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  • On the design of precision nanomedicines
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Xiaohe Tian, Stefano Angioletti-Uberti, Giuseppe Battaglia

    Tight control on the selectivity of nanoparticles’ interaction with biological systems is paramount for the development of targeted therapies. However, the large number of tunable parameters makes it difficult to identify optimal design “sweet spots” without guiding principles. Here, we combine superselectivity theory with soft matter physics into a unified theoretical framework and we prove its validity using blood brain barrier cells as target. We apply our approach to polymersomes functionalized with targeting ligands to identify the most selective combination of parameters in terms of particle size, brush length and density, as well as tether length, affinity, and ligand number. We show that the combination of multivalent interactions into multiplexed systems enable interaction as a function of the cell phenotype, that is, which receptors are expressed. We thus propose the design of a “bar-coding” targeting approach that can be tailor-made to unique cell populations enabling personalized therapies.

    更新日期:2020-01-26
  • Community detection in networks without observing edges
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Till Hoffmann, Leto Peel, Renaud Lambiotte, Nick S. Jones

    We develop a Bayesian hierarchical model to identify communities of time series. Fitting the model provides an end-to-end community detection algorithm that does not extract information as a sequence of point estimates but propagates uncertainties from the raw data to the community labels. Our approach naturally supports multiscale community detection and the selection of an optimal scale using model comparison. We study the properties of the algorithm using synthetic data and apply it to daily returns of constituents of the S&P100 index and climate data from U.S. cities.

    更新日期:2020-01-26
  • Small-scale universality in the spectral structure of transitional pipe flows
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Rory T. Cerbus, Chien-chia Liu, Gustavo Gioia, Pinaki Chakraborty

    Turbulent flows are not only everywhere, but every turbulent flow is the same at small scales. The extraordinary simplification engendered by this “small-scale universality” is a hallmark of turbulence theory. However, on the basis of the restrictive assumptions invoked by A. N. Kolmogorov to demonstrate this universality, it is widely thought that only idealized turbulent flows conform to this framework. Using experiments and simulations that span a wide range of Reynolds number, we show that small-scale universality governs the spectral structure of a class of flows with no apparent ties to the idealized flows: transitional pipe flows. Our results not only extend the universality of Kolmogorov’s framework beyond expectation but also establish an unexpected link between transitional pipe flows and Kolmogorovian turbulence.

    更新日期:2020-01-26
  • Can polarity-inverted membranes self-assemble on Titan?
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    H. Sandström, M. Rahm

    The environmental and chemical limits of life are two of the most central questions in astrobiology. Our understanding of life’s boundaries has implications on the efficacy of biosignature identification in exoplanet atmospheres and in the solar system. The lipid bilayer membrane is one of the central prerequisites for life as we know it. Previous studies based on molecular dynamics simulations have suggested that polarity-inverted membranes, azotosomes, made up of small nitrogen-containing molecules, are kinetically persistent and may function on cryogenic liquid hydrocarbon worlds, such as Saturn’s moon Titan. We here take the next step and evaluate the thermodynamic viability of azotosome formation. Quantum mechanical calculations predict that azotosomes are not viable candidates for self-assembly akin to lipid bilayers in liquid water. We argue that cell membranes may be unnecessary for hypothetical astrobiology under stringent anhydrous and low-temperature conditions akin to those of Titan.

    更新日期:2020-01-26
  • Environmental and genetic determinants of plasmid mobility in pathogenic Escherichia coli
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Jonathan H. Bethke, Adam Davidovich, Li Cheng, Allison J. Lopatkin, Wenchen Song, Joshua T. Thaden, Vance G. Fowler, Minfeng Xiao, Lingchong You

    Plasmids are key vehicles of horizontal gene transfer (HGT), mobilizing antibiotic resistance, virulence, and other traits among bacterial populations. The environmental and genetic forces that drive plasmid transfer are poorly understood, however, due to the lack of definitive quantification coupled with genomic analysis. Here, we integrate conjugative phenotype with plasmid genotype to provide quantitative analysis of HGT in clinical Escherichia coli pathogens. We find a substantial proportion of these pathogens (>25%) able to readily spread resistance to the most common classes of antibiotics. Antibiotics of varied modes of action had less than a 5-fold effect on conjugation efficiency in general, with one exception displaying 31-fold promotion upon exposure to macrolides and chloramphenicol. In contrast, genome sequencing reveals plasmid incompatibility group strongly correlates with transfer efficiency. Our findings offer new insights into the determinants of plasmid mobility and have implications for the development of treatments that target HGT.

    更新日期:2020-01-26
  • A highly scalable dielectric metamaterial with superior capacitor performance over a broad temperature
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Tian Zhang, Xin Chen, Yash Thakur, Biao Lu, Qiyan Zhang, J. Runt, Q. M. Zhang

    Although many polymers exhibit excellent dielectric performance including high energy density with high efficiency at room temperature, their electric and dielectric performance deteriorates at high temperatures (~150°C). Here, we show that nanofillers at very low volume content in a high-temperature (high–glass transition temperature) semicrystalline dipolar polymer, poly(arylene ether urea), can generate local structural changes, leading to a marked increase in both dielectric constant and breakdown field, and substantially reduce conduction losses at high electric fields and over a broad temperature range. Consequently, the polymer with a low nanofiller loading (0.2 volume %) generates a high discharged energy density of ca. 5 J/cm3 with high efficiency at 150°C. The experimental data reveal microstructure changes in the nanocomposites, which, at 0.2 volume % nanofiller loading, reduce constraints on dipole motions locally in the glassy state of the polymer, reduce the mean free path for the mobile charges, and enhance the deep trap level.

    更新日期:2020-01-26
  • Bioinspired structural color patch with anisotropic surface adhesion
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Yu Wang, Luoran Shang, Guopu Chen, Lingyu Sun, Xiaoxuan Zhang, Yuanjin Zhao

    Patch plays an important role in clinical medicine for its broad applications in tissue repair and regeneration. Here, inspired by the diverse adhesion, anti-adhesion, and responsive structural color phenomena in biological interfaces, we present a hybrid hydrogel film with an adhesive polydopamine (PDA) layer and an anti-adhesive poly(ethylene glycol) diacrylate (PEGDA) layer in an inverse opal scaffold. It was demonstrated that the resultant hydrogel film could serve as a functional tissue patch with an excellent adhesion property on one surface for repairing injured tissues and an anti-adhesion property on the other surface for preventing adverse adhesion. Besides, because of the responsive structural color, the patch was imparted with self-reporting mechanical capability, which could provide a real-time color-sensing feedback to monitor the heartbeat activity. Moreover, the catechol groups on PDA imparted the patch with high tissue adhesiveness and self-healing capability in vivo. These features give the bioinspired patch high potential in biomedical applications.

    更新日期:2020-01-26
  • The global-scale distributions of soil protists and their contributions to belowground systems
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Angela M. Oliverio, Stefan Geisen, Manuel Delgado-Baquerizo, Fernando T. Maestre, Benjamin L. Turner, Noah Fierer

    Protists are ubiquitous in soil, where they are key contributors to nutrient cycling and energy transfer. However, protists have received far less attention than other components of the soil microbiome. We used amplicon sequencing of soils from 180 locations across six continents to investigate the ecological preferences of protists and their functional contributions to belowground systems. We complemented these analyses with shotgun metagenomic sequencing of 46 soils to validate the identities of the more abundant protist lineages. We found that most soils are dominated by consumers, although parasites and phototrophs are particularly abundant in tropical and arid ecosystems, respectively. The best predictors of protist composition (primarily annual precipitation) are fundamentally distinct from those shaping bacterial and archaeal communities (namely, soil pH). Some protists and bacteria co-occur globally, highlighting the potential importance of these largely undescribed belowground interactions. Together, this study allowed us to identify the most abundant and ubiquitous protists living in soil, with our work providing a cross-ecosystem perspective on the factors structuring soil protist communities and their likely contributions to soil functioning.

    更新日期:2020-01-26
  • Multidimensional entanglement transport through single-mode fiber
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Jun Liu, Isaac Nape, Qainke Wang, Adam Vallés, Jian Wang, Andrew Forbes

    The global quantum network requires the distribution of entangled states over long distances, with substantial advances already demonstrated using polarization. While Hilbert spaces with higher dimensionality, e.g., spatial modes of light, allow higher information capacity per photon, such spatial mode entanglement transport requires custom multimode fiber and is limited by decoherence-induced mode coupling. Here, we circumvent this by transporting multidimensional entangled states down conventional single-mode fiber (SMF). By entangling the spin-orbit degrees of freedom of a biphoton pair, passing the polarization (spin) photon down the SMF while accessing multiple orbital angular momentum (orbital) subspaces with the other, we realize multidimensional entanglement transport. We show high-fidelity hybrid entanglement preservation down 250 m SMF across multiple 2 × 2 dimensions, confirmed by quantum state tomography, Bell violation measures, and a quantum eraser scheme. This work offers an alternative approach to spatial mode entanglement transport that facilitates deployment in legacy networks across conventional fiber.

