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Science 论文导读0428

时间: 2017年05月08日 | 作者: admin | 来源: 未知


1 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15


Ting Han, Maria Goralski, Nicholas Gaskill…Noelle S. Williams, Deepak Nijhawan


(导读 柳寒石)Indisulam是一种具有选择性抗肿瘤活性的芳基磺胺类药物。研究人员发现Indisulam能够RBM39募集CUL4-DCAF15 E3泛素连接酶,使RBM39多泛素化并通过蛋白酶体途径降解;而indisulam导致的RBM39失活会引起pre-mRNA的异常剪接。很多来自造血和淋巴系的肿瘤细胞系对于indisulam的敏感度和DCAF15的表达水平相关。因此DCAF15的表达可成为指导该类药品临床用药的生物标志。

Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam’s cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing. Many cancer cell lines derived from hematopoietic and lymphoid lineages are sensitive to indisulam, and their sensitivity correlates with DCAF15 expression levels. Two other clinically tested sulfonamides, tasisulam and chloroquinoxaline sulfonamide, share the same mechanism of action as indisulam. We propose that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides).

2 RETINOBLASTOMA RELATED1 mediates germline entry in Arabidopsis


Xin’Ai Zhao, Jonathan Bramsiepe, Matthias Van Durme…Moritz K. Nowack, Arp Schnittger



(导读 吴媛媛)开花植物通过减数分裂产生种子,本研究发现了一条拟南芥减数分裂起始相关的调节通路:KIP相关蛋白(KRP)抑制周期蛋白依赖激酶A(CDKA),解除CDKA对视网膜母细胞瘤相关蛋白1(RBR1)活性的抑制,活性RBR1抑制干细胞因子 WUSWUS的抑制使大孢子母细胞离开有丝分裂途径,开始减数分裂。RBR1是这一通路的枢纽。


To produce seeds, flowering plants need to specify somatic cells to undergo meiosis. Here, we reveal a regulatory cascade that controls the entry into meiosis starting with a group of redundantly acting cyclin-dependent kinase (CDK) inhibitors of the KIP-RELATED PROTEIN (KRP) class. KRPs function by restricting CDKA–dependent inactivation of the Arabidopsis Retinoblastoma homolog RBR1. In rbr1 and krp triple mutants, designated meiocytes undergo several mitotic divisions, resulting in the formation of supernumerary meiocytes that give rise to multiple reproductive units per future seed. One function of RBR1 is the direct repression of the stem cell factor WUSCHEL (WUS), which ectopically accumulates in meiocytes of triple krp and rbr1 mutants. Depleting WUS in rbr1 mutants restored the formation of only a single meiocyte.

3 The fading American dream: Trends in absolute income mobility since 1940


Raj Chetty, David Grusky, Maximilian Hell, Nathaniel Hendren, Robert Manduca, Jimmy Narang




(导读 郭思瑶)研究人员通过整合人口调查数据与税收数据估测了“绝对收入流动性”(收入超过父母的子女比率),发现其从20世纪40年代的90%下降到80年代的50%,GDP增长速率提高不能使绝对收入流动性恢复如初。重现美国梦时期的高绝对收入流动性需要更普遍的经济增长。

We estimated rates of “absolute income mobility”—the fraction of children who earn more than their parents—by combining data from U.S. Census and Current Population Survey cross sections with panel data from de-identified tax records. We found that rates of absolute mobility have fallen from approximately 90% for children born in 1940 to 50% for children born in the 1980s. Increasing Gross Domestic Product (GDP) growth rates alone cannot restore absolute mobility to the rates experienced by children born in the 1940s. However, distributing current GDP growth more equally across income groups as in the 1940 birth cohort would reverse more than 70% of the decline in mobility. These results imply that reviving the “American dream” of high rates of absolute mobility would require economic growth that is shared more broadly across the income distribution.

