Collision-induced dissociation of oligonucleotide anions fully modified at the 2'-position of the ribose: 2'-F/-H and 2'-F/-H/-OMe mix-mers

Gas-phase dissociation of various 2'-position modified oligonucleotide anions has been studied as a function of precursor ion charge state using ion trap and low energy beam-type collision-induced dissociation (CID). For a completely 2'-O-methyl modified 6-mer, all possible dissociation channels along the phosphodiester linkage, generating complementary (a-B)/w-, b/x-, c/y-, d/z-ion series, were observed with no single dominant type of dissociation pathway. Full sequence information was generated from each charge state via ion trap CID. More sequential fragmentation was noted under beam-type CID conditions. Comparison with model DNA, in which all 2'-OH groups are converted to 2'-H, and RNA anions suggests that the 2'-OMe substitution stabilizes the phosphodiester linkage with respect to fragmentation relative to both DNA and RNA oligomers. For modified mix-mer anions, comprised of DNA nucleotides and 2'-F substituted nucleotides or a mixture of DNA nucleotides and 2'-O-methyl (2'-OMe) and 2'-F substituted nucleotides, 3'-side backbone cleavage was found to be inhibited by the 2'-OMe or 2'-F modification on the nucleotides under ion trap CID conditions. Thus, the sequence information was limited to the a-Base/w-fragments from the cleavage of the 3' C-O bond of the 2'-H (DNA) nucleotides. Under beam-type CID conditions, limited additional cleavage adjacent to 2'-OMe substituted nucleotides was noted but 2'-F modified residues remained resistant to cleavage.     

基于信息准则的局域预测法邻近点的选取方法

基于信息准则,提出了选取局域预测法中邻近点个数的定量方法. 并用此方法分析Lorenz模型生成的混沌时间序列和Santa Fe时间序列竞赛的激光数据(Data A). 实验结果表明用该方法选取邻近点的局域预测法的一步和多步预测性能较好,在满足预测精度较高的条件下,计算量较小. 关键词： 邻近点 邻域 局域预测 信息准则     

Dinuclear Zn(II) catalysts as biomimics of RNA and DNA phosphoryl transfer enzymes: changing the medium from water to alcohol provides enzyme‐like rate enhancements

Phosphodiesters are notoriously hydrolytically inert compounds that are demonstrated to have large accelerations of P‐OR cleavage promoted by transition and lanthanide metal ions in methanol and ethanol media. This review commentary describes recent findings of how a simple mononuclear and a dinuclear Zn(II) complex promote the cleavage of a series of RNA models and DNA models in alcohol media. The discussion centers on the analysis of the mechanisms of cleavage, energetics of the catalytic process, on recent findings of electrophilic assistance of leaving group departure, and the observation of a rapid hydrolytic reaction of a DNA model promoted by the dinuclear Zn(II) complex in ethanol containing less than 2% water. Copyright © 2009 John Wiley & Sons, Ltd.     

Molecular devices for high fidelity of DNA replication and gene expression

Certain types of DNA lesions, produced through cellular metabolic processes and also by external environmental stresses, are responsible for the induction of mutations as well as of cancer. Most of these lesions can be eliminated by DNA repair enzymes, and cells carrying the remaining DNA lesions are subjected to apoptosis. The persistence of damaged bases in RNA can cause errors in gene expression, and the cells appear to possess a mechanism which can prevent damaged RNA molecules from entering the translation process. We have investigated these processes for high fidelity of DNA replication and gene expression, by using both biochemical and genetic means. We herein describe (1) the molecular mechanisms for accurate DNA synthesis, (2) mammalian proteins for sanitizing the DNA precursor pool, (3) error avoidance mechanisms for gene expression under oxidative stress, and (4) the roles of DNA repair and apoptosis in the prevention of cancer.     

