线性泛素化修饰研究进展

蛋白质泛素化修饰过程在调节各种细胞生物学功能的过程中发挥了非常重要的作用,如细胞周期进程、DNA损伤修复、信号转导和各种蛋白质膜定位等。泛素化修饰可分为多聚泛素化修饰和单泛素化修饰。多聚泛素化修饰系统可以通过对底物连接不同类型的多泛素化链调节蛋白质的功能。多聚泛素化修饰中已知7种泛素链连接方式均为泛素内赖氨酸连接方式。近几年发现了第8种类型的泛素链连接形式即线性泛素化,其泛素链的连接方式是由泛素甲硫氨酸的氨基基团与另一泛素甘氨酸的羧基基团相连形成泛素链标记。目前研究表明线性泛素化修饰在先天性免疫和炎症反应等多个过程中发挥着非常重要的作用。募集线性泛素链的泛素连接酶E3被称为LUBAC复合体,其组成底物以及其活性调控机制和功能所知甚少。本文综述了募集线性泛素化链的泛素连接酶、去泛素化酶、底物等活性调控机制及其在先天性免疫等多个领域中的功能,分析了后续研究方向,以期为相关研究提供参考。     

Usefulness of a new online patient-specific quality assurance system for respiratory-gated radiotherapy

PurposeThe accuracy of gated irradiation may decrease when treatment is performed with short “beam-on” times. Also, the dose is subject to variation between treatment sessions if the respiratory rate is irregular. We therefore evaluated the impact of the differences between gated and non-gated treatment on doses using a new online quality assurance (QA) system for respiratory-gated radiotherapy.MethodsWe generated dose estimation models to associate dose and pulse information using a 0.6 cc Farmer chamber and our QA system. During gated irradiation with each of seven regular and irregular respiratory patterns, with the Farmer chamber readings as references, we evaluated our QA system’s accuracy. We then used the QA system to assess the impact of respiratory patterns on dose distribution for three lung and three liver radiotherapy plans. Gated and non-gated plans were generated and compared.ResultsThere was agreement within 1.7% between the ionization chamber and our system for several regular and irregular motion patterns. For dose distributions with measured errors, there were larger differences between gated and non-gated treatment for high-dose regions within the planned treatment volume (PTV). Compared with a non-gated plan, PTV D_95% for a gated plan decreased by −1.5% to −2.6%. Doses to organs at risk were similar with both plans.ConclusionsOur simple system estimated the radiation dose to the patient using only pulse information from the linac, even during irregular respiration. The quality of gated irradiation for each patient can be verified fraction by fraction.     

Detailed study of a river corridor plant distribution pattern provides implications for river valley conservation

River valleys have been subjected to human-induced changes for centuries, but they are still considered regional hotspots of biodiversity. In central Europe, some vascular plant species demonstrate confinement to the corridors of large rivers. They are termed river corridor plants (RCPs). RCPs are an important component of regional biodiversity and include a high proportion of threatened species, thus they deserve attention. Here we examine: (1) the detailed distribution pattern of RCPs within a river valley, (2) the habitat preferences of RCP species, and (3) the correlation between the richness of RCP species and selected variables. The studied variables include: river bed proximity, distance from the river mouth, floodplain coverage, richness of native, red listed and invasive species, and number of habitats considered to be of Europaean Community importance. Surveys were conducted in 10 transects running perpendicularly to the San River bed (Poland, central Europe). Each transect was divided into 14 plots (1 km × 1 km). In each plot, the site locations of RCPs as well as their habitats were recorded. The occurrence of all vascular plant species in a particular plot was also noted. The richness and abundance of RCP species depended on the distance from the river and the floodplain coverage in a plot. The plots located in the vicinity of the river were the richest in RCP species and usually harbored the largest number of native, red-listed and invasive species. They were also characterized by the largest number of habitats considered to be of importance to the European Community. RCP species differed in the degree of confinement to habitats regarded as typical for them. Some of the RCP species were recorded only within typical habitats while others were found in several different types of habitats, including anthropogenic ones. Knowledge concerning the RCP distribution pattern and its correlates can make restoration initiatives in river valleys more effective. While implementing conservation measures in river valleys, one should keep in mind that: (1) hotspots of RCP and invasive species spatially overlap and (2) anthropogenic linear elements occurring within river valleys constitute important habitats for some RCP species.     

Linear nicking endonuclease-mediated strand-displacement DNA amplification

We describe a method for linear isothermal DNA amplification using nicking endonuclease-mediated strand displacement by a DNA polymerase. The nicking of one strand of a DNA target by the endonuclease produces a primer for the polymerase to initiate synthesis. As the polymerization proceeds, the downstream strand is displaced into a single-stranded form while the nicking site is also regenerated. The combined continuous repetitive action of nicking by the endonuclease and strand-displacement synthesis by the polymerase results in linear amplification of one strand of the DNA molecule. We demonstrate that DNA templates up to 5000 nucleotides can be linearly amplified using a nicking endonuclease with 7-bp recognition sequence and Sequenase version 2.0 in the presence of single-stranded DNA binding proteins. We also show that a mixture of three templates of 500, 1000, and 5000 nucleotides in length is linearly amplified with the original molar ratios of the templates preserved. Moreover, we demonstrate that a complex library of hydrodynamically sheared genomic DNA from bacteriophage lambda can be amplified linearly.     