4 Pcdhαc2 is required for axonal tiling and assembly of serotonergic circuitries in mice


Weisheng V. Chen, Chiamaka L. Nwakeze, Christine A. Denny…Qiang Wu, Tom Maniatis


(导读 韩宇)5-羟色胺能神经元轴突平铺排布可使其获得最优配置。研究发现敲除小鼠Pcdhαc2基因可破坏局部5-羟色胺能神经元轴突排布和5-羟色胺回路组装,导致小鼠抑郁样行为。Serotonergic neurons project their axons pervasively throughout the brain and innervate various target fields in a space-filling manner, leading to tiled arrangements of their axon terminals to allow optimal allocation of serotonin among target neurons. Here we show that conditional deletion of the mouse protocadherin α (Pcdhα) gene cluster in serotonergic neurons disrupts local axonal tiling and global assembly of serotonergic circuitries and results in depression-like behaviors. Genetic dissection and expression profiling revealed that this role is specifically mediated by Pcdhαc2, which is the only Pcdhα isoform expressed in serotonergic neurons. We conclude that, in contrast to neurite self-avoidance, which requires single-cell identity mediated by Pcdh diversity, a single cell-type identity mediated by the common C-type Pcdh isoform is required for axonal tiling and assembly of serotonergic circuitries.


5 Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly


George Mountoufaris, Weisheng V. Chen, Yusuke Hirabayashi…Franck Polleux, Tom Maniatis


(导读 韩宇)哺乳动物的Pcdh细胞表面抗原由三个基因簇共同编码。研究发现,这三个基因簇可联合为单个小鼠嗅觉感觉神经元(OSN)提供组装嗅小球所需的细胞表面多样性,其同时丢失可造成严重的轴突分枝缺陷和自回避性缺失,而3基因簇的单一表达会导致OSN轴突难以形成嗅小球。


Multiple Pcdh gene clusters are required for normal OSN axonal arborization and the formation of normal protoglomeruli.



The vertebrate clustered protocadherin (Pcdh) cell surface proteins are encoded by three closely linked gene clusters (Pcdhα, Pcdhβ, and Pcdhγ). Here, we show that all three gene clusters functionally cooperate to provide individual mouse olfactory sensory neurons (OSNs) with the cell surface diversity required for their assembly into distinct glomeruli in the olfactory bulb. Although deletion of individual Pcdh clusters had subtle phenotypic consequences, the loss of all three clusters (tricluster deletion) led to a severe axonal arborization defect and loss of self-avoidance. By contrast, when endogenous Pcdh diversity is overridden by the expression of a single–tricluster gene repertoire (α and β and γ), OSN axons fail to converge to form glomeruli, likely owing to contact-mediated repulsion between axons expressing identical combinations of Pcdh isoforms.

6 Rechargeable nickel–3D zinc batteries: An energy-dense, safer alternative to lithium-ion

【材料】可充电镍- 3D锌电池:一种能源密集且更安全的锂离子电池替代物

Joseph F. Parker, Christopher N. Chervin, Irina R. Pala, Meinrad Machler, Michael F. Burz, Jeffrey W. Long, Debra R. Rolison


(导读 卓思琪)水系锌电池中,阳极海绵结构锌可在镍-锌碱电池中循环上千次而不产生钝化或大规模枝晶。该3D锌电池提高了锌-镍碱电池在原电池理论放电深度、高倍率充放电循环和万级能量需求的占空比等三方面性能


The next generation of high-performance batteries should include alternative chemistries that are inherently safer to operate than nonaqueous lithium-based batteries. Aqueous zinc-based batteries can answer that challenge because monolithic zinc sponge anodes can be cycled in nickel–zinc alkaline cells hundreds to thousands of times without undergoing passivation or macroscale dendrite formation. We demonstrate that the three-dimensional (3D) zinc form-factor elevates the performance of nickel–zinc alkaline cells in three fields of use: (i) >90% theoretical depth of discharge (DODZn) in primary (single-use) cells, (ii) >100 high-rate cycles at 40% DODZn at lithium-ion–commensurate specific energy, and (iii) the tens of thousands of power-demanding duty cycles required for start-stop microhybrid vehicles.