DNA strand breaks induced by concerted interaction of H radicals and low-energy electrons

We propose a mechanism of DNA single strand breaks induced by low-energy electrons. Density functional theory calculations have been performed on a neutral, hydrogenated, and/or negatively charged nucleotide of cytosine in the gas phase to identify barriers for the phosphate-sugar O–C bond cleavage. Attachment of the first excess electron induces intermolecular proton transfer to cytosine. The resulting neutral radical of hydrogenated cytosine binds another excess electron, and the excess charge is localized primarily on the C6 atom. A barrier encountered for proton transfer from the C2’ atom of the adjacent sugar unit to the C6 atom of cytosine is 3.6 and 5.0 kcal/mol, based on the MPW1K and B3LYP electronic energies corrected for zero-point vibrations, respectively. The proton transfer is followed by a barrier-free sugar-phosphate C–O bond cleavage. The proton transfer is impossible for the neutral nucleotide, as there is no local minimum for the product. In the case of anionic and hydrogenated nucleotides the same barrier determined at the B3LYP level is as large as 29.3 and 22.4 kcal/mol respectively. This illustrates that the consecutive hydrogenation and electron attachment make the nucleotide of cytosine susceptible to a strand break. The rate of the C–O bond cleavage in the anion of hydrogenated nucleotide of cytosine is estimated to be ca. 10¹⁰  s^-1. The proposed mechanism proceeds through bound anionic states, not through metastable states with finite lifetimes and discrete energy positions with respect to the neutral target. The results suggest that at least for DNA without hydration even very low-energy electrons may cleave the DNA backbone.     

HCCCH experiment for through-bond correlation of thymine resonances in 13C-labeled DNA oligonucleotides

Application of heteronuclear magnetic resonance pulse methods to 13C, 15N-labeled nucleic acids is important for the accurate structure determination of larger RNA and DNA oligonucleotides and protein-nucleic acid complexes. These methods have been applied primarily to RNA, due to the availability of labeled samples. The two major differences between DNA and RNA are at the C2' of the ribose and deoxyribose and the additional methyl group on thymine versus uracil. We have enzymatically synthesized a 13C,15N-labeled 32 base DNA oligonucleotide that folds to form an intramolecular triplex. We present two- and three-dimensional versions of a new HCCCH-TOCSY experiment that provides intraresidue correlation between the thymine H6 and methyl resonances via the intervening carbons (H6-C6-C5-Cme-Hme).     

Enhancements of the Gaussian network model in describing nucleotide residue fluctuations for RNA

Gaussian network model (GNM) is an efficient method to investigate the structural dynamics of biomolecules. However, the application of GNM on RNAs is not as good as that on proteins, and there is still room to improve the model. In this study, two novel approaches, named the weighted GNM (wGNM) and the force-constant-decayed GNM (fcdGNM), were proposed to enhance the performance of ENM in investigating the structural dynamics of RNAs. In wGNM, the force constant for each spring is weighted by the number of interacting heavy atom pairs between two nucleotides. In fcdGNM, all the pairwise nucleotides were connected by springs and the force constant decayed exponentially with the separate distance of the nucleotide pairs. The performance of these two proposed models was evaluated by using a non-redundant RNA structure database composed of 51 RNA molecules. The calculation results show that both the proposed models outperform the conventional GNM in reproducing the experimental B-factors of RNA structures. Compared with the conventional GNM, the Pearson correlation coefficient between the predicted and experimental B-factors was improved by 9.85% and 6.76% for wGNM and fcdGNM, respectively. Our studies provide two candidate methods for better revealing the dynamical properties encoded in RNA structures.     

Statistical Dynamics of Clustering in the Genome Structure

Clustering and long-range correlations in the nucleotide sequences of different categories of organisms are studied. As a result of clustering, the size distribution of coding and non-coding DNA regions is estimated analytically using the Generalised Central Limit Theorem.The alternation of coding regions (which follow a short range size distribution) with non-coding regions (which follow a long range size distribution in higher organisms) leads to DNA structures which have a striking resemblance to random Cantor Fractals. For lower organisms (such as viruses, procaryotes etc.) long-range correlations are sporadically observed and the DNA structures do not present fractality.Statistical models are proposed based on biologically motivated dynamical mechanisms (such as aggregation of oligonucleotides, influx and DNA length reduction), which can account for the above statistical features.     

