生命科学信息工程设施以及在中国的实现

以组学数据为代表的生命科学数据呈指数增长.与高能物理、气象、地质、地理和环境科学等其他数据密集型学科一样,现代生命科学已经进入了高度信息化的时代——第四范式时代.国家跨组学信息工程大设施(China Information Engineering Infrastructure for Pan-Omics Studies,CIEIPOS)已经成为推动中国生命科学进一步发展、并使海量数据转化成知识与应用的必不可少的国家生命科学基础设施.本文介绍国内外生物数据收集、管理与利用的现状,提出建设CIEIPOS生物信息"集散地"的重要性与迫切性,阐述实现数据整合、搜索与可视化的挑战与可能方案.CIEIPOS的另外一个重要功能是支持对组学数据的管理、分析、挖掘与利用,这使得CIEIPOS不同于传统的国际生物信息中心,如美国国家生物信息技术中心(National Center for Biotechnology Information)与欧洲生物信息学研究所(European Bioinformatics Institute).本文以质谱平台产出的高通量蛋白质组数据为例,说明组学数据分析的复杂性.通过对跨组学数据在不同时空的模拟分析,进一步说明CIEIPOS的实际应用对计算机硬件与网络的要求.     

基于序列拓扑和二阶隐马尔可夫模型的跨膜蛋白亚细胞定位预测

现有蛋白质亚细胞定位方法针对水溶性蛋白质而设计,对跨膜蛋白并不适用。而专门的跨膜拓扑预测器,又不是为亚细胞定位而设计的。文章改进了跨膜拓扑预测器TMPHMMLoc的模型结构,设计了一个新的二阶隐马尔可夫模型;采用推广到二阶模型的Baum-Welch算法估计模型参数,并把将各个亚细胞位置建立的模型整合为一个预测器。数据集上测试结果表明,此方法性能显著优于针对可溶性蛋白设计的支持向量机方法和模糊k最邻近方法,也优于TMPHMMLoc中提出的隐马尔可夫模型方法,是一个有效的跨膜蛋白亚细胞定位预测方法。     

利用定点突变法研究精氨酸脱亚胺酶活性的影响机制

精氨酸脱亚胺酶(ADI)是一种针对精氨酸缺陷型癌症(如:肝癌、黑素瘤)的新药,目前处于临床三期试验。文中通过定点突变技术分析了精氨酸脱亚胺酶的特定氨基酸位点对酶活力的影响机制。针对已报道的关键氨基酸残基A128、H404、I410,采用QuikChange法进行定点突变,获得ADI突变株M1(A128T)、M2(H404R)、M3(I410L)和M4(A128T/H404R)。将突变株在大肠杆菌BL21(DE3)中进行重组表达,并对纯化获得的突变蛋白进行酶学性质研究。结果表明,突变位点A128T和H404R对ADI最适pH的提高,生理中性(pH 7.4)条件下的酶活力和稳定性的提高,以及Km值的降低均具有显著的作用。研究结果为阐明ADI的酶活力影响机制和蛋白质的理性改造提供了一定的依据。     

基于机制的生理药动- 药效学模型研究进展

生理药动- 药效学模型通过对生物学过程的描述,可预测体内药物的吸收、分布、代谢、排泄以及进一步的生理生化反应。这类模型是通过已知的生化/ 生理基础来构建,采用了一种“自下而上”的建模方法,并利用数学方法对生理过程及药物的作用机制作出准确的描述。其中药效学部分,根据预测目的和药物作用的复杂性,可进一步分为基于经验的和基于机制的效应模型,这两种模型均可与基于机制的生理药动学模型相连接,最终预测药物的体内处置和效应。基于机制的生理药动- 药效学模型的优势在于：可外推性、新的影响因素的可纳入性以及可用于未知领域的预测等。随着实验技术的不断革新,药物作用机制的逐渐明确,这类模型越来越多的被成功应用于药物研发及风险评估中。综述生理药动- 药效学模型的构建策略与分类以及在药物研发和风险评估中的应用研究。     

基于可视中国人高分辨人体结构数据集的辐射剂量模拟研究进展

中国数字化辐射虚拟人研究是以中国数字人高分辨三维结构数据集为基础,构建可用于蒙特卡洛辐射模拟的三维计算模型,并实现X射线、中子、质子等多粒子多能级的仿真计算。论著中讨论了基于高分辨人体结构数据集的辐射模型构建过程和特点,以及蒙特卡洛模拟软件,并将剂量测定结果与现有的国外人体模型模拟数据进行了比较。中国数字化辐射虚拟人模型是具备中国人体特征的辐射模型。计算结果很大程度上补充或校正了现有放射学计量数据集,为临床放疗规划、核医药、核辐射防护设计提供精确量化参考。     