    更新日期:2020-01-26
  • Structural and spectral dynamics of single-crystalline Ruddlesden-Popper phase halide perovskite blue light-emitting diodes
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Hong Chen, Jia Lin, Joohoon Kang, Qiao Kong, Dylan Lu, Jun Kang, Minliang Lai, Li Na Quan, Zhenni Lin, Jianbo Jin, Lin-wang Wang, Michael F. Toney, Peidong Yang

    Achieving perovskite-based high–color purity blue-emitting light-emitting diodes (LEDs) is still challenging. Here, we report successful synthesis of a series of blue-emissive two-dimensional Ruddlesden-Popper phase single crystals and their high–color purity blue-emitting LED demonstrations. Although this approach successfully achieves a series of bandgap emissions based on the different layer thicknesses, it still suffers from a conventional temperature-induced device degradation mechanism during high-voltage operations. To understand the underlying mechanism, we further elucidate temperature-induced device degradation by investigating the crystal structural and spectral evolution dynamics via in situ temperature-dependent single-crystal x-ray diffraction, photoluminescence (PL) characterization, and density functional theory calculation. The PL peak becomes asymmetrically broadened with a marked intensity decay, as temperature increases owing to [PbBr6]4− octahedra tilting and the organic chain disordering, which results in bandgap decrease. This study indicates that careful heat management under LED operation is a key factor to maintain the sharp and intense emission.

    更新日期:2020-01-26
  • Direct observation of glucose fingerprint using in vivo Raman spectroscopy
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Jeon Woong Kang, Yun Sang Park, Hojun Chang, Woochang Lee, Surya Pratap Singh, Wonjun Choi, Luis H. Galindo, Ramachandra R. Dasari, Sung Hyun Nam, Jongae Park, Peter T. C. So

    Noninvasive blood glucose monitoring has been a long-standing dream in diabetes management. The use of Raman spectroscopy, with its molecular specificity, has been investigated in this regard over the past decade. Previous studies reported on glucose sensing based on indirect evidence such as statistical correlation to the reference glucose concentration. However, these claims fail to demonstrate glucose Raman peaks, which has raised questions regarding the effectiveness of Raman spectroscopy for glucose sensing. Here, we demonstrate the first direct observation of glucose Raman peaks from in vivo skin. The signal intensities varied proportional to the reference glucose concentrations in three live swine glucose clamping experiments. Tracking spectral intensity based on linearity enabled accurate prospective prediction in within-subject and intersubject models. Our direct demonstration of glucose signal may quiet the long debate about whether glucose Raman spectra can be measured in vivo in transcutaneous glucose sensing.

    更新日期:2020-01-26
  • Weak-field induced nonmagnetic state in a Co-based honeycomb
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Ruidan Zhong, Tong Gao, Nai Phuan Ong, Robert J. Cava

    Layered honeycomb magnets are of interest as potential realizations of the Kitaev quantum spin liquid (KQSL), a quantum state with long-range spin entanglement and an exactly solvable Hamiltonian. Conventional magnetically ordered states are present for all currently known candidate materials, however, because non-Kitaev terms in the Hamiltonians obscure the Kitaev physics. Current experimental studies of the KQSL are focused on 4d or 5d transition metal–based honeycombs, in which strong spin-orbit coupling can be expected, yielding Kitaev interaction that dominates in an applied magnetic field. In contrast, for 3d-based layered honeycomb magnets, spin-orbit coupling is weak, and thus, Kitaev physics should be substantially less accessible. Here, we report our studies on BaCo2(AsO4)2, for which we find that the magnetic order associated with the non-Kitaev interactions can be fully suppressed by a relatively low magnetic field, yielding a nonmagnetic material and implying the presence of strong magnetic frustration and weak non-Kitaev interactions.

    更新日期:2020-01-26
  • Cargo capture and transport by colloidal swarms
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Yuguang Yang, Michael A. Bevan

    Controlling active colloidal particle swarms could enable useful microscopic functions in emerging applications at the interface of nanotechnology and robotics. Here, we present a computational study of controlling self-propelled colloidal particle propulsion speeds to cooperatively capture and transport cargo particles, which otherwise produce random dispersions. By sensing swarm and cargo coordinates, each particle’s speed is actuated according to a control policy based on multiagent assignment and path planning strategies that navigate stochastic particle trajectories to targets around cargo. Colloidal swarms are shown to dynamically cage cargo at their center via inward radial forces while simultaneously translating via directional forces. Speed, power, and efficiency of swarm tasks display emergent coupled dependences on swarm size and pair interactions and approach asymptotic limits indicating near-optimal performance. This scheme exploits unique interactions and stochastic dynamics in colloidal swarms to capture and transport microscopic cargo in a robust, stable, error-tolerant, and dynamic manner.

    更新日期:2020-01-26
  • Large-scale synthesis of crystalline g-C3N4 nanosheets and high-temperature H2 sieving from assembled films
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-24
    Luis Francisco Villalobos, Mohammad Tohidi Vahdat, Mostapha Dakhchoune, Zahra Nadizadeh, Mounir Mensi, Emad Oveisi, Davide Campi, Nicola Marzari, Kumar Varoon Agrawal

    Poly(triazine imide) (PTI), a crystalline g-C3N4, hosting two-dimensional nanoporous structure with an electron density gap of 0.34 nm, is highly promising for high-temperature hydrogen sieving because of its high chemical and thermal robustness. Currently, layered PTI is synthesized in potentially unsafe vacuum ampules in milligram quantities. Here, we demonstrate a scalable and safe ambient pressure synthesis route leading to several grams of layered PTI platelets in a single batch with 70% yield with respect to the precursor. Solvent exfoliation under anhydrous conditions led to single-layer PTI nanosheets evidenced by the observation of triangular g-C3N4 nanopores. Gas permeation studies confirm that PTI nanopores can sieve He and H2 from larger molecules. Last, high-temperature H2 sieving from PTI nanosheet–based membranes, prepared by the scalable filter coating technique, is demonstrated with H2 permeance reaching 1500 gas permeation units, with H2/CO2, H2/N2, and H2/CH4 selectivities reaching 10, 50, and 60, respectively, at 250°C.

    更新日期:2020-01-26
  • Single-cell morphology encodes metastatic potential
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Pei-Hsun Wu, Daniele M. Gilkes, Jude M. Phillip, Akshay Narkar, Thomas Wen-Tao Cheng, Jorge Marchand, Meng-Horng Lee, Rong Li, Denis Wirtz

    A central goal of precision medicine is to predict disease outcomes and design treatments based on multidimensional information from afflicted cells and tissues. Cell morphology is an emergent readout of the molecular underpinnings of a cell’s functions and, thus, can be used as a method to define the functional state of an individual cell. We measured 216 features derived from cell and nucleus morphology for more than 30,000 breast cancer cells. We find that single cell–derived clones (SCCs) established from the same parental cells exhibit distinct and heritable morphological traits associated with genomic (ploidy) and transcriptomic phenotypes. Using unsupervised clustering analysis, we find that the morphological classes of SCCs predict distinct tumorigenic and metastatic potentials in vivo using multiple mouse models of breast cancer. These findings lay the groundwork for using quantitative morpho-profiling in vitro as a potentially convenient and economical method for phenotyping function in cancer in vivo.

    更新日期:2020-01-23
  • Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Kezhi Yan, Justine Rousseau, Keren Machol, Laura A. Cross, Katherine E. Agre, Cynthia Forster Gibson, Anne Goverde, Kendra L. Engleman, Hannah Verdin, Elfride De Baere, Lorraine Potocki, Dihong Zhou, Maxime Cadieux-Dion, Gary A. Bellus, Monisa D. Wagner, Rebecca J. Hale, Natacha Esber, Alan F. Riley, Benjamin D. Solomon, Megan T. Cho, Kirsty McWalter, Roy Eyal, Meagan K. Hainlen, Bryce A. Mendelsohn, Hillary M. Porter, Brendan C. Lanpher, Andrea M. Lewis, Juliann Savatt, Isabelle Thiffault, Bert Callewaert, Philippe M. Campeau, Xiang-Jiao Yang

    Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.