Linear and nonlinear mixed-effects models for censored HIV viral loads using normal/independent distributions

HIV RNA viral load measures are often subjected to some upper and lower detection limits depending on the quantification assays. Hence, the responses are either left or right censored. Linear (and nonlinear) mixed-effects models (with modifications to accommodate censoring) are routinely used to analyze this type of data and are based on normality assumptions for the random terms. However, those analyses might not provide robust inference when the normality assumptions are questionable. In this article, we develop a Bayesian framework for censored linear (and nonlinear) models replacing the Gaussian assumptions for the random terms with normal/independent (NI) distributions. The NI is an attractive class of symmetric heavy-tailed densities that includes the normal, Student's-t, slash, and the contaminated normal distributions as special cases. The marginal likelihood is tractable (using approximations for nonlinear models) and can be used to develop Bayesian case-deletion influence diagnostics based on the Kullback-Leibler divergence. The newly developed procedures are illustrated with two HIV AIDS studies on viral loads that were initially analyzed using normal (censored) mixed-effects models, as well as simulations.     

Synthesis, crystal structure and magnetic properties of cubane and linear trinuclear nickel complexes formed by 3,5-dichloro-2-hydroxybenzylaminoacetic acid

The reaction of Ni(ClO₄)₂·6H₂O with 3,5-dichloro-2-hydroxy-benzylaminoacetic acid (H₂dchaa), NaN₃ and triethylamine in methanol solution or water solution under solvothermal methods leads to the formation of two completely different Ni^II compounds: [HN(C₂H₅)₃]₈·[Ni₄(dchaa)₄(N₃)₄]₂ (1) and [HN(C₂H₅)₃]₂·[Ni₃(dchaa)₄(H₂O)₄]₂·(H₂O)₂ (2). The complexes 1 and 2 have been characterized by elemental analyses, IR spectra and single-crystal X-ray diffraction. Structure analyses reveal that complex 1 is a cubane cluster, while the complex 2 is a linear trinuclear cluster. The magnetic investigation shows that complexes 1 and 2 exhibit a ferromagnetic coupling between Ni^II ions. Ac susceptibilities of 1 and 2 reveal no frequency-dependent out-of-phase signals and the corresponding magnetic properties were discussed.     

Higher order inference for the consensus mean in inter-laboratory studies

In inter-laboratory studies, a fundamental problem of interest is inference concerning the consensus mean, when the measurements are made by several laboratories which may exhibit different within-laboratory variances, apart from the between laboratory variability. A heteroscedastic one-way random model is very often used to model this scenario. Under such a model, a modified signed log-likelihood ratio procedure is developed for the interval estimation of the common mean. Furthermore, simulation results are presented to show the accuracy of the proposed confidence interval, especially for small samples. The results are illustrated using an example on the determination of selenium in non-fat milk powder by combining the results of four methods. Here, the sample size is small, and the confidence limits for the common mean obtained by different methods produce very different results. The confidence interval based on the modified signed log-likelihood ratio procedure appears to be quite satisfactory.     

An analytical contrast between fitness maximization and selection for mixability

It has been recently shown numerically that sex enables selection for alleles that perform well across different genetic contexts, i.e., selection for mixability. Here we capture this result analytically in a simple case. This serves a dual purpose. First, it provides a clear distinction between fitness maximization and selection for mixability. Second, it points out a limitation of the traditional analytical approach as applied to mixability.     

The Multivariate Nonparametric Methods for Identifying Gene Sets with Differential Expression

Background

Gene Set Analysis (GSA) identifies differential expression gene sets amid the different phenotypes. The results of published papers in this filed are inconsistent and there is no consensus on the best method. In this paper two new methods, in comparison to the previous ones, are introduced for GSA.

Methods

The MMGSA and MRGSA methods based on multivariate nonparametric techniques were presented. The implementation of five GSA methods (Hotelling's T², Globaltest, Abs_Cat, Med_Cat and Rs_Cat) and the novel methods to detect differential gene expression between phenotypes were compared using simulated and real microarray data sets.

Results

In a real dataset, the results showed that the powers of MMGSA and MRGSA were as well as Globaltest and Tsai. The MRGSA method has not a good performance in the simulation dataset.

Conclusions

The Globaltest method is the best method in the real or simulation datasets. The performance of MMGSA in simulation dataset is good in small-size gene sets. The GLS methods are not good in the simulated data, except the Med_Cat method in large-size gene sets.     

综合性医院平均住院日绩效指标集的构建与应用

目的 构建以平均住院日为核心的绩效指标集,在此基础上,制定绩效目标及关键控制举措,并跟踪实际的执行效果。方法 收集2008年12月—2013年6月共计55个月的重点科室平均住院日数据,运用相关性分析和多元线性回归提取影响平均住院日的显著因素,根据模型结论,研究分析绩效控制目标和举措并进行应用。结果 现阶段有效缩短平均住院日应主要解决“收容收治比及床位资源的利用效率”两对关键矛盾,模型应用后,医院院整体平均住院日由原来的15.7天降低为11.6天,重点科室平均住院日由19.2天降低为14.6天。结论 平均住院日绩效指标集的应用有助于优化医院资源配置,达到显著提高整体运营效率的目的。