements. It also advocates creating a new line of $350 million missions targeting seven observations, with competitions to choose three for flight in the next 10 years.
Cuba's 100-year plan for climate change Science (IF 37.205) Pub Date : 2018-01-12 Richard Stone
On its deadly run through the Caribbean last September, Hurricane Irma lashed northern Cuba, inundating coastal settlements and scouring away vegetation. Irma lent new urgency to a Cuban national plan, called Tarea Vida, or Project Life, that bans construction of new homes in threatened coastal areas, mandates relocating people from communities doomed by rising sea levels, calls for an overhaul of the country's agricultural system to shift crop production away from saltwater-contaminated areas, and spells out the need to shore up coastal defenses, including by restoring degraded habitat. Project Life stands out for taking a long view: It intends to prepare Cuba for climatological impacts over the next century. Much of the initial funding could come from a $100 million proposal that Cuba plans to submit soon to the Global Climate Fund.
Cliffs of ice spied on Mars Science (IF 37.205) Pub Date : 2018-01-12 Paul Voosen
Scientists have discovered eight cliffs of nearly pure water ice on Mars, some of which stand nearly 100 meters tall. The discovery points to large stores of underground ice buried only a meter or two below the surface at surprisingly low martian latitudes, in regions where ice had not yet been detected. Each cliff seems to be the naked face of a glacier, tantalizing scientists with the promise of a layer-cake record of past martian climates and space enthusiasts with a potential resource for future human bases. Scientists discovered the cliffs with a high-resolution camera on the Mars Reconnaissance Orbiter, revisiting the sites to show their subsequent retreat as a result of vaporization, and their persistence in the martian summer. The hunt should now be on, scientists say, for similar sites closer to the equator.
The long shadow of Frankenstein Science (IF 37.205) Pub Date : 2018-01-12 Kai Kupferschmidt
In January 1818, Mary Shelley published her book Frankenstein, a terrifying story of a doctor who builds a creature from scavenged body parts, then recoils in horror, spurns it, and sees his friends and family destroyed by the monster. Two hundred years later, Frankenstein is still essential reading for anyone working in science. In this special issue, Science examines the lasting legacy of Shelley's book on science and popular culture as well as the potential risks from modern-day, real-life Frankensteins.
How a horror story haunts science Science (IF 37.205) Pub Date : 2018-01-12 Jon Cohen
In conceiving her novel Frankenstein, Mary Shelley was influenced by the nascent medical science of the day and by early experiments on electricity. In return, Frankenstein has haunted science ever since. Shelley's book and subsequent films and plays have become what one author calls "the governing myth of modern biology": a cautionary tale of scientific hubris. The scientific literature, like the popular press, is rife with references to Frankenfood, Frankencells, and Frankendrugs—most of them supposedly monstrous creations. Other papers mentioning Frankenstein analyze the science behind the novel, analyze Shelley's state of mind, or even, in a bizarre twist, draw inspiration from the tale.
Creating a modern monster Science (IF 37.205) Pub Date : 2018-01-12 David Shultz
When Mary Shelley published her story of Victor Frankenstein and his misshapen monster in 1818, she provided little detail about how exactly the doctor built his creation, except that "the dissecting room and the slaughter-house furnished many of [his] materials" and that he infused "a spark of being in the lifeless thing." But what if Shelley had written her book today? Here is an overview of current and future technologies—from lab-grown organs and bionics to gene editing—that she might call on to produce her iconic creature.
Taming the monsters of tomorrow Science (IF 37.205) Pub Date : 2018-01-12 Kai Kupferschmidt
In Mary Shelley's novel, the scientist Victor Frankenstein fears that creating a female companion to his unhappy monster could lead to a "race of devils" that could drive humanity extinct. Today, some scientists worry about scientific advances in the real world that could kill all of humanity, or at least end civilization as we know it. Some two dozen researchers at three academic centers are studying these "existential risks"—including labmade viruses, armies of nanobots, and artificial intelligence—and what can be done about them. But critics say their scenarios are far-fetched and distract from real existential dangers, including climate change and nuclear war.
