1 【生物】The target landscape of clinical kinase drugs
Susan Klaeger et.al
Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the “druggable” kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD–positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
2.【生物】Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils
Camilla Engblom et.al
（导读 阿金）积聚在肿瘤内的骨髓细胞可促进肿瘤发展，但此种生长环境对肿瘤生长的作用还知之甚少。本研究发现在患肺腺癌的小鼠身上，即使肺部腺癌病灶未发生骨转移，其成骨钙蛋白表达（Ocn+）骨细胞活性仍有所增加。这些细胞能够为SiglecFhigh 嗜中性粒细胞提供远程支持，从而促进肺部肿瘤生长。而减少Ocn+细胞数目则明显抑制该嗜中性粒细胞反应和肿瘤生长。
Bone marrow–derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn+) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecFhigh neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn+ cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecFhigh neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.
3 【生态】Ocean biogeochemistry modeled with emergent trait-based genomics
V. J. Coles et.al
Marine ecosystem models have advanced to incorporate metabolic pathways discovered with genomic sequencing, but direct comparisons between models and “omics” data are lacking. We developed a model that directly simulates metagenomes and metatranscriptomes for comparison with observations. Model microbes were randomly assigned genes for specialized functions, and communities of 68 species were simulated in the Atlantic Ocean. Unfit organisms were replaced, and the model self-organized to develop community genomes and transcriptomes. Emergent communities from simulations that were initialized with different cohorts of randomly generated microbes all produced realistic vertical and horizontal ocean nutrient, genome, and transcriptome gradients. Thus, the library of gene functions available to the community, rather than the distribution of functions among specific organisms, drove community assembly and biogeochemical gradients in the model ocean.
4 【地球注册新宝GG】Observations and modeling of the elastogravity signals preceding direct seismic waves
Martin Vallée et.al
After an earthquake, the earliest deformation signals are not expected to be carried by the fastest (P) elastic waves but by the speed-of-light changes of the gravitational field. However, these perturbations are weak and, so far, their detection has not been accurate enough to fully understand their origins and to use them for a highly valuable rapid estimate of the earthquake magnitude. We show that gravity perturbations are particularly well observed with broadband seismometers at distances between 1000 and 2000 kilometers from the source of the 2011, moment magnitude 9.1, Tohoku earthquake. We can accurately model them by a new formalism, taking into account both the gravity changes and the gravity-induced motion. These prompt elastogravity signals open the window for minute time-scale magnitude determination for great earthquakes.
5 【化学】Numerical evidence of fluctuating stripes in the normal state of high-Tc cuprate superconductors
Edwin W. Huang et.al
Upon doping, Mott insulators often exhibit symmetry breaking where charge carriers and their spins organize into patterns known as stripes. For high–transition temperature cuprate superconductors, stripes are widely suspected to exist in a fluctuating form. We used numerically exact determinant quantum Monte Carlo calculations to demonstrate dynamical stripe correlations in the three-band Hubbard model, which represents the local electronic structure of the copper-oxygen plane. Our results, which are robust to varying parameters, cluster size, and boundary conditions, support the interpretation of experimental observations such as the hourglass magnetic dispersion and the Yamada plot of incommensurability versus doping in terms of the physics of fluctuating stripes. These findings provide a different perspective on the intertwined orders emerging from the cuprates’ normal state.
6 【化学】Organocalcium-mediated nucleophilic alkylation of benzene
Andrew S. S. Wilson et.al
The electrophilic aromatic substitution of a C–H bond of benzene is one of the archetypal transformations of organic chemistry. In contrast, the electron-rich π-system of benzene is highly resistant to reactions with electron-rich and negatively charged organic nucleophiles. Here, we report that this previously insurmountable electronic repulsion may be overcome through the use of sufficiently potent organocalcium nucleophiles. Calcium n-alkyl derivatives—synthesized by reaction of ethene, but-1-ene, and hex-1-ene with a dimeric calcium hydride—react with protio and deutero benzene at 60°C through nucleophilic substitution of an aromatic C–D/H bond. These reactions produce the n-alkyl benzenes with regeneration of the calcium hydride. Density functional theory calculations implicate an unstabilized Meisenheimer complex in the C–H activation transition state.