    更新日期:2020-01-23
  • Animal simulations facilitate smart drug design through prediction of nanomaterial transport to individual tissue cells
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Edward Price, Andre J. Gesquiere

    Smart drug design for antibody and nanomaterial-based therapies allows optimization of drug efficacy and more efficient early-stage preclinical trials. The ideal drug must display maximum efficacy at target tissue sites, with transport from tissue vasculature to the cellular environment being critical. Biological simulations, when coupled with in vitro approaches, can predict this exposure in a rapid and efficient manner. As a result, it becomes possible to predict drug biodistribution within single cells of live animal tissue without the need for animal studies. Here, we successfully utilized an in vitro assay and a computational fluid dynamic model to translate in vitro cell kinetics (accounting for cell-induced degradation) to whole-body simulations for multiple species as well as nanomaterial types to predict drug distribution into individual tissue cells. We expect this work to assist in refining, reducing, and replacing animal testing, while providing scientists with a new perspective during the drug development process.

    更新日期:2020-01-23
  • Compression-induced dedifferentiation of adipocytes promotes tumor progression
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Yiwei Li, Angelo S. Mao, Bo Ri Seo, Xing Zhao, Satish Kumar Gupta, Maorong Chen, Yu Long Han, Ting-Yu Shih, David J. Mooney, Ming Guo

    Dysregulated physical stresses are generated during tumorigenesis that affect the surrounding compliant tissues including adipocytes. However, the effect of physical stressors on the behavior of adipocytes and their cross-talk with tumor cells remain elusive. Here, we demonstrate that compression of cells, resulting from various types of physical stresses, can induce dedifferentiation of adipocytes via mechanically activating Wnt/β-catenin signaling. The compression-induced dedifferentiated adipocytes (CiDAs) have a distinct transcriptome profile, long-term self-renewal, and serial clonogenicity, but do not form teratomas. We then show that CiDAs notably enhance human mammary adenocarcinoma proliferation both in vitro and in a xenograft model, owing to myofibrogenesis of CiDAs in the tumor-conditioned environment. Collectively, our results highlight unique physical interplay in the tumor ecosystem; tumor-induced physical stresses stimulate de novo generation of CiDAs, which feedback to tumor growth.

    更新日期:2020-01-23
  • Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    K. Xhima, K. Markham-Coultes, H. Nedev, S. Heinen, H. U. Saragovi, K. Hynynen, I. Aubert

    The degeneration of cholinergic neurons is a prominent feature of Alzheimer’s disease (AD). In animal models of injury and aging, nerve growth factor (NGF) enhances cholinergic cell survival and function, contributing to improved memory. In the presence of AD pathology, however, NGF-related therapeutics have yet to fulfill their regenerative potential. We propose that stimulating the TrkA receptor, without p75NTR activation, is key for therapeutic efficacy. Supporting this hypothesis, the selective TrkA agonist D3 rescued neurotrophin signaling in TgCRND8 mice, whereas NGF, interacting with both TrkA and p75NTR, did not. D3, delivered intravenously and noninvasively to the basal forebrain using MRI-guided focused ultrasound (MRIgFUS)–mediated blood-brain barrier (BBB) permeability activated TrkA-related signaling cascades and enhanced cholinergic neurotransmission. Recent clinical trials support the safety and feasibility of MRIgFUS BBB modulation in AD patients. Neuroprotective agents targeting TrkA, combined with MRIgFUS BBB modulation, represent a promising strategy to counter neurodegeneration in AD.

    更新日期:2020-01-23
  • Different motilities of microtubules driven by kinesin-1 and kinesin-14 motors patterned on nanopillars
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Taikopaul Kaneko, Ken’ya Furuta, Kazuhiro Oiwa, Hirofumi Shintaku, Hidetoshi Kotera, Ryuji Yokokawa

    Kinesin is a motor protein that plays important roles in a variety of cellular functions. In vivo, multiple kinesin molecules are bound to cargo and work as a team to produce larger forces or higher speeds than a single kinesin. However, the coordination of kinesins remains poorly understood because of the experimental difficulty in controlling the number and arrangement of kinesins, which are considered to affect their coordination. Here, we report that both the number and spacing significantly influence the velocity of microtubules driven by nonprocessive kinesin-14 (Ncd), whereas neither the number nor the spacing changes the velocity in the case of highly processive kinesin-1. This result was realized by the optimum nanopatterning method of kinesins that enables immobilization of a single kinesin on a nanopillar. Our proposed method enables us to study the individual effects of the number and spacing of motors on the collective dynamics of multiple motors.

    更新日期:2020-01-23
  • Molecular identification of fungi microfossils in a Neoproterozoic shale rock
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    S. Bonneville, F. Delpomdor, A. Préat, C. Chevalier, T. Araki, M. Kazemian, A. Steele, A. Schreiber, R. Wirth, L. G. Benning

    Precambrian fossils of fungi are sparse, and the knowledge of their early evolution and the role they played in the colonization of land surface are limited. Here, we report the discovery of fungi fossils in a 810 to 715 million year old dolomitic shale from the Mbuji-Mayi Supergroup, Democratic Republic of Congo. Syngenetically preserved in a transitional, subaerially exposed paleoenvironment, these carbonaceous filaments of ~5 μm in width exhibit low-frequency septation (pseudosepta) and high-angle branching that can form dense interconnected mycelium-like structures. Using an array of microscopic (SEM, TEM, and confocal laser scanning fluorescence microscopy) and spectroscopic techniques (Raman, FTIR, and XANES), we demonstrated the presence of vestigial chitin in these fossil filaments and document the eukaryotic nature of their precursor. Based on those combined evidences, these fossil filaments and mycelium-like structures are identified as remnants of fungal networks and represent the oldest, molecularly identified remains of Fungi.

    更新日期:2020-01-23
  • Novel CD11b+Gr-1+Sca-1+ myeloid cells drive mortality in bacterial infection
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Min Young Park, Hyung Sik Kim, Ha Young Lee, Brian A. Zabel, Yoe-Sik Bae

    Extreme pathophysiological stressors induce expansion of otherwise infrequent leukocyte populations. Here, we found a previously unidentified CD11b+Gr-1+ myeloid cell population that expresses stem cell antigen-1 (Sca-1) induced upon experimental infection with Staphylococcus aureus. Although CD11b+Gr-1+Sca-1+ cells have impaired migratory capacity and superoxide anion–producing activity, they secrete increased levels of several cytokines and chemokines compared to Sca-1− counterparts. The generation of CD11b+Gr-1+Sca-1+ cells is dependent on IFN-γ in vivo, and in vitro stimulation of bone marrow cells or granulocyte-macrophage progenitors with IFN-γ generated CD11b+Gr-1+Sca-1+ cells. Depletion of CD11b+Gr-1+Sca-1+ cells by administrating anti–Sca-1 antibody strongly increased survival rates in an S. aureus infection model by reducing organ damage and inflammatory cytokines. However, adoptive transfer of CD11b+Gr-1+Sca-1+ cells decreased survival rates by worsening the pathogenesis of S. aureus infection. Together, we found a previously unidentified pathogenic CD11b+Gr-1+Sca-1+ population that plays an essential role in mortality during bacterial infection.

    更新日期:2020-01-23
  • Multi-isotope evidence for the emergence of cultural alterity in Late Neolithic Europe
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    T. Fernández-Crespo, C. Snoeck, J. Ordoño, N. J. de Winter, A. Czermak, N. Mattielli, J. A. Lee-Thorp, R. J. Schulting

    The coexistence of cultural identities and their interaction is a fundamental topic of social sciences that is not easily addressed in prehistory. Differences in mortuary treatment can help approach this issue. Here, we present a multi-isotope study to track both diet and mobility through the life histories of 32 broadly coeval Late Neolithic individuals interred in caves and in megalithic graves of a restricted region of northern Iberia. The results show significant differences in infant- and child-rearing practices, in subsistence strategies, and in landscape use between burial locations. From this, we posit that the presence of communities with distinct lifestyles and cultural backgrounds is a primary reason for Late Neolithic variability in burial location in Western Europe and provides evidence of an early “them and us” scenario. We argue that this differentiation could have played a role in the building of lasting structures of socioeconomic inequality and, occasionally, violent conflict.

    更新日期:2020-01-23
  • Atmospheric CO2 levels from 2.7 billion years ago inferred from micrometeorite oxidation
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    O. R. Lehmer, D. C. Catling, R. Buick, D. E. Brownlee, S. Newport

    Earth’s atmospheric composition during the Archean eon of 4 to 2.5 billion years ago has few constraints. However, the geochemistry of recently discovered iron-rich micrometeorites from 2.7 billion–year–old limestones could serve as a proxy for ancient gas concentrations. When micrometeorites entered the atmosphere, they melted and preserved a record of atmospheric interaction. We model the motion, evaporation, and kinetic oxidation by CO2 of micrometeorites entering a CO2-rich atmosphere. We consider a CO2-rich rather than an O2-rich atmosphere, as considered previously, because this better represents likely atmospheric conditions in the anoxic Archean. Our model reproduces the observed oxidation state of micrometeorites at 2.7 Ga for an estimated atmospheric CO2 concentration of >70% by volume. Even if the early atmosphere was thinner than today, the elevated CO2 level indicated by our model result would help resolve how the Late Archean Earth remained warm when the young Sun was ~20% fainter.

