当前位置: 主页 > 平台网址

Science论文导读 1201

时间: 2017年12月12日 | 作者: admin | 来源: 未知
Science20171201 1 【生物】 The target landscape of clinical kinase drugs Susan Klaeger et.al 临床激酶药物的靶点 全局观 http://science.sciencemag.org/content/358/6367/eaan4368 Kinase inhibitors are important cancer therapeuti



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.


(导读 郭怿暄)对蛋白激酶抑制剂药物靶点的全面认识将有助于理解其治疗肿瘤的作用机理。本研究利用化学蛋白质组学分析了243种经临床评估的蛋白激酶药物的作用靶点。研究揭示了已知药物的未知靶点及药物非蛋白激酶脱靶靶点,建立了可用于药物设计的蛋白激酶组。此外还结合磷酸蛋白质组数据优化了药物作用通路,发现药物反应标记,明确组合治疗的重要性。这一研究为基础药物研究以及临床治疗策略的制定提供极大帮助。


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




(导读 阿金)整合了基因测序代谢通路的海洋生态模型与组学数据之间缺乏直接比较。本研究开发出一套直接模拟宏基因组和宏转录组的模型可用于与观察值进行比较。起始于随机生成微生物不同组合的群落模拟都呈现逼真的垂直向和水平向的海洋养分、基因组和转录组梯度分布。表明群落中可获得的基因功能库,而非微生物中的基因功能分布,驱动了群落的组成和海洋中的生物地球化学梯度。

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



(导读 阿金)地震后地球重力场会受到扰动,但信号过于微弱,目前仍无法充分了解其来源。本研究通过宽带地震仪在2011年日本东北地区9.1级地震距离地震震央10002000千米之间观测到重力扰动信号。通过考虑重力变化和重力诱导运动,可进一步优化扰动信号模型。研究结果使快速辨识大地震发生的时间探测尺度缩短到分钟量级。

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



(导读 阿金)掺杂情况下,Mott绝缘体中载流子及其自旋会形成条纹形式其中Tc铜酸盐超导体的条纹被认为是以波动形式存在。本研究使用数值精确的行列式量子蒙特卡罗计算展示了材料铜氧面上的局部电子结构该结果支持波动式条纹的假设,可解释多项既有实验结果,为铜酸盐超导体正常态中出现的交织有序性提供新观点。



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




(导读 阿金)苯分子的富电子π键系统对电子和负电荷的有机亲核试剂高度排斥,因此苯碳氢键的亲电芳香取代反应难以发生。本研究报道使用一种足够强力的有机钙亲核试剂可克服此电荷斥力,60条件下n-烷基钙衍生物可与苯分子发生亲核取代反应生成n-烷基苯和氢化钙。本研究还使用计算方法揭示了反应机理。





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



(导读 阿金)扇贝拥有一套由200只眼睛组成的视觉系统,扇贝眼使用反射镜而非凸透镜(晶状体)来聚焦光线。本研究展示扇贝眼后的分层反射镜结构能够调整反射光的波长,并通过平铺的正方形鸟嘌呤晶体片,来减少光学视差,从而在双层视网膜上分别形成视野周遭和中心的图像,类似于分段式望远镜的功能。





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


(导读 阿金)天然材料中非线性响应的微弱属性限制了光学混频过程的效率。本研究使用集成等离子体间隙波导技术,通过纳米聚焦将光横截面强化到几十纳米尺度模式,从而产生强烈非线性响应,促进四波混频(FWM)在通信波段距离上的有效积累。研究结果使得有效的宽带混频与硅光电子学集成成为可能。

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)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DT,并使用该方法对18种药物分子进行了DT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.

(导读 葛鹏)量子化本征能级与其相关的波函数为量子多体系统的预测提供了丰富的信息。本研究使用九个超导量子比特链,分析了相互作用光子的能级。通过捕捉预测的磁场中二维电子复杂能谱的主要特征,对该方法进行测试。研究结果展示了使用多体光谱技术研究物质的量子相位的方法。



11 【材料】A generic interface to reduce the efficiency-stability-cost gap of perovskite solar cells

Yi Hou    et.al




(导读 阿金)妨碍钙钛矿薄膜太阳能电池进一步商业化的主要瓶颈是器件中的界面损失。本研究展示一个由钽掺杂的氧化钨形成阻挡层的通用界面构架。这种界面结合了溶液处理和低成本的空穴传输材料,不会影响电池本身的效率、稳定性和可扩展性。测试器件实现了21.2%的最大效率,且光照稳定性超过1000小时。

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



(导读 阿金)ATR激酶是人类体内DNA损伤反应和复制压力的主要调控因子,但尚未清楚其激活机制。本研究使用冷冻电镜技术,成功解析分辨率达到3.9埃,与ATR-ATRIP蛋白存在同源关系的酵母Med1-Ddc2蛋白复合物结构,揭示出ATR激酶的调节位点,为进一步了解ATR调控机制提供新的结构框架。



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 trapsNETs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,DNase1DNase1-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




(导读 阿金)材料催化活性与晶材料中的晶界密度被认为有关联性,但缺乏直接证据。本研究利用电化学测量和具备微米分辨率的扫描电化学显微镜技术,表明金的晶界表面终止区域比晶粒表面在CO2电还原为CO时具有更高的活性,但与H2析出反应没有可比的活性。研究结果为进一步探索异质催化剂中晶界效应提供新策略。

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.


(导读 郭怿暄)恐龙蛋可提供脊椎动物的繁殖和早期生长信息但极其罕见。本研究首次报道在中国一白垩纪早期勘测点发现了数百枚立体天山哈密翼龙蛋化石,其中16个仍有胚胎保存。研究发现其胚胎末期骨胳仍未彻底骨化,暗示刚孵化幼崽不甚早熟,不能飞行,以及此翼龙可能为群居筑巢。