A glossary of Frankenwords Science (IF 37.205) Pub Date : 2018-01-12 Jon Cohen
Along with fears about scientific overreach, Mary Shelley's novel has inspired hundreds of whimsical names for products and phenomena—from Frankencells and Frankengenes to Frankenslime and Frankenswine. Here's a selection.
Detecting the building blocks of aromatics Science (IF 37.205) Pub Date : 2018-01-12 Christine Joblin, José Cernicharo
Interstellar clouds are sites of active organic chemistry (1). Many small, gasphase molecules are found in the dark parts of the clouds that are protected from ultraviolet (UV) photons, but these molecules photodissociate in the external layers of the cloud that are exposed to stellar radiation (see the photo). These irradiated regions are populated by large polycyclic aromatic hydrocarbons (PAHs) with characteristic infrared (IR) emission features. These large aromatics are expected to form from benzene (C6H6), which is, however, difficult to detect because it does not have a permanent dipole moment and can only be detected via its IR absorption transitions against a strong background source (2). On page 202 of this issue, McGuire et al. (3) report the detection of benzonitrile (c-C6H5CN) with radio telescopes. Benzonitrile likely forms in the reaction of CN with benzene; from its observation, it is therefore possible to estimate the abundance of benzene itself.
Improbable Big Birds Science (IF 37.205) Pub Date : 2018-01-12 Catherine E. Wagner
Darwin's finches, a group of 18 species endemic to the Galápagos archipelago, are a classic example of adaptive radiation—the process whereby a single ancestral species multiplies in number to produce divergent species, often in rapid succession (1). These birds are evolutionary biologists' most celebrated example of natural selection in action. On page 224 of this issue, Lamichhaney et al. (2) have succeeded in observing a process even more elusive than natural selection—the formation of a new species (speciation). Because speciation typically takes place on time scales that are too long for direct human observation, before now it was only in organisms with very fast generation times, such as viruses and bacteria, that scientists had directly observed this process [for example, (3)]. Lamichhaney et al. show through direct observation and DNA sequencing that new species can form very rapidly: within three generations. The key, in this case, is hybridization between different species.
Malaria parasite evolution in a test tube Science (IF 37.205) Pub Date : 2018-01-12 Jane M. Carlton
Malaria is an infectious disease caused by the Plasmodium parasite, and transmitted by Anopheles mosquitoes. In 2016, a staggering 216 million cases of malaria and 445,000 deaths were recorded, mostly in Africa, although half of the world's population in 91 countries is at risk of the disease (1). Malaria prevention methods include control of the mosquito with insecticide-treated bed nets and indoor residual spraying of insecticides. Prompt diagnosis through the use of rapid diagnostic tests is also key. Although there is a malaria vaccine, RTS,S/AS01, it shows limited efficacy and has yet to be used widely. However, the frontline against malaria is antimalarial drugs, in particular artemisinin-based combination therapies (ACTs), which are mixtures of artemisinin and its derivatives from the Chinese sweet wormwood herb, with drugs such as piperaquine. Alarmingly, the parasite is now resistant to most drugs that have been developed (see the figure). It is imperative that we identify new inhibitors if progress in reducing malaria is to be sustained. On page 191 of this issue, Cowell et al. (2) present a major step forward, revealing new antimalarial drug targets and their possible resistance mechanisms.
TRPM channels come into focus Science (IF 37.205) Pub Date : 2018-01-12 Chanhyung Bae, Andres Jara-Oseguera, Kenton J. Swartz
Transient receptor potential (TRP) channels were first identified in photoreceptors of the fruit fly (1, 2). In mammals, six major families of TRP channels play key roles in sensing stimuli such as light, temperature, membrane lipids, and intracellular Ca2+. In 2013, two landmark publications revealed the cryo–electron microscopy (cryo-EM) structure of the heat- and capsaicin-activated TRPV1 channel (3, 4). Two articles in this issue report cryo-EM structures of cation-selective TRPM channels. On page 228, Autzen et al. (5) describe TRPM4, which is activated by intracellular Ca2+ and involved in controlling arterial tone, cardiac rhythm, and the immune response (6). On page 237, Yin et al. (7) report on TRPM8, which senses cold and menthol and may serve as a cancer biomarker (8).