生理房室药动学模型

生理药动学模型较ｎ房室模型能更准确地描述药物在体内的处置过程,但在实际应用中由于其计算结果有较大的误差而限制其应用和推广．在生理模型中,某一组织器官中血液分布容积相对于单位时间的血流量来说,如果太大,就去给计算结果带来较大的误差．本文提出的生理房室模型可以减小这种误差,从而更准确地模拟药物在体内的处置过程．文中对一组模拟的生理和生化参数分别求出了生理房室模型和生理模型的数值解．通过两组解的比较,说明生理房室模型可以描述药物在体内处置过程中的细微变化．     

流域尺度海量生态环境数据建库关键技术——以塔里木河流域为例

流域尺度海量生态环境数据库构建是生态环境精准化研究的基础。以塔里木河流域生态环境数据库构建为例,对流域尺度海量生态环境数据建库的无缝数据拼接、建库规范设计、要素代码设计、空间索引设计、特征展示表及一键入库设计等关键技术进行了探讨。针对流域跨带裂缝问题,从缝隙源出发,通过分离物理数据层和逻辑数据层并区分矢量数据和栅格数据,在统一的多尺度空间框架体系下实现了海量数据的跨带无缝拼接;数据库规范设计和要素代码设计是数据入库前的关键工作,针对流域实际,分别采用规范化英文字母和图形数据比例尺设置数据库命名规范和建立代码标准;在ArcSDE框架下,采用格网索引设计和多级金字塔结构分别构建矢量数据和栅格数据的空间索引,提高了数据的快速检索和浏览;通过建立特征展示表并提出"一键入库"策略,提高了系统响应及数据入库效率等。通过构建流域尺度海量生态环境数据库系统,实现了流域尺度多源、多类型、跨带海量生态环境数据的有效存储和管理,为流域一体化管理和生态环境研究提供了基础数据支撑。     

生理组学:传统向现代的升华北大核心CSCD

近三十年来,分子生物学领域包括人体基因组学、蛋白质组学等新学科和新技术蓬勃兴起,并取得了令人瞩目的成果,但深层次微观研究的局限亦日渐明显。生命科学研究的最终目的不仅是揭示生命的奥秘,更重要的是解决疾病问题,促进人类健康和福祉。正如诺贝尔奖得主James Black指出"分子生物学研究所获得的信息如果不结合组织器官和整体分析,则将成为孤独的分子结构和机制的一张无序的清单"。而生理学可能正是将此无序的"碎片(puzzle)"拼接成一幅有序画面的"整合者"。上世纪九十年代国际生理科学联合会(International Union of Physiological Sciences,IUPS)提出了"生理组计划",近年来随着计算机等技术的进步,生理组学研究正方兴未艾,并在生理功能的预测、药物研发模型的建立等方面发挥越来越重要的作用,但不少生理学工作者至今对于生理组学的概念仍相对生疏。高峰等教授撰写此文,从生理组学概念的提出及发展,到重点介绍生理组学与经典生理学和系统生物学之间的关系,讨论了面对当今生命科学研究的机遇和挑战,生理学家能否借助生理组学发展平台,有效地整合当今多种相关"组学"的信息,以促进现代生理学的发展,并在认识生命与健康、解决疾病问题中发挥引领作用。此文值得一读,文中提出的问题也值得读者思考。     

大熊猫演化保护生物学研究

研究珍稀濒危动物的演化历史、濒危机制及适应性演化对策,既是保护生物学研究的重大科学问题,也是国家生态文明建设和生物多样性可持续发展的重大需求.大熊猫(Ailuropoda melanoleuca)是探讨物种濒危灭绝及适应性演化机制的理想模型.本研究团队率先将种群基因组学和宏基因组学等新技术引入大熊猫研究中,开拓了濒危动物种群基因组学与宏基因组学研究领域,系统阐明了大熊猫的种群历史、濒危原因、适应性演化机制与演化潜力等科学问题.以大熊猫为模型揭示了食性特化动物类群在食性转换和特化历程中如何在形态、行为、生理、遗传和肠道微生物等方面产生适应性演化的规律,积极推动了国家大熊猫放归和栖息地廊道建设工程的实施.     

多组学大数据共享平台研究进展

高通量检测技术的快速发展催生了海量的多组学数据，数据驱动型研究规模正逐步超越传统假设型研究。不同层次组学数据的组合，通过对系统生物学和疾病发展更深入和全面的解读，持续改变生物医学研究方式。同时，多组学数据庞大的数据规模、异质的数据特性，以及强烈的数据共享内源性需求，都推动组学数据向规模化、平台化、标准化共享的方向发展。该文首先介绍了代表性的多组学平台和各组学数据的特点，接着以多维组学数据百科全书NODE为例，从多组学数据融合和多组学数据安全共享两方面对相应的方法和技术进行了细致的阐述，并展望了多组学数据平台未来的发展方向。     

Nest and nest-site reuse within and between breeding seasons by three neotropical flycatchers (Tyrannidae).

