Development of a Novel Tool To Demystify Drug Distribution at Tissue-Blood Barriers

Tissue endothelial cells express ABC-transporter enzymes that change the concentration of small molecules within different tissue compartments. These “blood-tissue barriers” have been shown to directly affect the efficacy and toxicity of anticancer, antimicrobial, psychiatric, and anti-epileptic drugs. Currently this phenomenon is best studied for the blood-brain barrier, but remains enigmatic for most other tissues. In addition, canonical pharmacokinetic theory specifically assumes an equal concentration of free drug within all tissue compartments. Inspired by Lipinski's “rule of 5,” we here clarify current knowledge on drug–tissue distribution by: 1) curating the in-vivo literature on 73 drugs across 23 tissues and 2) developing two graphical web-based applications to visually describe and interpret data. These curated in-vivo dataset and visualization tools enabled us to achieve new insights into the logic of the barrier-tissue organization and showed remarkable correspondence to whole-body imaging of radiolabeled molecules.     

用多时延信息论构建基因调控网络

最近涌现出大量基因调控网络重构的模型和方法,但是都没有涉及到基因数据尺寸大小对算法精度的影响问题。文中研究了基因数据尺寸大小对信息论方法构建基因调控网络精度的影响,实验表明基因调控网络构建的精度会在一定数据尺寸规模下达到一个稳态。为了克服互信息的一些缺点,引入文中多时延互信息值来计算两个基因之间的调控关系,所构建的基因调控网络取得了很好的查全率和查准率。并应用它对两个真实的生物分子网络进行重构,结果表明基于多时延的策略下,所构建的基因调控网络取得了很高的特异度和精确度。     

Constructing and characterizing a bioactive small molecule and microRNA association network for Alzheimer's disease

Alzheimer''s disease (AD) is an incurable neurodegenerative disorder. Much effort has been devoted to developing effective therapeutic agents. Recently, targeting microRNAs (miRNAs) with small molecules has become a novel therapy for human diseases. In this study, we present a systematic computational approach to construct a bioactive Small molecule and miRNA association Network in AD (SmiRN-AD), which is based on the gene expression signatures of bioactive small molecule perturbation and AD-related miRNA regulation. We also performed topological and functional analysis of the SmiRN-AD from multiple perspectives. At the significance level of p ≤ 0.01, 496 small molecule–miRNA associations, including 25 AD-related miRNAs and 275 small molecules, were recognized and used to construct the SmiRN-AD. The drugs that were connected with the same miRNA tended to share common drug targets (p = 1.72 × 10⁻⁴) and belong to the same therapeutic category (p = 4.22 × 10⁻⁸). The miRNAs that were linked to the same small molecule regulated more common miRNA targets (p = 6.07 × 10⁻³). Further analysis of the positive connections (quinostatin and miR-148b, amantadine and miR-15a) and the negative connections (melatonin and miR-30e-5p) indicated that our large-scale predictions afforded specific biological insights into AD pathogenesis and therapy. This study proposes a holistic strategy for deciphering the associations between small molecules and miRNAs in AD, which may be helpful for developing a novel effective miRNA-associated therapeutic strategy for AD. A comprehensive database for the SmiRN-AD and the differential expression patterns of the miRNA targets in AD is freely available at http://bioinfo.hrbmu.edu.cn/SmiRN-AD/.     

基于元分析的差异表达基因识别

针对传统差异表达基因识别方法不能处理异质性数据集以及分析结果偏差较大的问题,提出了一个基于元分析及标准差过滤技术的差异表达基因识别算法标准差排序分析(RS-DM)。对来自于不同实验平台的数据进行整合分析,过滤掉伪差异表达基因PDEGs,并找出遗失的真正的差异表达基因TDEGs。经实验验证,算法简单有效。     

“天河一号”在生命科学研究中的应用

本文首先对高性能计算和"天河一号"超级计算机进行了简要概述。随后详细描述了高性能计算在生命科学领域中的两大重要应用:一个是生物大分子的动力学模拟,介绍用户在"天河一号"取得的一些应用成果和进行的应用性能测试;另一个是生物信息学研究,重点介绍了华大基因在基于"天河一号"开展的GPU并行软件测试取得的良好结果。最后展望了高性能计算在生命科学领域中的发展趋势。     

基于随机复杂度约束的高维特征自动选择算法

高维特征选择问题是机器学习研究领域的公开问题,当前流行的1-范数约束正则化解决方案存在的主要问题是缺乏特征组选能力和特征选择能力受样本容量限制.本文从随机复杂度理论的模型冗余度最优下界推导得出了一种易于求解的基于零-范数约束的特征选择算法模型.该算法不仅可证优化,而且具备自动特征选择能力,克服了1-范数约束方法的主要缺...     

烟草PP2C家族基因降雨量响应表达模式分析

PP2C是一类单体丝氨酸/苏氨酸蛋白磷酸酶,广泛参与生物体内多个信号转导。PP2C基因家族的鉴定和功能研究已在多种作物上报道。为探明不同降雨量条件下烟草PP2C基因家族表达特征,通过塑料大棚内模拟人工定量喷灌试验和不同降雨量的田间试验,利用RNA-Seq技术对移栽后40和60 d烟叶中PP2C家族基因进行了表达分析。结果显示,18个烟草PP2C家族基因的表达明显受降雨量影响,可分成9个亚族。其中6个PP2C家族成员的表达随着降雨量增大而降低,4个PP2C家族成员的表达随着降雨量增大而升高。本研究初步探明了云烟87中受降雨量影响的PP2C基因家族种类及其表达特点,为抗旱育种和抗旱栽培提供参考。     

链霉菌MY0504纤溶酶YG4基因的克隆及生物信息学分析

本研究获得了海洋链霉菌MY0504纤溶酶YG4基因,并对其进行生物信息学分析。利用依据同源序列设计的兼并引物,对提取的链霉菌MY0504的基因组DNA进行PCR扩增,将得到的DNA片段连接到pMD18-T载体后转化感受态Trans10细胞,然后对阳性克隆进行测序,并对序列进行生物信息学分析。最终克隆了1083bp的海洋链霉菌MY0504纤溶酶YG4基因。将获得的YG4基因输入Gen Bank网站,进行检索比对,结果显示与丝氨酸蛋白酶基因碱基序列同源性100%。对16s rDNA序列分析结果表明,该菌株与达格斯地链霉菌、氢化链霉菌、嫩白黄链霉菌、浅紫链霉菌的亲缘关系较近;通过对YG4基因编码蛋白的一级结构、二级结构、亚细胞定位和三级结构的预测和分析,结果表明:该基因编码360个氨基酸,其编码产物为稳定的亲水蛋白;二级结构以α螺旋和β折叠为主,无信号肽和跨膜结构域,有40个磷酸化位点;高级结构以无规则卷曲为主。本研究结果为研究海洋链霉菌MY0504纤溶酶YG4基因的表达机制及目的蛋白表达水平的提高提供了重要信息。