7 【生物】The image-forming mirror in the eye of the scallop
Benjamin A. Palmer et.al
Scallops possess a visual system comprising up to 200 eyes, each containing a concave mirror rather than a lens to focus light. The hierarchical organization of the multilayered mirror is controlled for image formation, from the component guanine crystals at the nanoscale to the complex three-dimensional morphology at the millimeter level. The layered structure of the mirror is tuned to reflect the wavelengths of light penetrating the scallop’s habitat and is tiled with a mosaic of square guanine crystals, which reduces optical aberrations. The mirror forms images on a double-layered retina used for separately imaging the peripheral and central fields of view. The tiled, off-axis mirror of the scallop eye bears a striking resemblance to the segmented mirrors of reflecting telescopes.
8 【物理】Giant nonlinear response at a plasmonic nanofocus drives efficient four-wave mixing
Michael P. Nielsen, et.al
Efficient optical frequency mixing typically must accumulate over large interaction lengths because nonlinear responses in natural materials are inherently weak. This limits the efficiency of mixing processes owing to the requirement of phase matching. Here, we report efficient four-wave mixing (FWM) over micrometer-scale interaction lengths at telecommunications wavelengths on silicon. We used an integrated plasmonic gap waveguide that strongly confines light within a nonlinear organic polymer. The gap waveguide intensifies light by nanofocusing it to a mode cross-section of a few tens of nanometers, thus generating a nonlinear response so strong that efficient FWM accumulates over wavelength-scale distances. This technique opens up nonlinear optics to a regime of relaxed phase matching, with the possibility of compact, broadband, and efficient frequency mixing integrated with silicon photonics.
9 【化学】Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds
Yong Yao Loh et.al
（导读 甜甜）氘（D）和氚（T）标记的药物化合物可用来追踪药物分子在体内的动态，是药物研发中的重要工具。本研究提出了一种有效的光氧化还原氢原子传输方法，可利用同位素标记的水作为同位素来源，在α-氨基的sp3 C-H键上选择性地安装D和T，并使用该方法对18种药物分子进行了D、T标记。此外，本研究还提出了由T2合成T2O的简便方法。
Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp3 carbon-hydrogen bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T2, providing access to high-specific-activity T2O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.
10.【物理】Spectroscopic signatures of localization with interacting photons in superconducting qubits
P. Roushan, D. G. Angelakis,et al.
Quantized eigenenergies and their associated wave functions provide extensive information for predicting the physics of quantum many-body systems. Using a chain of nine superconducting qubits, we implement a technique for resolving the energy levels of interacting photons. We benchmark this method by capturing the main features of the intricate energy spectrum predicted for two-dimensional electrons in a magnetic field—the Hofstadter butterfly. We introduce disorder to study the statistics of the energy levels of the system as it undergoes the transition from a thermalized to a localized phase. Our work introduces a many-body spectroscopy technique to study quantum phases of matter.
11 【材料】A generic interface to reduce the efficiency-stability-cost gap of perovskite solar cells
Yi Hou et.al
A major bottleneck delaying the further commercialization of thin-film solar cells based on hybrid organohalide lead perovskites is interface loss in state-of-the-art devices. We present a generic interface architecture that combines solution-processed, reliable, and cost-efficient hole-transporting materials without compromising efficiency, stability, or scalability of perovskite solar cells. Tantalum-doped tungsten oxide (Ta-WOx)/conjugated polymer multilayers offer a surprisingly small interface barrier and form quasi-ohmic contacts universally with various scalable conjugated polymers. In a simple device with regular planar architecture and a self-assembled monolayer, Ta-WOx–doped interface–based perovskite solar cells achieve maximum efficiencies of 21.2% and offer more than 1000 hours of light stability. By eliminating additional ionic dopants, these findings open up the entire class of organics as scalable hole-transporting materials for perovskite solar cells.