    更新日期:2020-01-23
  • Seismic evidence for megathrust fault-valve behavior during episodic tremor and slip
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Jeremy M. Gosselin, Pascal Audet, Clément Estève, Morgan McLellan, Stephen G. Mosher, Andrew J. Schaeffer

    Fault slip behavior during episodic tremor and slow slip (ETS) events, which occur at the deep extension of subduction zone megathrust faults, is believed to be related to cyclic fluid processes that necessitate fluctuations in pore-fluid pressures. In most subduction zones, a layer of anomalously low seismic wave velocities [low-velocity layer (LVL)] is observed in the vicinity of ETS and suggests high pore-fluid pressures that weaken the megathrust. Using repeated seismic scattering observations in the Cascadia subduction zone, we observe a change in the seismic velocity associated with the LVL after ETS events, which we interpret as a response to fluctuations in pore-fluid pressure. These results provide direct evidence of megathrust fault-valve processes during ETS.

    更新日期:2020-01-23
  • Isothermal digital detection of microRNAs using background-free molecular circuit
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Guillaume Gines, Roberta Menezes, Kaori Nara, Anne-Sophie Kirstetter, Valerie Taly, Yannick Rondelez

    MicroRNAs, a class of transcripts involved in the regulation of gene expression, are emerging as promising disease-specific biomarkers accessible from tissues or bodily fluids. However, their accurate quantification from biological samples remains challenging. We report a sensitive and quantitative microRNA detection method using an isothermal amplification chemistry adapted to a droplet digital readout. Building on molecular programming concepts, we design a DNA circuit that converts, thresholds, amplifies, and reports the presence of a specific microRNA, down to the femtomolar concentration. Using a leak absorption mechanism, we were able to suppress nonspecific amplification, classically encountered in other exponential amplification reactions. As a result, we demonstrate that this isothermal amplification scheme is adapted to digital counting of microRNAs: By partitioning the reaction mixture into water-in-oil droplets, resulting in single microRNA encapsulation and amplification, the method provides absolute target quantification. The modularity of our approach enables to repurpose the assay for various microRNA sequences.

    更新日期:2020-01-23
  • Imperceptible magnetic sensor matrix system integrated with organic driver and amplifier circuits
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    M. Kondo, M. Melzer, D. Karnaushenko, T. Uemura, S. Yoshimoto, M. Akiyama, Y. Noda, T. Araki, O. G. Schmidt, T. Sekitani

    Artificial electronic skins (e-skins) comprise an integrated matrix of flexible devices arranged on a soft, reconfigurable surface. These sensors must perceive physical interaction spaces between external objects and robots or humans. Among various types of sensors, flexible magnetic sensors and the matrix configuration are preferable for such position sensing. However, sensor matrices must efficiently map the magnetic field with real-time encoding of the positions and motions of magnetic objects. This paper reports an ultrathin magnetic sensor matrix system comprising a 2 × 4 array of magnetoresistance sensors, a bootstrap organic shift register driving the sensor matrix, and organic signal amplifiers integrated within a single imperceptible platform. The system demonstrates high magnetic sensitivity owing to the use of organic amplifiers. Moreover, the shift register enabled real-time mapping of 2D magnetic field distribution.

    更新日期:2020-01-23
  • Dense hydroxyl polyethylene glycol dendrimer targets activated glia in multiple CNS disorders
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Anjali Sharma, Rishi Sharma, Zhi Zhang, Kevin Liaw, Siva P. Kambhampati, Joshua E. Porterfield, Ku Chien Lin, Louis B. DeRidder, Sujatha Kannan, Rangaramanujam M. Kannan

    Poor transport of neuropharmaceutics through central nervous system (CNS) barriers limits the development of effective treatments for CNS disorders. We present the facile synthesis of a novel neuroinflammation-targeting polyethylene glycol–based dendrimer (PEGOL-60) using an efficient click chemistry approach. PEGOL-60 reduces synthetic burden by achieving high hydroxyl surface density at low generation, which plays a key role in brain penetration and glia targeting of dendrimers in CNS disorders. Systemically administered PEGOL-60 crosses impaired CNS barriers and specifically targets activated microglia/macrophages at the injured site in diverse animal models for cerebral palsy, glioblastoma, and age-related macular degeneration, demonstrating its potential to overcome impaired blood-brain, blood-tumor-brain, and blood-retinal barriers and target key cells in the CNS. PEGOL-60 also exhibits powerful intrinsic anti-oxidant and anti-inflammatory effects in inflamed microglia in vitro. Therefore, PEGOL-60 is an effective vehicle to specifically deliver therapies to sites of CNS injury for enhanced therapeutic outcomes in a range of neuroinflammatory diseases.

    更新日期:2020-01-23
  • Monoubiquitination of p120-catenin is essential for TGFβ-induced epithelial-mesenchymal transition and tumor metastasis
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Qingang Wu, Gao Li, Chengwen Wen, Taoling Zeng, Yuxi Fan, Chunyan Liu, Guo-Feng Fu, Changchuan Xie, Qi Lin, Liping Xie, Lei Huang, Pengpeng Pu, Zhong Ouyang, Hong-Lin Chan, Tong-Jin Zhao, Xiao Lei Chen, Guo Fu, Hong-Rui Wang

    Disassembly of intercellular junctions is a hallmark of epithelial-mesenchymal transition (EMT). However, how the junctions disassemble remains largely unknown. Here, we report that E3 ubiquitin ligase Smurf1 targets p120-catenin, a core component of adherens junction (AJ) complex, for monoubiquitination during transforming growth factor β (TGFβ)–induced EMT, thereby leading to AJ dissociation. Upon TGFβ treatment, activated extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. Inhibition of T900 phosphorylation or ubiquitination of p120-catenin abrogates TGFβ-induced AJ dissociation and consequent tight junction (TJ) dissociation and cytoskeleton rearrangement, hence markedly blocking lung metastasis of murine breast cancer. Moreover, the T900 phosphorylation level of p120-catenin is positively correlated with malignancy of human breast cancer. Hence, our study reveals the underlying mechanism by which TGFβ induces dissociation of AJs during EMT and provides a potential strategy to block tumor metastasis.

    更新日期:2020-01-23
  • Poly(vinyl alcohol) boosting therapeutic potential of p-boronophenylalanine in neutron capture therapy by modulating metabolism
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-22
    Takahiro Nomoto, Yukiya Inoue, Ying Yao, Minoru Suzuki, Kaito Kanamori, Hiroyasu Takemoto, Makoto Matsui, Keishiro Tomoda, Nobuhiro Nishiyama

    In the current clinical boron neutron capture therapy (BNCT), p-boronophenylalanine (BPA) has been the most powerful drug owing to its ability to accumulate selectively within cancers through cancer-related amino acid transporters including LAT1. However, the therapeutic success of BPA has been sometimes compromised by its unfavorable efflux from cytosol due to their antiport mechanism. Here, we report that poly(vinyl alcohol) (PVA) can form complexes with BPA through reversible boronate esters in aqueous solution, and the complex termed PVA-BPA can be internalized into cancer cells through LAT1-mediated endocytosis, thereby enhancing cellular uptake and slowing the untoward efflux. In in vivo study, compared with clinically used fructose-BPA complexes, PVA-BPA exhibited efficient tumor accumulation and prolonged tumor retention with quick clearance from bloodstream and normal organs. Ultimately, PVA-BPA showed critically enhanced antitumor activity in BNCT. The facile technique proposed in this study offers an approach for drug delivery focusing on drug metabolism.

    更新日期:2020-01-23
  • Four-dimensional micro-building blocks
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    T.-Y. Huang, H.-W. Huang, D. D. Jin, Q. Y. Chen, J. Y. Huang, L. Zhang, H. L. Duan

    Four-dimensional (4D) printing relies on multimaterial printing, reinforcement patterns, or micro/nanofibrous additives as programmable tools to achieve desired shape reconfigurations. However, existing programming approaches still follow the so-called origami design principle to generate reconfigurable structures by self-folding stacked 2D materials, particularly at small scales. Here, we propose a programmable modular design that directly constructs 3D reconfigurable microstructures capable of sophisticated 3D-to-3D shape transformations by assembling 4D micro-building blocks. 4D direct laser writing is used to print two-photon polymerizable, stimuli-responsive hydrogels to construct building blocks at micrometer scales. Denavit-Hartenberg (DH) parameters, used to define robotic arm kinematics, are introduced as guidelines for how to assemble the micro-building blocks and plan the 3D motion of assembled chain blocks. Last, a 3D-printed microscaled transformer capable of changing its shape from a race car to a humanoid robot is devised and fabricated using the DH parameters to guide the motion of various assembled compartments.

