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31.
RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago–miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity.  相似文献   
32.
An important and perhaps critical clue to the mechanism driving the explosion of massive stars as supernovae is provided by the accumulating evidence for asymmetry in the explosion. Indirect evidence comes from high pulsar velocities, associations of supernovae with long-soft gamma-ray bursts, and asymmetries in late-time emission-line profiles. Spectropolarimetry provides a direct probe of young supernova geometry, with higher polarization generally indicating a greater departure from spherical symmetry. Large polarizations have been measured for 'stripped-envelope' (that is, type Ic; ref. 7) supernovae, which confirms their non-spherical morphology; but the explosions of massive stars with intact hydrogen envelopes (type II-P supernovae) have shown only weak polarizations at the early times observed. Here we report multi-epoch spectropolarimetry of a classic type II-P supernova that reveals the abrupt appearance of significant polarization when the inner core is first exposed in the thinning ejecta (approximately 90 days after explosion). We infer a departure from spherical symmetry of at least 30 per cent for the inner ejecta. Combined with earlier results, this suggests that a strongly non-spherical explosion may be a generic feature of core-collapse supernovae of all types, where the asphericity in type II-P supernovae is cloaked at early times by the massive, opaque, hydrogen envelope.  相似文献   
33.
The medium and warm deformation behaviors of an indirect-extruded Mg-8Sn-1Al-1Zn alloy were investigated by compression tests at temperatures between 298 and 523 K and strain rates of 0.001–10 s?1. It was found that the twinning-slip transition temperature was strain rate dependent, and all the true stress-true strain curves could be divided into two groups: concave and convex curves. Associated microstructural investigations indicated that the dynamic recrystallization (DRX) behavior of the alloy varied with deformation conditions. At high strain rate and low temperature, dynamically recrystallized grains preferentially nucleated and developed in the twinned regions, indicating that twinning-induced DRX was dominant. While, at low strain rate, DRX developed extensively at grain boundaries and twins, and the process of twinning contributed to both oriented nucleation and selective growth. For the studied alloy, cracks mainly initiated from the shear band and twinning lamellar over the ranges of temperature and strain rate currently applied.  相似文献   
34.
35.
Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP kinase kinase kinase, is activated by several death stimuli and is tightly regulated by several mechanisms such as interactions with regulatory proteins and post-translational modifications. Here, we report that dual-specificity phosphatase 13A (DUSP13A) functions as a novel regulator of ASK1. DUSP13A interacts with the N-terminal domain of ASK1 and induces ASK1-mediated apoptosis through the activation of caspase-3. DUSP13A enhances ASK1 kinase activity and thus its downstream factors. Small interfering RNA (siRNA) analyses show that knock-down of DUSP13A in human neuroblastoma SK-N-SH cells reduces ASK1 kinase activity. The phosphatase activity of DUSP13A is not required for the regulation of ASK1. This regulatory action of DSUP13 on ASK1 activity involves competition with Akt1, a negative regulator of ASK1, for binding to ASK1. Taken together, this study provides novel insights into the role of DUSP13A in the precise regulation of ASK1.  相似文献   
36.
对用仿形磨削方法磨削硬质合金可转位刀片周边的仿形凸轮机构进行了运动学分析,根据凸轮机构的运动学特性开发出一套设计和绘制仿形凸轮的CAD和CAG软件,采用该软件可以省去大量的繁复计算与绘图工作量,缩短设计制造周期,实现设计、绘图自动化。  相似文献   
37.
Stream-power incision model has always been applied to detecting the steady-state situation of ranges. Oblique arc-continent collision occurring during the period of Penglai Orogeny caused the Taiwan mountain belt to develop landscape of three evolution stages, namely stages of pre-steady-state (growing ranges in southern Taiwan), steady-state (ranges in central Taiwan) and post-steady-state (decaying ranges in northern Taiwan). In the analysis on streams of the Taiwan mountain belt made by exploring the relationship between the slope of bedrock channel (S) and the catchment area (A), the topographic features of the ranges at these three stages are acquired. The S-A plot of the steady-state ranges is in a linear form, revealing that the riverbed height of bedrock channel does not change over time (dz/dt = 0). The slope and intercept of the straight line S-A are related to evolution time of steady-state topography and tectonic uplift rate respectively. The S-A plots of the southern and northern ranges of Taiwan mountain belt appear to be in convex and concave forms respectively, implying that the riverbed height of bedrock channel at the two ranges rises (dz/dt > 0) and falls (dz/dt < 0) over time respectively. Their tangent intercept can still reflect the tectonic uplift rate. This study develops an empirical stream-power erosion model of pre-steady-state and post-steady-state topography.  相似文献   
38.
模拟一般是为了应用于特定领域的问题而设计的,而模拟语言可以设计通用领域的问题,相对难度较大.开发模拟软件,有必要提供使用者容易掌握的参数和模拟技术环境,从而降低开发难度.介绍一种灵活的利用总体构造信息和各种规模参数自动建立模型的设计方法.构建以程序文档作为模拟技术中各种模型的基础,储存于模型数据库,选定相应模型的模板,输入相应参数,就可自动生成所需的特定模型.利用这一系统,建模者可以用最小的工作量形成复杂的大模型.选用两个案例实验验证其实用性和有效性.  相似文献   
39.
Park SY  Lytton-Jean AK  Lee B  Weigand S  Schatz GC  Mirkin CA 《Nature》2008,451(7178):553-556
It was first shown more than ten years ago that DNA oligonucleotides can be attached to gold nanoparticles rationally to direct the formation of larger assemblies. Since then, oligonucleotide-functionalized nanoparticles have been developed into powerful diagnostic tools for nucleic acids and proteins, and into intracellular probes and gene regulators. In contrast, the conceptually simple yet powerful idea that functionalized nanoparticles might serve as basic building blocks that can be rationally assembled through programmable base-pairing interactions into highly ordered macroscopic materials remains poorly developed. So far, the approach has mainly resulted in polymerization, with modest control over the placement of, the periodicity in, and the distance between particles within the assembled material. That is, most of the materials obtained thus far are best classified as amorphous polymers, although a few examples of colloidal crystal formation exist. Here, we demonstrate that DNA can be used to control the crystallization of nanoparticle-oligonucleotide conjugates to the extent that different DNA sequences guide the assembly of the same type of inorganic nanoparticle into different crystalline states. We show that the choice of DNA sequences attached to the nanoparticle building blocks, the DNA linking molecules and the absence or presence of a non-bonding single-base flexor can be adjusted so that gold nanoparticles assemble into micrometre-sized face-centred-cubic or body-centred-cubic crystal structures. Our findings thus clearly demonstrate that synthetically programmable colloidal crystallization is possible, and that a single-component system can be directed to form different structures.  相似文献   
40.
Sung BJ  Hwang KY  Jeon YH  Lee JI  Heo YS  Kim JH  Moon J  Yoon JM  Hyun YL  Kim E  Eum SJ  Park SY  Lee JO  Lee TG  Ro S  Cho JM 《Nature》2003,425(6953):98-102
Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.  相似文献   
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