Bis‐4,9‐diazapyrenium dications: synthesis of the methylenedibenzyl‐analogue,interactions with nucleotides,DNA, RNA. The antitumour activity of all till now prepared analogues

Novel bis‐4,9‐diazapyrenium dication has shown reversible pH dependent formation of 4,9‐ diazapyrenium pseudobase in water characteristic for most 4,9‐diazapyrenium derivatives. The compound has formed non‐covalent complexes with nucleotides in water, whose stability is controlled dominantly by aromatic stacking interactions. No cooperativity between two 4,9‐diazapyrenium subunits was observed in binding of nucleotides. Novel bis‐4,9‐diazapyrenium dication formed mono‐intercalative complexes with studied double stranded DNA and RNA. Additional interactions of non‐intercalated part were found to depend significantly on the polynucleotide secondary structure, yielding strong DNA over RNA preference. Appearance of ICD band of 3 was found to be specific for DNA polynucleotides and together with observed destabilisation of double stranded RNA is attributed to the aggregation of compound in one of the RNA grooves. All bis‐4,9‐diazapyrenium dications prepared till now have shown considerable antiproliferative activity against five human tumour cell lines, which suggested mechanism of action by interacting with cell DNA. Copyright © 2007 John Wiley & Sons, Ltd.     

Microeconomics of the ideal gas like market models

We develop a framework based on microeconomic theory from which the ideal gas like market models can be addressed. A kinetic exchange model based on that framework is proposed and its distributional features have been studied by considering its moments. Next, we derive the moments of the CC model (Eur. Phys. J. B 17 (2000) 167) as well. Some precise solutions are obtained which conform with the solutions obtained earlier. Finally, an output market is introduced with global price determination in the model with some necessary modifications.     

Using solid-state 31P{19F} REDOR NMR to measure distances between a trifluoromethyl group and a phosphodiester in nucleic acids

REDOR is a solid-state NMR technique frequently applied to biological structure problems. Through incorporation of phosphorothioate groups in the nucleic acid backbone and mono-fluorinated nucleotides, 31P{19F} REDOR has been used to study the binding of DNA to drugs and RNA to proteins through the detection of internuclear distances as large as 13-14 A. In this work, 31P{19F} REDOR is further refined for use in nucleic acids by the combined use of selective placement of phosphorothioate groups and the introduction of nucleotides containing trifluoromethyl (-CF3) groups. To ascertain the REDOR-detectable distance limit between an unique phosphorous spin and a trifluoromethyl group and to assess interference from intermolecular couplings, a series of model compounds and DNA dodecamers were synthesized each containing a unique phosphorous label and trifluoromethyl group or a single 19F nucleus. The dipolar coupling constants of the various 31P and 19F or -CF3 containing compounds were compared using experimental and theoretical dephasing curves involving several models for intermolecular interactions.     

电离辐射诱导组蛋白乙酰化引起的染色质结构解聚研究

真核生物的DNA分子经高度压缩以染色质形式存在于细胞核中,染色质动态结构在DNA复制、基因转录和DNA修复等过程中起着重要的调控作用。核内染色质结构的原位高分辨解析和其结构变化定量表征一直受困于显微成像观测分辨率的限制。通过点击化学荧光标记EdU和STORM单分子定位显微成像,实验得到了细胞核内超分辨率染色质结构图像。基于提出的单分子团簇分析和最近邻距离算法分析发现,X射线辐照和TSA处理后的细胞核内核小体团簇数量显著增多,核小体团簇所占细胞核内的面积比相对于对照组增加,且团簇内平均EdU分子数降低。同时,重离子辐照活细胞在线成像实验获得的XRCC1招募动力学速率常数表明乙酰化处理使得DNA损伤密度降低。这些结果表明电离辐射和乙酰化处理均导致了染色质结构的松散化。STORM超分辨成像方法和分析算法及其获得的核小体团簇分布规律为染色质结构的松散提供了直接的定量表征数据支持。     

Three-level rate-equations-based model of quantum cascade lasers with a single solution regime

The three-level rate-equations-based QCL models can possess multiple DC solution regimes for nonnegative values of injection currents. We show that using the proposed variable transformation, the three-level rate-equations based models, considering the gain-saturation terms, can possess single solution regime and hence, the circuit-level simulation results will always converge to the positive laser output powers. By using the proposed equivalent circuit-level model, the effects of injection current on QCL static and dynamic behaviors are investigated. It has been shown that the proposed circuit-level model accurately predicts the operating characteristics of the QCLs.     