    更新日期:2020-01-17
  • When and how self-cleaning of superhydrophobic surfaces works
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Florian Geyer, Maria D’Acunzi, Azadeh Sharifi-Aghili, Alexander Saal, Nan Gao, Anke Kaltbeitzel, Tim-Frederik Sloot, Rüdiger Berger, Hans-Jürgen Butt, Doris Vollmer

    Despite the enormous interest in superhydrophobicity for self-cleaning, a clear picture of contaminant removal is missing, in particular, on a single-particle level. Here, we monitor the removal of individual contaminant particles on the micrometer scale by confocal microscopy. We correlate this space- and time-resolved information with measurements of the friction force. The balance of capillary and adhesion force between the drop and the contamination on the substrate determines the friction force of drops during self-cleaning. These friction forces are in the range of micro-Newtons. We show that hydrophilic and hydrophobic particles hardly influence superhydrophobicity provided that the particle size exceeds the pore size or the thickness of the contamination falls below the height of the protrusions. These detailed insights into self-cleaning allow the rational design of superhydrophobic surfaces that resist contamination as demonstrated by outdoor environmental (>200 days) and industrial standardized contamination experiments.

    更新日期:2020-01-17
  • Anisotropic dynamics and kinetic arrest of dense colloidal ellipsoids in the presence of an external field studied by differential dynamic microscopy
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Antara Pal, Vincent A. Martinez, Thiago H. Ito, Jochen Arlt, Jérôme J. Crassous, Wilson C. K. Poon, Peter Schurtenberger

    Anisotropic dynamics on the colloidal length scale is ubiquitous in nature. Of particular interest is the dynamics of systems approaching a kinetically arrested state. The failure of classical techniques for investigating the dynamics of highly turbid suspensions has contributed toward the limited experimental information available up until now. Exploiting the recent developments in the technique of differential dynamic microscopy (DDM), we report the first experimental study of the anisotropic collective dynamics of colloidal ellipsoids with a magnetic hematite core over a wide concentration range approaching kinetic arrest. In addition, we have investigated the effect of an external magnetic field on the resulting anisotropic collective diffusion. We combine DDM with small-angle x-ray scattering and rheological measurements to locate the glass transition and to relate the collective short- and long-time diffusion coefficients to the structural correlations and the evolution of the zero shear viscosity as the system approaches an arrested state.

    更新日期:2020-01-17
  • Ultrafast x-ray diffraction study of melt-front dynamics in polycrystalline thin films
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Tadesse A. Assefa, Yue Cao, Soham Banerjee, Sungwon Kim, Dongjin Kim, Heemin Lee, Sunam Kim, Jae Hyuk Lee, Sang-Youn Park, Intae Eom, Jaeku Park, Daewoog Nam, Sangsoo Kim, Sae Hwan Chun, Hyojung Hyun, Kyung sook Kim, Pavol Juhas, Emil S. Bozin, Ming Lu, Changyong Song, Hyunjung Kim, Simon J. L. Billinge, Ian K. Robinson

    Melting is a fundamental process of matter that is still not fully understood at the microscopic level. Here, we use time-resolved x-ray diffraction to examine the ultrafast melting of polycrystalline gold thin films using an optical laser pump followed by a delayed hard x-ray probe pulse. We observe the formation of an intermediate new diffraction peak, which we attribute to material trapped between the solid and melted states, that forms 50 ps after laser excitation and persists beyond 500 ps. The peak width grows rapidly for 50 ps and then narrows distinctly at longer time scales. We attribute this to a melting band originating from the grain boundaries and propagating into the grains. Our observation of this intermediate state has implications for the use of ultrafast lasers for ablation during pulsed laser deposition.

    更新日期:2020-01-17
  • Shape-morphing living composites
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    L. K. Rivera-Tarazona, V. D. Bhat, H. Kim, Z. T. Campbell, T. H. Ware

    This work establishes a means to exploit genetic networks to create living synthetic composites that change shape in response to specific biochemical or physical stimuli. Baker’s yeast embedded in a hydrogel forms a responsive material where cellular proliferation leads to a controllable increase in the composite volume of up to 400%. Genetic manipulation of the yeast enables composites where volume change on exposure to l-histidine is 14× higher than volume change when exposed to d-histidine or other amino acids. By encoding an optogenetic switch into the yeast, spatiotemporally controlled shape change is induced with pulses of dim blue light (2.7 mW/cm2). These living, shape-changing materials may enable sensors or medical devices that respond to highly specific cues found within a biological milieu.

    更新日期:2020-01-17
  • Light-degradable hydrogels as dynamic triggers for gastrointestinal applications
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Ritu Raman, Tiffany Hua, Declan Gwynne, Joy Collins, Siddartha Tamang, Jianlin Zhou, Tina Esfandiary, Vance Soares, Simo Pajovic, Alison Hayward, Robert Langer, Giovanni Traverso

    Triggerable materials capable of being degraded by selective stimuli stand to transform our capacity to precisely control biomedical device activity and performance while reducing the need for invasive interventions. Here, we describe the development of a modular and tunable light-triggerable hydrogel system capable of interfacing with implantable devices. We apply these materials to two applications in the gastrointestinal (GI) tract: a bariatric balloon and an esophageal stent. We demonstrate biocompatibility and on-demand triggering of the material in vitro, ex vivo, and in vivo. Moreover, we characterize performance of the system in a porcine large animal model with an accompanying ingestible LED. Light-triggerable hydrogels have the potential to be applied broadly throughout the GI tract and other anatomic areas. By demonstrating the first use of light-degradable hydrogels in vivo, we provide biomedical engineers and clinicians with a previously unavailable, safe, dynamically deliverable, and precise tool to design dynamically actuated implantable devices.

    更新日期:2020-01-17
  • Access to tetracyclic aromatics with bridgehead metals via metalla-click reactions
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Zhengyu Lu, Qin Zhu, Yuanting Cai, Zhixin Chen, Kaiyue Zhuo, Jun Zhu, Hong Zhang, Haiping Xia

    The never-ending pursuits for exploring aromatic molecular architectures result in the large libraries of aromatics with fascinating structures, which have greatly broadened the scope of aromaticity. Despite extensive efforts that have been paid to develop aromatic frameworks, the construction of polycyclic aromatics that share a bridgehead atom with more than three rings has never been accomplished. Here, an unprecedented family of aromatics, in which a metal center shared by 4 five-membered aromatic rings, has been achieved by using the metalla-click reactions with excellent yields and remarkable regioselectivity. The distinctive tetracyclic aromatics exhibit a broad absorption in the ultraviolet-visible near-infrared region and excellent thermal stability in air, enabling their potential applications in photoelectric materials and biomedicine. This study now makes it possible to incorporate four aromatic rings with one common sharing metal center by a straightforward strategy that would promote further development of previously unknown polycyclic complex motifs in aromatic chemistry.

    更新日期:2020-01-17
  • Monolithic mtesla-level magnetic induction by self-rolled-up membrane technology
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Wen Huang, Zhendong Yang, Mark D. Kraman, Qingyi Wang, Zihao Ou, Miguel Muñoz Rojo, Ananth Saran Yalamarthy, Victoria Chen, Feifei Lian, Jimmy H. Ni, Siyu Liu, Haotian Yu, Lei Sang, Julian Michaels, Dane J. Sievers, J. Gary Eden, Paul V. Braun, Qian Chen, Songbin Gong, Debbie G. Senesky, Eric Pop, Xiuling Li

    Monolithic strong magnetic induction at the mtesla to tesla level provides essential functionalities to physical, chemical, and medical systems. Current design options are constrained by existing capabilities in three-dimensional (3D) structure construction, current handling, and magnetic material integration. We report here geometric transformation of large-area and relatively thick (~100 to 250 nm) 2D nanomembranes into multiturn 3D air-core microtubes by a vapor-phase self-rolled-up membrane (S-RuM) nanotechnology, combined with postrolling integration of ferrofluid magnetic materials by capillary force. Hundreds of S-RuM power inductors on sapphire are designed and tested, with maximum operating frequency exceeding 500 MHz. An inductance of 1.24 μH at 10 kHz has been achieved for a single microtube inductor, with corresponding areal and volumetric inductance densities of 3 μH/mm2 and 23 μH/mm3, respectively. The simulated intensity of the magnetic induction reaches tens of mtesla in fabricated devices at 10 MHz.