Coherent excitations revealed and calculated Science (IF 37.205) Pub Date : 2018-01-12 Antoine Georges
Quantum entities manifest themselves as either particles or waves. In a physical system containing a very large number of identical particles, such as electrons in a material, individualistic (particle-like) behavior prevails at high temperatures. At low temperatures, collective behavior emerges, and excitations of the system in this regime are best described as waves—long-lived phenomena that are periodic in both space and time and often dubbed “coherent excitations” by physicists. On page 186 of this issue, Goremychkin et al. (1) used experiment and theory to describe the emergence of coherent excitations in a complex quantum system with strong interactions. They studied a cerium-palladium compound, CePd3, in which the very localized electrons of 4f orbitals of Ce interact with the much more itinerant conduction electrons of the extended d orbitals of Pd at low temperatures to create a wavelike state.
Silencing stemness in T cell differentiation Science (IF 37.205) Pub Date : 2018-01-12 Amanda N. Henning, Christopher A. Klebanoff, Nicholas P. Restifo
Functional diversity in multicellular organisms is achieved through the differentiation of stem cells. During this process, stem cells must retain both the capacity for self-renewal and the ability to differentiate into highly specialized cell types to produce a diverse array of tissues, each with distinct functions and organization. This plasticity is achieved through alterations to the epigenome, heritable and reversible modifications to DNA and histones that affect chromatin structure and gene transcription without altering the DNA sequence itself. Alterations to the epigenome enable cell type–specific transcriptional control that can change dynamically over the life of a cell. Such flexibility and responsiveness are instrumental in directing gene expression changes throughout cellular differentiation and lineage specification. The acquisition of more specialized functions during differentiation requires not only that the epigenome turn “on” genes involved in lineage commitment, it also necessitates that genes associated with stemness are simultaneously turned “off” (1). On page 177 of this issue, Pace et al. (2) demonstrate that this phenomenon exists in CD8+ T cells, in which epigenetic repression of stemness-associated genes by the histone methyltransferase SUV39H1 is required for T cell effector differentiation. Understanding these mechanisms addresses important questions in immunology and is applicable to cancer immunotherapy.
Global science for city policy Science (IF 37.205) Pub Date : 2018-01-12 Michele Acuto
Research and data are increasingly at the heart of how we conceive of urban governance. Urban control rooms and city dashboards championed by cities like Chicago, São Paulo, and London have been promising real-time snapshots and tracking over time of urban systems, via geolocated mobility data sets, social media inputs, environmental sensors, and other tools (1). At the international level, the importance of urban research and data has been enshrined in major United Nations (UN) processes, from the UN New Urban Agenda, the Sendai Framework for Disaster Risk Reduction, and the Sustainable Development Goals (SDGs) to the World Data Forum (2). Yet overall, the global state of data-informed urban governance remains underdeveloped, often promising, as with the dashboards, more than it actually delivers. It is time for a step change. A truly global reform of scientific advice to cities must take place on multiple interconnected fronts, linking a UN action plan on science and the future of cities, a “good advice” commitment by the private sector, and formalized partnerships for urban science at the local level. This scientifically informed urban reform, ripe for discussion at the upcoming UN World Urban Forum in February, can be uniquely bold in recognizing the potential of municipal action on global challenges. Despite being considered the “lowest” level of governance, cities have developed a track record of global action on key matters like climate, disasters, and health, often surpassing, in speed, commitments, and global coverage, that of nations.
Revisit a cautionary classic Science (IF 37.205) Pub Date : 2018-01-12 Dov Greenbaum
The tale of Victor Frankenstein and his monstrous creation has become a universal touchstone that encapsulates our visceral fears regarding the promises, perils, and pitfalls of countless diverse areas of science and technology. A new annotated volume of Mary Shelley's original work is an effort to reintroduce the story to new generations of researchers who, like many before them, ought to take its lessons to heart.
Our idiosyncracies Science (IF 37.205) Pub Date : 2018-01-12 Michael A. Goldman
Joining the ranks of a burgeoning number of professional scientists turned professional writers, Liam Drew, a practicing neuroscientist for 12 years, has put down his microfuge tubes and taken up the charge of communicating with the public about science. His first book, I, Mammal: The Story of What Makes Us Mammals, stands out as a clear, conversational (sometimes to a fault), and engaging work that is especially good at explaining how evolutionary biology works.