12 【生物】3.9 structure of the yeast Mec1-Ddc2 complex, a homolog of human ATR-ATRIP
Xuejuan Wang et.al
The ataxia telangiectasia–mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans, but the mechanism of its activation remains unclear. ATR acts together with its partner ATRIP. Using cryo–electron microscopy, we determined the structure of intact Mec1-Ddc2 (the yeast homolog of ATR-ATRIP), which is poised for catalysis, at a resolution of 3.9 angstroms. Mec1-Ddc2 forms a dimer of heterodimers through the PRD and FAT domains of Mec1 and the coiled-coil domain of Ddc2. The PRD and Bridge domains in Mec1 constitute critical regulatory sites. The activation loop of Mec1 is inhibited by the PRD, revealing an allosteric mechanism of kinase activation. Our study clarifies the architecture of ATR-ATRIP and provides a structural framework for the understanding of ATR regulation.
13 【生物】Host DNases prevent vascular occlusion by neutrophil extracellular traps
Miguel Jiménez-Alcázar et.al
Platelet and fibrin clots occlude blood vessels in hemostasis and thrombosis. Here we report a noncanonical mechanism for vascular occlusion based on neutrophil extracellular traps (NETs), DNA fibers released by neutrophils during inflammation. We investigated which host factors control NETs in vivo and found that two deoxyribonucleases (DNases), DNase1 and DNase1-like 3, degraded NETs in circulation during sterile neutrophilia and septicemia. In the absence of both DNases, intravascular NETs formed clots that obstructed blood vessels and caused organ damage. Vascular occlusions in patients with severe bacterial infections were associated with a defect to degrade NETs ex vivo and the formation of intravascular NET clots. DNase1 and DNase1-like 3 are independently expressed and thus provide dual host protection against deleterious effects of intravascular NETs.
（导读 科研圈AI）血小板和纤维蛋白原是凝血和血栓的主要形成物，导致血管阻塞。本文研究了一种炎症反应中，基于中性粒细胞胞外陷阱（nesophil extracellular traps，NETs）的非经典血管阻塞机制。在中性白细胞增多症和败血症患者中，DNase1和DNase1-like 3能够降解血液循环系统中的NETs。当这两种酶不存在时，血管中的NETs就会形成凝结块阻塞血管。细菌感染病人出现血管阻塞的同时，也缺乏这两种酶对NETs的降解。两种酶独立表达，为集体对抗血管内NETs带来的有害作用提供双重保护。
14 【材料】Selective increase in CO2 electroreduction activity at grain-boundary surface terminations
Ruperto G. Mariano et.al
Altering a material’s catalytic properties requires identifying structural features that give rise to active surfaces. Grain boundaries create strained regions in polycrystalline materials by stabilizing dislocations and may provide a way to create high-energy surfaces for catalysis that are kinetically trapped. Although grain-boundary density has previously been correlated with catalytic activity for some reactions, direct evidence that grain boundaries create surfaces with enhanced activity is lacking. We used a combination of bulk electrochemical measurements and scanning electrochemical cell microscopy with submicrometer resolution to show that grain-boundary surface terminations in gold electrodes are more active than grain surfaces for electrochemical carbon dioxide (CO2) reduction to carbon monoxide (CO) but not for the competing hydrogen (H2) evolution reaction. The catalytic footprint of the grain boundary is commensurate with its dislocation-induced strain field, providing a strategy for broader exploitation of grain-boundary effects in heterogeneous catalysis.
15 【古生物】Egg accumulation with 3D embryos provides insight into the life history of a pterosaur
Xiaolin Wang et.al
Fossil eggs and embryos that provide unique information about the reproduction and early growth of vertebrates are exceedingly rare, particularly for pterosaurs. Here we report on hundreds of three-dimensional (3D) eggs of the species Hamipterus tianshanensis from a Lower Cretaceous site in China, 16 of which contain embryonic remains. Computed tomography scanning, osteohistology, and micropreparation reveal that some bones lack extensive ossification in potentially late-term embryos, suggesting that hatchlings might have been flightless and less precocious than previously assumed. The geological context, including at least four levels with embryos and eggs, indicates that this deposit was formed by a rare combination of events, with storms acting on a nesting ground. This discovery supports colonial nesting behavior and potential nesting site fidelity in the Pterosauria.
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