    更新日期:2020-01-17
  • Imaging an unsupported metal–metal bond in dirhenium molecules at the atomic scale
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Kecheng Cao, Stephen T. Skowron, Johannes Biskupek, Craig T. Stoppiello, Christopher Leist, Elena Besley, Andrei N. Khlobystov, Ute Kaiser

    Metallic bonds remain one of the most important and least understood of the chemical bonds. In this study, we generated Re2 molecules in which the Re–Re core is unsupported by ligands. Real-time imaging of the atomic-scale dynamics of Re2 adsorbed on a graphitic lattice allows direct measurement of Re–Re bond lengths for individual molecules that changes in discrete steps correlating with bond order from one to four. Direct imaging of the Re–Re bond breaking process reveals a new bonding state with the bond order less than one and a high-amplitude vibrational stretch, preceding the bond dissociation. The methodology, based on aberration-corrected transmission electron microscopy imaging, is shown to be a powerful analytical tool for the investigation of dynamics of metallic bonding at the atomic level.

    更新日期:2020-01-17
  • Picosecond-resolution phase-sensitive imaging of transparent objects in a single shot
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Taewoo Kim, Jinyang Liang, Liren Zhu, Lihong V. Wang

    With the growing interest in the optical imaging of ultrafast phenomena in transparent objects, from shock wave to neuronal action potentials, high contrast imaging at high frame rates has become desirable. While phase sensitivity provides the contrast, the frame rates and sequence depths are highly limited by the detectors. Here, we present phase-sensitive compressed ultrafast photography (pCUP) for single-shot real-time ultrafast imaging of transparent objects by combining the contrast of dark-field imaging with the speed and the sequence depth of CUP. By imaging the optical Kerr effect and shock wave propagation, we demonstrate that pCUP can image light-speed phase signals in a single shot with up to 350 frames captured at up to 1 trillion frames per second. We expect pCUP to be broadly used for a vast range of fundamental and applied sciences.

    更新日期:2020-01-17
  • Biophysical and biomolecular interactions of malaria-infected erythrocytes in engineered human capillaries
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Christopher Arakawa, Celina Gunnarsson, Caitlin Howard, Maria Bernabeu, Kiet Phong, Eric Yang, Cole A. DeForest, Joseph D. Smith, Ying Zheng

    Microcirculatory obstruction is a hallmark of severe malaria, but mechanisms of parasite sequestration are only partially understood. Here, we developed a robust three-dimensional microvessel model that mimics the arteriole-capillary-venule (ACV) transition consisting of a narrow 5- to 10-μm-diameter capillary region flanked by arteriole- or venule-sized vessels. Using this platform, we investigated red blood cell (RBC) transit at the single cell and at physiological hematocrits. We showed normal RBCs deformed via in vivo–like stretching and tumbling with negligible interactions with the vessel wall. By comparison, Plasmodium falciparum–infected RBCs exhibited virtually no deformation and rapidly accumulated in the capillary-sized region. Comparison of wild-type parasites to those lacking either cytoadhesion ligands or membrane-stiffening knobs showed highly distinctive spatial and temporal kinetics of accumulation, linked to velocity transition in ACVs. Our findings shed light on mechanisms of microcirculatory obstruction in malaria and establish a new platform to study hematologic and microvascular diseases.

    更新日期:2020-01-17
  • Ultrafast optically induced spin transfer in ferromagnetic alloys
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    M. Hofherr, S. Häuser, J. K. Dewhurst, P. Tengdin, S. Sakshath, H. T. Nembach, S. T. Weber, J. M. Shaw, T. J. Silva, H. C. Kapteyn, M. Cinchetti, B. Rethfeld, M. M. Murnane, D. Steil, B. Stadtmüller, S. Sharma, M. Aeschlimann, S. Mathias

    The vision of using light to manipulate electronic and spin excitations in materials on their fundamental time and length scales requires new approaches in experiment and theory to observe and understand these excitations. The ultimate speed limit for all-optical manipulation requires control schemes for which the electronic or magnetic subsystems of the materials are coherently manipulated on the time scale of the laser excitation pulse. In our work, we provide experimental evidence of such a direct, ultrafast, and coherent spin transfer between two magnetic subsystems of an alloy of Fe and Ni. Our experimental findings are fully supported by time-dependent density functional theory simulations and, hence, suggest the possibility of coherently controlling spin dynamics on subfemtosecond time scales, i.e., the birth of the research area of attomagnetism.

    更新日期:2020-01-17
  • Nearly room temperature ferromagnetism in a magnetic metal-rich van der Waals metal
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Junho Seo, Duck Young Kim, Eun Su An, Kyoo Kim, Gi-Yeop Kim, Soo-Yoon Hwang, Dong Wook Kim, Bo Gyu Jang, Heejung Kim, Gyeongsik Eom, Seung Young Seo, Roland Stania, Matthias Muntwiler, Jinwon Lee, Kenji Watanabe, Takashi Taniguchi, Youn Jung Jo, Jieun Lee, Byung Il Min, Moon Ho Jo, Han Woong Yeom, Si-Young Choi, Ji Hoon Shim, Jun Sung Kim

    In spintronics, two-dimensional van der Waals crystals constitute a most promising material class for long-distance spin transport or effective spin manipulation at room temperature. To realize all-vdW-material–based spintronic devices, however, vdW materials with itinerant ferromagnetism at room temperature are needed for spin current generation and thereby serve as an effective spin source. We report theoretical design and experimental realization of a iron-based vdW material, Fe4GeTe2, showing a nearly room temperature ferromagnetic order, together with a large magnetization and high conductivity. These properties are well retained even in cleaved crystals down to seven layers, with notable improvement in perpendicular magnetic anisotropy. Our findings highlight Fe4GeTe2 and its nanometer-thick crystals as a promising candidate for spin source operation at nearly room temperature and hold promise to further increase Tc in vdW ferromagnets by theory-guided material discovery.

    更新日期:2020-01-17
  • Real-time observation of water radiolysis and hydrated electron formation induced by extreme-ultraviolet pulses
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Vít Svoboda, Rupert Michiels, Aaron C. LaForge, Jakub Med, Frank Stienkemeier, Petr Slavíček, Hans Jakob Wörner

    The dominant pathway of radiation damage begins with the ionization of water. Thus far, however, the underlying primary processes could not be conclusively elucidated. Here, we directly study the earliest steps of extreme ultraviolet (XUV)–induced water radiolysis through one-photon excitation of large water clusters using time-resolved photoelectron imaging. Results are presented for H2O and D2O clusters using femtosecond pump pulses centered at 133 or 80 nm. In both excitation schemes, hydrogen or proton transfer is observed to yield a prehydrated electron within 30 to 60 fs, followed by its solvation in 0.3 to 1.0 ps and its decay through geminate recombination on a ∼10-ps time scale. These results are interpreted by comparison with detailed multiconfigurational non-adiabatic ab-initio molecular dynamics calculations. Our results provide the first comprehensive picture of the primary steps of radiation chemistry and radiation damage and demonstrate new approaches for their study with unprecedented time resolution.

    更新日期:2020-01-17
  • Direct light–induced spin transfer between different elements in a spintronic Heusler material via femtosecond laser excitation
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-17
    Phoebe Tengdin, Christian Gentry, Adam Blonsky, Dmitriy Zusin, Michael Gerrity, Lukas Hellbrück, Moritz Hofherr, Justin Shaw, Yaroslav Kvashnin, Erna K. Delczeg-Czirjak, Monika Arora, Hans Nembach, Tom J. Silva, Stefan Mathias, Martin Aeschlimann, Henry C. Kapteyn, Danny Thonig, Konstantinos Koumpouras, Olle Eriksson, Margaret M. Murnane

    Heusler compounds are exciting materials for future spintronics applications because they display a wide range of tunable electronic and magnetic interactions. Here, we use a femtosecond laser to directly transfer spin polarization from one element to another in a half-metallic Heusler material, Co2MnGe. This spin transfer initiates as soon as light is incident on the material, demonstrating spatial transfer of angular momentum between neighboring atomic sites on time scales < 10 fs. Using ultrafast high harmonic pulses to simultaneously and independently probe the magnetic state of two elements during laser excitation, we find that the magnetization of Co is enhanced, while that of Mn rapidly quenches. Density functional theory calculations show that the optical excitation directly transfers spin from one magnetic sublattice to another through preferred spin-polarized excitation pathways. This direct manipulation of spins via light provides a path toward spintronic devices that can operate on few-femtosecond or faster time scales.