Nest and or nest site reuse within and between breeding seasons was reported by the Euler's Flycatcher (Lathrotriccus euleri), the Sepia-capped Flycatcher (Leptopogon amaurocephalus) and the Gray-hooded Flycatcher (Mionectes -rufiventris) in forest fragments from southeastern Brazil. Nest and or nest site reuse between some years was frequent within a single breeding season by the Sepia-capped Flycatcher. Nest reuse, however, was not related to nesting success in the previous breeding attempt. Nest turnover rates (movement to a new site between years) were low for L. amaurocephalus, intermediate for L. euleri and high for M. rufiventris.     

Modeling the membrane potential generation of bacteriorhodopsin

The archaeon Halobacterium salinarum can grow phototrophically with only light as its energy source. It uses the retinal containing and light-driven proton pump bacteriorhodopsin to enhance the membrane potential which drives the ATP synthase. Therefore, a model of the membrane potential generation of bacteriorhodopsin is of central importance to the development of a mathematical model of the bioenergetics of H. salinarum. To measure the current produced by bacteriorhodopsin at different light intensities and clamped voltages, we expressed the gene in Xenopus laevis oocytes. We present current-voltage measurements and a mathematical model of the current-voltage relationship of bacteriorhodopsin and its generation of the membrane potential. The model consists of three intermediate states, the BR, L, and M states, and comparisons between model predictions and experimental data show that the L to M reaction must be inhibited by the membrane potential. The model is not able to fit the current-voltage measurements when only the M to BR phase is membrane potential dependent, while it is able to do so when either only the L to M reaction or both reactions (L to M and M to BR) are membrane potential dependent. We also show that a decay term is necessary for modeling the rate of change of the membrane potential.     

Material Reuse Modeling

The techniques of water distribution modeling, a well-developed subject, have been applied to water management in an industrial park-the Bayport chemical manufacturing complex in Houston, Texas in the United States. Linear and other mathematical programming approaches were used to evaluate water reuse opportunities for a variety of scenarios, including redesigning the industrial water use network, adding a facility to the network, limiting the total water available to the network, and varying the price of water rhe results of the modeling demonstrate that a number of economical water reuse opportunities may exist for this network of facilities. More generally, the types of mathematical models developed for water reuse may find application in reuse modeling for other materials.     

High-throughput functional curation of cellular electrophysiology models

Effective reuse of a quantitative mathematical model requires not just access to curated versions of the model equations, but also an understanding of the functional capabilities of the model, and the advisable scope of its application. To enable this “functional curation” we have developed a simulation environment that provides high-throughput evaluation of a mathematical model’s functional response to an arbitrary user-defined protocol, and optionally compares the results against experimental data. In this study we demonstrate the efficacy of this simulation environment on 31 cardiac electrophysiology cell models using two test cases. The S1-S2 response is evaluated to characterise the models’ restitution curves, and their L-type calcium channel current-voltage curves are evaluated. The significant variation in the response of these models, even when the models represent the same species and temperature, demonstrates the importance of knowing the functional characteristics of a model prior to its reuse.We also discuss the wider implications for this approach, in improving the selection of models for reuse, enabling the identification of models that exhibit particular experimentally observed phenomena, and making the incremental development of models more robust.     

Biodegradation of Phenol by Actinobacillus Sp.: Mathematical Interpretation and Effect of Some Growth Conditions

Models of the cultivation process of Actinobacillus sp. cells in two media, rich (NB) and minimal (M9) that includes phenol as a sole carbon source, have not been described in the available literature. For these reasons, several single-substrate inhibition models (Monod, Andrew, and Tesseir) were investigated in order to determine the mathematical expression of Actinobacillus sp. growth rate. The experimental data for both nutrient broth and M9 media were fitted to the above models mentioning that Andrews' model best fits these data adequately for both media with regression coefficient of 0.973 and 0.962, respectively. The maximum predicted growth rate by this model is 0.37 h^{- 1} for both media obtained when the initial concentration of phenol is 100 mg/L. The half-saturation concentration constant, K_P, is 1.00 mg/L, which represents the phenol concentration when μ is equal to half μ_max. On the other hand, the inhibition constant, K_p is 13,000.00 mg/L for broth medium and 12,000 mg/L for M9 medium, which is a measure of sensitivity to inhibition by inhibitory substances. When cells are grown in nutrient broth and minimal media, the rate of cell production with time can be expressed by the Reccati and Voltera models. Voltera model better fits in the case of M9 minimal medium plus phenol as sole carbon source. The pH of 7, the incubation temperature of 35°C to 37°C, and the agitation rate of 150 rpm are the optimal conditions for achieving the higher percentage of phenol degradation by Actinobacillus sp. Succinic acid and glycine as carbon and nitrogen source, respectively, were the most efficient of the cosubstrates (out of 10 substrates tested) for removal of phenol on an mg/L basis.