7 Measurement of the small-scale structure of the intergalactic medium using close quasar pairs


Alberto Rorai, Joseph F. Hennawi, Jose Oñorbe…Zarija Lukić, Khee-Gan Lee


(导读 肖坤)星系际介质(IGM)中扩散气体的分布会在遥远类星体光谱背景下呈现一系列氢吸收线,而宇宙动力学模拟预测IGM的密度涨落在热压与重力平衡的特征尺度上会受到抑制。本研究通过量化近邻类星体对的吸收特性来测量这种压力-平滑尺度,其结果与描述紫外辐射背景的光电离标准模型一致。


The distribution of diffuse gas in the intergalactic medium (IGM) imprints a series of hydrogen absorption lines on the spectra of distant background quasars known as the Lyman-α forest. Cosmological hydrodynamical simulations predict that IGM density fluctuations are suppressed below a characteristic scale where thermal pressure balances gravity. We measured this pressure-smoothing scale by quantifying absorption correlations in a sample of close quasar pairs. We compared our measurements to hydrodynamical simulations, where pressure smoothing is determined by the integrated thermal history of the IGM. Our findings are consistent with standard models for photoionization heating by the ultraviolet radiation backgrounds that reionized the universe.

8 Formation of matter-wave soliton trains by modulational instability


Jason H. V. Nguyen, De Luo, Randall G. Hulet


(导读 肖坤)非线性系统可以展现出一系列对初始条件敏感的动力学特征,例如调制不稳定性。本研究利用Feshbach共振的浅零点交叉,描述了调制不稳定性及其在波色-爱因斯坦凝聚中产生物质波孤子链所起的作用。通过实时成像,研究人员讨论了孤子链的产生究竟是来自有效排斥近邻相互作用还是演化形成。


Nonlinear systems can exhibit a rich set of dynamics that are inherently sensitive to their initial conditions. One such example is modulational instability, which is believed to be one of the most prevalent instabilities in nature. By exploiting a shallow zero-crossing of a Feshbach resonance, we characterize modulational instability and its role in the formation of matter-wave soliton trains from a Bose-Einstein condensate. We examine the universal scaling laws exhibited by the system and, through real-time imaging, address a long-standing question of whether the solitons in trains are created with effectively repulsive nearest-neighbor interactions or rather evolve into such a structure.

9 A multifunctional catalyst that stereoselectively assembles prodrugs


Daniel A. DiRocco, Yining Ji, Edward C. Sherer…Louis-Charles Campeau, Ian W. Davies


(导读 韩宇)磷手性的磷酰胺酸前体药物是用于治疗病毒性疾病和癌症的核苷酸疗法的关键组成部分。本研究发展了用于合成磷手性磷酰胺酸前体的动态立体选择性催化方法,经催化机制研究后合理设计的多功能催化剂,可以以高达99:1的选择性将磷立体异构氨基磷酸酯安装到核苷上。



Development of a stereoselective phosphoramidation.




The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.

10 Water harvesting from air with metal-organic frameworks powered by natural sunlight


Hyunho Kim, Sungwoo Yang, Sameer R. Rao…Omar M. Yaghi, Evelyn N. Wang




(导读 王腾)大气水是重要的淡水资源(约占地球淡水资源的10%),然而目前并无从低湿度空气中捕获和输运水分的有效方法。研究人员设计出基于多孔金属有机骨架{MOF-801, [Zr6O4(OH)4(fumarate)6]} 材料的水分收集设备,该设备可以在低于1Kw/m2自然光照的低能量条件下从空气中捕获水分。


Atmospheric water is a resource equivalent to ~10% of all fresh water in lakes on Earth. However, an efficient process for capturing and delivering water from air, especially at low humidity levels (down to 20%), has not been developed. We report the design and demonstration of a device based on a porous metal-organic framework {MOF-801, [Zr6O4(OH)4(fumarate)6]} that captures water from the atmosphere at ambient conditions by using low-grade heat from natural sunlight at a flux of less than 1 sun (1 kilowatt per square meter). This device is capable of harvesting 2.8 liters of water per kilogram of MOF daily at relative humidity levels as low as 20% and requires no additional input of energy.