The epigenetic control of stemness in CD8+ T cell fate commitment Science (IF 37.205) Pub Date : 2018-01-12 Luigia Pace, Christel Goudot, Elina Zueva, Paul Gueguen, Nina Burgdorf, Joshua J. Waterfall, Jean-Pierre Quivy, Geneviève Almouzni, Sebastian Amigorena
After priming, naïve CD8+ T lymphocytes establish specific heritable transcription programs that define progression to long-lasting memory cells or to short-lived effector cells. Although lineage specification is critical for protection, it remains unclear how chromatin dynamics contributes to the control of gene expression programs. We explored the role of gene silencing by the histone methyltransferase Suv39h1. In murine CD8+ T cells activated after Listeria monocytogenes infection, Suv39h1-dependent trimethylation of histone H3 lysine 9 controls the expression of a set of stem cell–related memory genes. Single-cell RNA sequencing revealed a defect in silencing of stem/memory genes selectively in Suv39h1-defective T cell effectors. As a result, Suv39h1-defective CD8+ T cells show sustained survival and increased long-term memory reprogramming capacity. Thus, Suv39h1 plays a critical role in marking chromatin to silence stem/memory genes during CD8+ T effector terminal differentiation.
Coherent band excitations in CePd3: A comparison of neutron scattering and ab initio theory Science (IF 37.205) Pub Date : 2018-01-12 Eugene A. Goremychkin, Hyowon Park, Raymond Osborn, Stephan Rosenkranz, John-Paul Castellan, Victor R. Fanelli, Andrew D. Christianson, Matthew B. Stone, Eric D. Bauer, Kenneth J. McClellan, Darrin D. Byler, Jon M. Lawrence
In common with many strongly correlated electron systems, intermediate valence compounds are believed to display a crossover from a high-temperature regime of incoherently fluctuating local moments to a low-temperature regime of coherent hybridized bands. We show that inelastic neutron scattering measurements of the dynamic magnetic susceptibility of CePd3 provides a benchmark for ab initio calculations based on dynamical mean field theory. The magnetic response is strongly momentum dependent thanks to the formation of coherent f-electron bands at low temperature, with an amplitude that is strongly enhanced by local particle-hole interactions. The agreement between experiment and theory shows that we have a robust first-principles understanding of the temperature dependence of f-electron coherence.
Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics Science (IF 37.205) Pub Date : 2018-01-12 Annie N. Cowell, Eva S. Istvan, Amanda K. Lukens, Maria G. Gomez-Lorenzo, Manu Vanaerschot, Tomoyo Sakata-Kato, Erika L. Flannery, Pamela Magistrado, Edward Owen, Matthew Abraham, Gregory LaMonte, Heather J. Painter, Roy M. Williams, Virginia Franco, Maria Linares, Ignacio Arriaga, Selina Bopp, Victoria C. Corey, Nina F. Gnädig, Olivia Coburn-Flynn, Christin Reimer, Purva Gupta, James M. Murithi, Pedro A. Moura, Olivia Fuchs, Erika Sasaki, Sang W. Kim, Christine H. Teng, Lawrence T. Wang, Aslı Akidil, Sophie Adjalley, Paul A. Willis, Dionicio Siegel, Olga Tanaseichuk, Yang Zhong, Yingyao Zhou, Manuel Llinás, Sabine Ottilie, Francisco-Javier Gamo, Marcus C. S. Lee, Daniel E. Goldberg, David A. Fidock, Dyann F. Wirth, Elizabeth A. Winzeler
Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.
Exposed subsurface ice sheets in the Martian mid-latitudes Science (IF 37.205) Pub Date : 2018-01-12 Colin M. Dundas, Ali M. Bramson, Lujendra Ojha, James J. Wray, Michael T. Mellon, Shane Byrne, Alfred S. McEwen, Nathaniel E. Putzig, Donna Viola, Sarah Sutton, Erin Clark, John W. Holt
Thick deposits cover broad regions of the Martian mid-latitudes with a smooth mantle; erosion in these regions creates scarps that expose the internal structure of the mantle. We investigated eight of these locations and found that they expose deposits of water ice that can be >100 meters thick, extending downward from depths as shallow as 1 to 2 meters below the surface. The scarps are actively retreating because of sublimation of the exposed water ice. The ice deposits likely originated as snowfall during Mars’ high-obliquity periods and have now compacted into massive, fractured, and layered ice. We expect the vertical structure of Martian ice-rich deposits to preserve a record of ice deposition and past climate.