Cooperative impulsive formation control for networked uncertain Euler–Lagrange systems with communication delays

This paper investigates the cooperative formation problem via impulsive control for a class of networked Euler–Lagrange systems. To reduce the energy consumption and communication frequency, the impulsive control method and cooperative formation control approach are combined. With the consideration of system uncertainties and communication delays among agents, neural networks-based adaptive technique is used for the controller design. Firstly, under the constraint that each agent interacts with its neighbors only at some sampling moments, an adaptive neural-networks impulsive formation control algorithm is proposed for the networked uncertain Euler–Lagrange systems without communication delays. Using Lyapunov stability theory and Laplacian potential function in the graph theory, we conclude that the formation can be achieved by properly choosing the constant control gains. Further, when considering communication delays,a modified impulsive formation control algorithm is proposed, in which the extended Halanay differential inequality is used to analyze the stability of the impulsive delayed dynamical systems. Finally, numerical examples and performance comparisons with continuous algorithm are provided to illustrate the effectiveness of the proposed methods.     

Metastable decay of DNA components and their compositions – a perspective on the role of reactive electron scattering in radiation damage

Here we review recent studies on the metastable fragmentation of individual DNA and RNA building blocks and their compositions using matrix assisted laser desorption/ionization mass spectrometry (MALDI). To compare the fragmentation channels of small DNA components with larger compositions we have studied the metastable fragmentation of the deprotonated nucleobases, ribose, ribose-monophoshates, the nucleosides, the nucleoside 5′-monophosphates and selected oligonucleotides. Both previously published and unpublished data are reported. To gain a comprehensive picture of the fragmentation of individual components, metastable fragmentation of native components are in many cases compared to chemically modified components and isotopic labelling is used to unambiguously identify fragments. Furthermore, to shed light on the underlying fragmentation mechanisms we complement the experimental studies with classical dynamics simulations of the fragmentation of selected compounds. For the DNA and RNA components where dissociative electron attachment studies have been conducted we compare these to the metastable fragmentation channels observed here.     

Statistical Dynamics of Clustering in the Genome Structure

Clustering and long-range correlations in the nucleotide sequences of different categories of organisms are discussed. Clustering, mostly observed in higher eucaryotes, can be found at different length scales in DNA and Central Limit Theorems are used as links between these length scales. Several dynamical, statistical, mean-field models are proposed based on biologically motivated dynamical mechanisms and they successfully reproduce both the short range behavior observed in coding DNA and the long range, out-of-equilibrium features of non-coding DNA. Such dynamical mechanisms include aggregation of oligonucleotides, influx and DNA length reduction schemes, transpositions, and fusions of large DNA macromolecules. Fractality can be inferred from the short and long range correlations observed in the sequence structure of higher eucaryotes, where the non-coding part is relatively extended. In these organisms the DNA coding/non-coding alternation has the characteristics of finite size, fractal, random sets.     

Chaotic cascades with Kolmogorov 1941 scaling

We define a (chaotic) deterministic variant of random multiplicative cascade models of turbulence. It preserves the hierarchical tree structure, thanks to the addition of infinitesimal noise. The zero-noise limit can be handled by Perron-Frobenius theory, just like the zero-diffusivity limit for the fast dynamo problem. Random multiplicative models do not possess Kolmogorov 1941 (K41) scaling because of a large-deviations effect. Our numerical studies indicate thatdeterministic multiplicative models can be chaotic and still have exact K41 scaling. A mechanism is suggested for avoiding large deviations, which is present in maps with a neutrally unstable fixed point.