11 Direction-specific van der Waals attraction between rutile TiO2 nanocrystals


Xin Zhang, Yang He, Maria L. Sushko…Chongmin Wang, Kevin M. Rosso


(导读 卓思琪)本研究测量了金红石纳米晶体间的范德华吸引力。在几十纳米范围内,引力微弱且和方位角及表面水合无关;当距离为约一个水合层间距时,引力与方位角强关联并使其递减。这些引力行为与Lifshiz理论的预测十分接近,表明分散的力可以在溶液粒子间或材料颗粒间产生力矩。


Mutual lattice orientations dictate the types and magnitudes of forces between crystalline particles. When lattice polarizability is anisotropic, the van der Waals dispersion attraction can, in principle, contribute to this direction dependence. We report measurement of this attraction between rutile nanocrystals, as a function of their mutual orientation and surface hydration extent. At tens of nanometers of separation, the attraction is weak and shows no dependence on azimuthal alignment or surface hydration. At separations of approximately one hydration layer, the attraction is strongly dependent on azimuthal alignment and systematically decreases as intervening water density increases. Measured forces closely agree with predictions from Lifshitz theory and show that dispersion forces can generate a torque between particles interacting in solution and between grains in materials.


12 Nucleic acid detection with CRISPR-Cas13a/C2c2


Jonathan S. Gootenberg, Omar O. Abudayyeh, Jeong Wook Lee…James J. Collins, Feng Zhang


(导读 榴莲君)本研究将靶向RNA的CRISPR/Cas13a系统与等温核酸扩增法结合起来开发出名为“SHERLOCK”的技术,能高效方便地检测组织中微量的RNA或DNA的存在,也能检测到DNA上单个碱基的突变。SHERLOCK在疾病诊断和分子生物学上具有重要应用意义。


Rapid, inexpensive, and sensitive nucleic acid detection may aid point-of-care pathogen detection, genotyping, and disease monitoring. The RNA-guided, RNA-targeting clustered regularly interspaced short palindromic repeats (CRISPR) effector Cas13a (previously known as C2c2) exhibits a “collateral effect” of promiscuous ribonuclease activity upon target recognition. We combine the collateral effect of Cas13a with isothermal amplification to establish a CRISPR-based diagnostic (CRISPR-Dx), providing rapid DNA or RNA detection with attomolar sensitivity and single-base mismatch specificity. We use this Cas13a-based molecular detection platform, termed Specific High-Sensitivity Enzymatic Reporter UnLOCKing (SHERLOCK), to detect specific strains of Zika and Dengue virus, distinguish pathogenic bacteria, genotype human DNA, and identify mutations in cell-free tumor DNA. Furthermore, SHERLOCK reaction reagents can be lyophilized for cold-chain independence and long-term storage and be readily reconstituted on paper for field applications.

13 Ancient genomic changes associated with domestication of the horse


Pablo Librado, Cristina Gamba, Charleen Gaunitz…Eske Willerslev, Ludovic Orlando





(导读 郭思瑶)马匹驯养相关的基因变化尚不清楚。研究人员检测了青铜器时代到铁器时代14个早期驯养马匹的基因,发现了支持神经嵴假说的早期驯养选择模式,提供了共同驯养特征的统一起源,揭示铁器时代西塞亚草原游牧民的驯养策略和选择方向。

The genomic changes underlying both early and late stages of horse domestication remain largely unknown. We examined the genomes of 14 early domestic horses from the Bronze and Iron Ages, dating to between ~4.1 and 2.3 thousand years before present. We find early domestication selection patterns supporting the neural crest hypothesis, which provides a unified developmental origin for common domestic traits. Within the past 2.3 thousand years, horses lost genetic diversity and archaic DNA tracts introgressed from a now-extinct lineage. They accumulated deleterious mutations later than expected under the cost-of-domestication hypothesis, probably because of breeding from limited numbers of stallions. We also reveal that Iron Age Scythian steppe nomads implemented breeding strategies involving no detectable inbreeding and selection for coat-color variation and robust forelimbs.