    更新日期:2020-01-17
  • Antibiotic production in Streptomyces is organized by a division of labor through terminal genomic differentiation
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Zheren Zhang, Chao Du, Frédérique de Barsy, Michael Liem, Apostolos Liakopoulos, Gilles P. van Wezel, Young H. Choi, Dennis Claessen, Daniel E. Rozen

    One of the hallmark behaviors of social groups is division of labor, where different group members become specialized to carry out complementary tasks. By dividing labor, cooperative groups increase efficiency, thereby raising group fitness even if these behaviors reduce individual fitness. We find that antibiotic production in colonies of Streptomyces coelicolor is coordinated by a division of labor. We show that S. coelicolor colonies are genetically heterogeneous because of amplifications and deletions to the chromosome. Cells with chromosomal changes produce diversified secondary metabolites and secrete more antibiotics; however, these changes reduced individual fitness, providing evidence for a trade-off between antibiotic production and fitness. Last, we show that colonies containing mixtures of mutants and their parents produce significantly more antibiotics, while colony-wide spore production remains unchanged. By generating specialized mutants that hyper-produce antibiotics, streptomycetes reduce the fitness costs of secreted secondary metabolites while maximizing the yield and diversity of these products.

    更新日期:2020-01-16
  • Shallow slow slip events along the Nankai Trough detected by GNSS-A
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Yusuke Yokota, Tadashi Ishikawa

    Various slow earthquakes (SEQs), including tremors, very low frequency events, and slow slip events (SSEs), occur along megathrust zones. In a shallow plate boundary region, although many SEQs have been observed along pan-Pacific subduction zones, SSEs with a duration on the order of a year or with a large slip have not yet been detected due to difficulty in offshore observation. We try to statistically detect transient seafloor crustal deformations from seafloor geodetic data obtained by the Global Navigation Satellite System-Acoustic (GNSS-A) combination technique, which enables monitoring the seafloor absolute position. Here, we report the first detection of signals probably caused by shallow large SSEs along the Nankai Trough and indicate the timings and approximate locations of probable SSEs. The results show the existence of large SSEs around the shallow side of strong coupling regions and indicate the spatiotemporal relationship with other SEQ activities expected in past studies.

    更新日期:2020-01-16
  • Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Jason R. Plemel, Jo Anne Stratton, Nathan J. Michaels, Khalil S. Rawji, Eric Zhang, Sarthak Sinha, Charbel S. Baaklini, Yifei Dong, Madelene Ho, Kevin Thorburn, Timothy N. Friedman, Sana Jawad, Claudia Silva, Andrew V. Caprariello, Vahid Hoghooghi, Julie Yue, Arzina Jaffer, Kelly Lee, Bradley J. Kerr, Raj Midha, Peter K. Stys, Jeff Biernaskie, V. Wee Yong

    Microglia and infiltrating macrophages are thought to orchestrate the central nervous system (CNS) response to injury; however, the similarities between these cells make it challenging to distinguish their relative contributions. We genetically labeled microglia and CNS-associated macrophages to distinguish them from infiltrating macrophages. Using single-cell RNA sequencing, we describe multiple microglia activation states, one of which was enriched for interferon associated signaling. Although blood-derived macrophages acutely infiltrated the demyelinated lesion, microglia progressively monopolized the lesion environment where they surrounded infiltrating macrophages. In the microglia-devoid sciatic nerve, the infiltrating macrophage response was sustained. In the CNS, the preferential proliferation of microglia and sparse microglia death contributed to microglia dominating the lesion. Microglia ablation reversed the spatial restriction of macrophages with the demyelinated spinal cord, highlighting an unrealized macrophages-microglia interaction. The restriction of peripheral inflammation by microglia may be a previously unidentified mechanism by which the CNS maintains its “immune privileged” status.

    更新日期:2020-01-16
  • Modulation of lymphocyte-mediated tissue repair by rational design of heterocyclic aryl hydrocarbon receptor agonists
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Jiaxuan Chen, Carolyn A. Haller, Finith E. Jernigan, Steffi K. Koerner, Daniel J. Wong, Yiqiang Wang, Jae Eun Cheong, Revanth Kosaraju, Julian Kwan, Diane D. Park, Beena Thomas, Swati Bhasin, Roberto C. De La Rosa, Alykhan M. Premji, Liying Liu, Eden Park, Alan C. Moss, Andrew Emili, Manoj Bhasin, Lijun Sun, Elliot L. Chaikof

    Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium–induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.

    更新日期:2020-01-16
  • The 22 December 2018 tsunami from flank collapse of Anak Krakatau volcano during eruption
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Lingling Ye, Hiroo Kanamori, Luis Rivera, Thorne Lay, Yu Zhou, Dimas Sianipar, Kenji Satake

    On 22 December 2018, a devastating tsunami struck Sunda Strait, Indonesia without warning, leaving 437 dead and thousands injured along the western Java and southern Sumatra coastlines. Synthetic aperture radar and broadband seismic observations demonstrate that a small, <~0.2 km3 landslide on the southwestern flank of the actively erupting volcano Anak Krakatau generated the tsunami. The landslide did not produce strong short-period seismic waves; thus, precursory ground shaking did not provide a tsunami warning. The source of long-period ground motions during the landslide can be represented as a 12° upward-dipping single-force directed northeastward, with peak magnitude of ~6.1 × 1011 N and quasi-sinusoidal time duration of ~70 s. Rapid quantification of a landslide source process by long-period seismic wave inversions for moment-tensor and single-force parameterizations using regional seismic data available within ~8 min can provide a basis for future fast tsunami warnings, as is also the case for tsunami earthquakes.

    更新日期:2020-01-16
  • Triangular correlation (TrC) between cancer aggressiveness, cell uptake capability, and cell deformability
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Yifat Brill-Karniely, Dvir Dror, Tal Duanis-Assaf, Yoel Goldstein, Ouri Schwob, Talya Millo, Natalie Orehov, Tal Stern, Mohammad Jaber, Netanel Loyfer, Margarita Vosk-Artzi, Hadar Benyamini, Diane Bielenberg, Tommy Kaplan, Yosef Buganim, Meital Reches, Ofra Benny

    The malignancy potential is correlated with the mechanical deformability of the cancer cells. However, mechanical tests for clinical applications are limited. We present here a Triangular Correlation (TrC) between cell deformability, phagocytic capacity, and cancer aggressiveness, suggesting that phagocytic measurements can be a mechanical surrogate marker of malignancy. The TrC was proved in human prostate cancer cells with different malignancy potential, and in human bladder cancer and melanoma cells that were sorted into subpopulations based solely on their phagocytic capacity. The more phagocytic subpopulations showed elevated aggressiveness ex vivo and in vivo. The uptake potential was preserved, and differences in gene expression and in epigenetic signature were detected. In all cases, enhanced phagocytic and aggressiveness phenotypes were correlated with greater cell deformability and predicted by a computational model. Our multidisciplinary study provides the proof of concept that phagocytic measurements can be applied for cancer diagnostics and precision medicine.

    更新日期:2020-01-16
  • Decreased nonspecific adhesivity, receptor-targeted therapeutic nanoparticles for primary and metastatic breast cancer
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Jimena G. Dancy, Aniket S. Wadajkar, Nina P. Connolly, Rebeca Galisteo, Heather M. Ames, Sen Peng, Nhan L. Tran, Olga G. Goloubeva, Graeme F. Woodworth, Jeffrey A. Winkles, Anthony J. Kim

    Development of effective tumor cell–targeted nanodrug formulations has been quite challenging, as many nanocarriers and targeting moieties exhibit nonspecific binding to cellular, extracellular, and intravascular components. We have developed a therapeutic nanoparticle formulation approach that balances cell surface receptor-specific binding affinity while maintaining minimal interactions with blood and tumor tissue components (termed “DART” nanoparticles), thereby improving blood circulation time, biodistribution, and tumor cell–specific uptake. Here, we report that paclitaxel (PTX)–DART nanoparticles directed to the cell surface receptor fibroblast growth factor–inducible 14 (Fn14) outperformed both the corresponding PTX-loaded, nontargeted nanoparticles and Abraxane, an FDA-approved PTX nanoformulation, in both a primary triple-negative breast cancer (TNBC) model and an intracranial model reflecting TNBC growth following metastatic dissemination to the brain. These results provide new insights into methods for effective development of therapeutic nanoparticles as well as support the continued development of the DART platform for primary and metastatic tumors.