Detection of the aromatic molecule benzonitrile (c-C6H5CN) in the interstellar medium Science (IF 37.205) Pub Date : 2018-01-12 Brett A. McGuire, Andrew M. Burkhardt, Sergei Kalenskii, Christopher N. Shingledecker, Anthony J. Remijan, Eric Herbst, Michael C. McCarthy
Polycyclic aromatic hydrocarbons and polycyclic aromatic nitrogen heterocycles are thought to be widespread throughout the universe, because these classes of molecules are probably responsible for the unidentified infrared bands, a set of emission features seen in numerous Galactic and extragalactic sources. Despite their expected ubiquity, astronomical identification of specific aromatic molecules has proven elusive. We present the discovery of benzonitrile (c-C6H5CN), one of the simplest nitrogen-bearing aromatic molecules, in the interstellar medium. We observed hyperfine-resolved transitions of benzonitrile in emission from the molecular cloud TMC-1. Simple aromatic molecules such as benzonitrile may be precursors for polycyclic aromatic hydrocarbon formation, providing a chemical link to the carriers of the unidentified infrared bands.
Ordered macro-microporous metal-organic framework single crystals Science (IF 37.205) Pub Date : 2018-01-12 Kui Shen, Lei Zhang, Xiaodong Chen, Lingmei Liu, Daliang Zhang, Yu Han, Junying Chen, Jilan Long, Rafael Luque, Yingwei Li, Banglin Chen
We constructed highly oriented and ordered macropores within metal-organic framework (MOF) single crystals, opening up the area of three-dimensional–ordered macro-microporous materials (that is, materials containing both macro- and micropores) in single-crystalline form. Our methodology relies on the strong shaping effects of a polystyrene nanosphere monolith template and a double-solvent–induced heterogeneous nucleation approach. This process synergistically enabled the in situ growth of MOFs within ordered voids, rendering a single crystal with oriented and ordered macro-microporous structure. The improved mass diffusion properties of such hierarchical frameworks, together with their robust single-crystalline nature, endow them with superior catalytic activity and recyclability for bulky-molecule reactions, as compared with conventional, polycrystalline hollow, and disordered macroporous ZIF-8.
Antagonism toward the intestinal microbiota and its effect on Vibrio cholerae virulence Science (IF 37.205) Pub Date : 2018-01-12 Wenjing Zhao, Florence Caro, William Robins, John J. Mekalanos
The bacterial type VI secretion system (T6SS) is a nanomachine that delivers toxic effector proteins into target cells, killing them. In mice, we found that the Vibrio cholerae T6SS attacks members of the host commensal microbiota in vivo, facilitating the pathogen’s colonization of the gut. This microbial antagonistic interaction drives measurable changes in the pathogenicity of V. cholerae through enhanced intestinal colonization, expression of bacterial virulence genes, and activation of host innate immune genes. Because ablation of mouse commensals by this enteric pathogen correlated with more severe diarrheal symptoms, we conclude that antagonism toward the gut microbiota could improve the fitness of V. cholerae as a pathogen by elevating its transmission to new susceptible hosts.
Spatial representations of self and other in the hippocampus Science (IF 37.205) Pub Date : 2018-01-12 Teruko Danjo, Taro Toyoizumi, Shigeyoshi Fujisawa
An animal’s awareness of its location in space depends on the activity of place cells in the hippocampus. How the brain encodes the spatial position of others has not yet been identified. We investigated neuronal representations of other animals’ locations in the dorsal CA1 region of the hippocampus with an observational T-maze task in which one rat was required to observe another rat’s trajectory to successfully retrieve a reward. Information reflecting the spatial location of both the self and the other was jointly and discretely encoded by CA1 pyramidal cells in the observer rat. A subset of CA1 pyramidal cells exhibited spatial receptive fields that were identical for the self and the other. These findings demonstrate that hippocampal spatial representations include dimensions for both self and nonself.
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