    更新日期:2020-01-16
  • Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Kuan-Wei Huang, Fu-Fei Hsu, Jiantai Timothy Qiu, Guann-Jen Chern, Yi-An Lee, Chih-Chun Chang, Yu-Ting Huang, Yun-Chieh Sung, Cheng-Chin Chiang, Rui-Lin Huang, Chu-Chi Lin, Trinh Kieu Dinh, Hsi-Chien Huang, Yu-Chuan Shih, Donia Alson, Chun-Yen Lin, Yung-Chang Lin, Po-Chiao Chang, Shu-Yi Lin, Yunching Chen

    While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)–cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2–encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

    更新日期:2020-01-16
  • The Euler spiral of rat whiskers
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Eugene L. Starostin, Robyn A. Grant, Gary Dougill, Gert H. M. van der Heijden, Victor G. A. Goss

    This paper reports on an analytical study of the intrinsic shapes of 523 whiskers from 15 rats. We show that the variety of whiskers on a rat’s cheek, each of which has different lengths and shapes, can be described by a simple mathematical equation such that each whisker is represented as an interval on the Euler spiral. When all the representative curves of mystacial vibrissae for a single rat are assembled together, they span an interval extending from one coiled domain of the Euler spiral to the other. We additionally find that each whisker makes nearly the same angle of 47∘ with the normal to the spherical virtual surface formed by the tips of whiskers, which constitutes the rat’s tactile sensory shroud or “search space.” The implications of the linear curvature model for gaining insight into relationships between growth, form, and function are discussed.

    更新日期:2020-01-16
  • Aquatic and terrestrial cyanobacteria produce methane
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    M. Bižić, T. Klintzsch, D. Ionescu, M. Y. Hindiyeh, M. Günthel, A. M. Muro-Pastor, W. Eckert, T. Urich, F. Keppler, H.-P. Grossart

    Evidence is accumulating to challenge the paradigm that biogenic methanogenesis, considered a strictly anaerobic process, is exclusive to archaea. We demonstrate that cyanobacteria living in marine, freshwater, and terrestrial environments produce methane at substantial rates under light, dark, oxic, and anoxic conditions, linking methane production with light-driven primary productivity in a globally relevant and ancient group of photoautotrophs. Methane production, attributed to cyanobacteria using stable isotope labeling techniques, was enhanced during oxygenic photosynthesis. We suggest that the formation of methane by cyanobacteria contributes to methane accumulation in oxygen-saturated marine and limnic surface waters. In these environments, frequent cyanobacterial blooms are predicted to further increase because of global warming potentially having a direct positive feedback on climate change. We conclude that this newly identified source contributes to the current natural methane budget and most likely has been producing methane since cyanobacteria first evolved on Earth.

    更新日期:2020-01-16
  • Structure-guided discovery of a single-domain antibody agonist against human apelin receptor
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Yanbin Ma, Yao Ding, Xianqiang Song, Xiaochuan Ma, Xun Li, Ning Zhang, Yunpeng Song, Yaping Sun, Yuqing Shen, Wenge Zhong, Liaoyuan A. Hu, Yingli Ma, Mei-Yun Zhang

    Developing antibody agonists targeting the human apelin receptor (APJ) is a promising therapeutic approach for the treatment of chronic heart failure. Here, we report the structure-guided discovery of a single-domain antibody (sdAb) agonist JN241-9, based on the cocrystal structure of APJ with an sdAb antagonist JN241, the first cocrystal structure of a class A G protein–coupled receptor (GPCR) with a functional antibody. As revealed by the structure, JN241 binds to the extracellular side of APJ, makes critical contacts with the second extracellular loop, and inserts the CDR3 into the ligand-binding pocket. We converted JN241 into a full agonist JN241-9 by inserting a tyrosine into the CDR3. Modeling and molecular dynamics simulation shed light on JN241-9–stimulated receptor activation, providing structural insights for finding agonistic antibodies against class A GPCRs.

    更新日期:2020-01-16
  • A low-mass planet candidate orbiting Proxima Centauri at a distance of 1.5 AU
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Mario Damasso, Fabio Del Sordo, Guillem Anglada-Escudé, Paolo Giacobbe, Alessandro Sozzetti, Alessandro Morbidelli, Grzegorz Pojmanski, Domenico Barbato, R. Paul Butler, Hugh R. A. Jones, Franz-Josef Hambsch, James S. Jenkins, María José López-González, Nicolás Morales, Pablo A. Peña Rojas, Cristina Rodríguez-López, Eloy Rodríguez, Pedro J. Amado, Guillem Anglada, Fabo Feng, Jose F. Gómez

    Our nearest neighbor, Proxima Centauri, hosts a temperate terrestrial planet. We detected in radial velocities evidence of a possible second planet with minimum mass mc sin ic = 5.8 ± 1.9M⊕ and orbital period Pc=5.21−0.22+0.26 years. The analysis of photometric data and spectro-scopic activity diagnostics does not explain the signal in terms of a stellar activity cycle, but follow-up is required in the coming years for confirming its planetary origin. We show that the existence of the planet can be ascertained, and its true mass can be determined with high accuracy, by combining Gaia astrometry and radial velocities. Proxima c could become a prime target for follow-up and characterization with next-generation direct imaging instrumentation due to the large maximum angular separation of ~1 arc second from the parent star. The candidate planet represents a challenge for the models of super-Earth formation and evolution.

    更新日期:2020-01-16
  • Atmospheric fungal nanoparticle bursts
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Michael J. Lawler, Danielle C. Draper, James N. Smith

    Aerosol nanoparticles play an important role in the climate system by affecting cloud formation and properties, as well as in human health because of their deep reach into lungs and the circulatory system. Determining nanoparticle sources and composition is a major challenge in assessing their impacts in these areas. The sudden appearance of large numbers of atmospheric nanoparticles is commonly attributed to secondary formation from gas-phase precursors, but in many cases, the evidence for this is equivocal. We report the detection of a mode of fungal fragments with a mobility diameter of roughly 30 nm released in episodic bursts in ambient air over an agricultural area in northern Oklahoma. These events reached concentrations orders of magnitude higher than other reports of biological particles and show similarities to unclarified events reported previously in the Amazon. These particles potentially represent a large source of both cloud-forming ice nuclei and respirable allergens in a variety of ecosystems.

    更新日期:2020-01-16
  • Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant–driven tumor growth
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Seung-Min Shin, Ji-Sun Kim, Seong-Wook Park, Sei-Yong Jun, Hye-Jin Kweon, Dong-Ki Choi, Dakeun Lee, Yong Beom Cho, Yong-Sung Kim

    Oncogenic RAS mutant (RASMUT) proteins have been considered undruggable via conventional antibody regimens owing to the intracellular location restricting conventional-antibody accessibility. Here, we report a pan-RAS–targeting IgG antibody, inRas37, which directly targets the intracellularly activated form of various RASMUT subtypes after tumor cell–specific internalization into the cytosol to block the interactions with effector proteins, thereby suppressing the downstream signaling. Systemic administration of inRas37 exerted a potent antitumor activity in a subset of RASMUT tumor xenografts in mice, but little efficacy in RASMUT tumors with concurrent downstream PI3K mutations, which were overcome by combination with a PI3K inhibitor. The YAP1 protein was up-regulated as an adaptive resistance-inducing response to inRas37 in RASMUT-dependent colorectal tumors; accordingly, a combination of inRas37 with a YAP1 inhibitor manifested synergistic antitumor effects in vitro and in vivo. Our study offers a promising pan-RAS–targeting antibody and the corresponding therapeutic strategy against RASMUT tumors.

    更新日期:2020-01-16
  • Functional validity, role, and implications of heavy alcohol consumption genetic loci
    Sci. Adv. (IF 12.804) Pub Date : 2020-01-15
    Andrew Thompson, James Cook, Hélène Choquet, Eric Jorgenson, Jie Yin, Tarja Kinnunen, Jeff Barclay, Andrew P. Morris, Munir Pirmohamed

    High alcohol consumption is a risk factor for morbidity and mortality, yet few genetic loci have been robustly associated with alcohol intake. Here, we use U.K. Biobank (n = 125,249) and GERA (n = 47,967) datasets to determine genetic factors associated with extreme population-level alcohol consumption and examine the functional validity of outcomes using model organisms and in silico techniques. We identified six loci attaining genome-wide significant association with alcohol consumption after meta-analysis and meeting our criteria for replication: ADH1B (lead SNP: rs1229984), KLB (rs13130794), BTF3P13 (rs144198753), GCKR (rs1260326), SLC39A8 (rs13107325), and DRD2 (rs11214609). A conserved role in phenotypic responses to alcohol was observed for all genetic targets available for investigation (ADH1B, GCKR, SLC39A8, and KLB) in Caenorhabditis elegans. Evidence of causal links to lung cancer, and shared genetic architecture with gout and hypertension was also found. These findings offer insight into genes, pathways, and relationships for disease risk associated with high alcohol consumption.

    更新日期:2020-01-16
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