Towards precise reconstruction of gene regulatory networks by data integration

Background: More and more high-throughput datasets are available from multiple levels of measuring gene regulations. The reverse engineering of gene regulatory networks from these data offers a valuable research paradigm to decipher regulatory mechanisms. So far, numerous methods have been developed for reconstructing gene regulatory networks. Results: In this paper, we provide a review of bioinformatics methods for inferring gene regulatory network from omics data. To achieve the precision reconstruction of gene regulatory networks, an intuitive alternative is to integrate these available resources in a rational framework. We also provide computational perspectives in the endeavors of inferring gene regulatory networks from heterogeneous data. We highlight the importance of multi-omics data integration with prior knowledge in gene regulatory network inferences. Conclusions: We provide computational perspectives of inferring gene regulatory networks from multiple omics data and present theoretical analyses of existing challenges and possible solutions. We emphasize on prior knowledge and data integration in network inferences owing to their abilities of identifying regulatory causality.     

希木龙念珠菌研究进展

希木龙念珠菌Candida haemulonii是一种与耳念珠菌亲缘关系十分相近的物种。近年来,由其引发的侵袭性真菌疾病的发病率不断升高。作为一种多重耐药真菌,希木龙念珠菌对常见抗真菌药物的耐药性甚至超过耳念珠菌。体外药敏试验证实大部分希木龙念珠菌菌株对唑类、多烯类以及棘白菌素类等抗真菌药物耐药,尤其是对两性霉素B具有天然抗性。不仅如此,临床传统的生化方法难以对该菌准确鉴定,常用的商品化鉴定产品往往将其错误鉴定为毕赤酵母或者新型隐球菌。为了进一步加深对希木龙念珠菌的认识,本文结合国内外的流行病学数据与研究进展,从感染现状、生物学特征、耐药性进行综述,同时总结该菌目前诊断、治疗和预防措施。     

A survey of web resources and tools for the study of TCM network pharmacology

Background: Traditional Chinese medicine (TCM) treats diseases in a holistic manner, while TCM formulae are multi-component, multi-target agents at the molecular level. Thus there are many parallels between the key ideas of TCM pharmacology and network pharmacology. These years, TCM network pharmacology has developed as an interdisciplinary of TCM science and network pharmacology, which studies the mechanism of TCM at the molecular level and in the context of biological networks. It provides a new research paradigm that can use modern biomedical science to interpret the mechanism of TCM, which is promising to accelerate the modernization and internationalization of TCM. Results: In this paper we introduce state-of-the-art free data sources, web servers and softwares that can be used in the TCM network pharmacology, including databases of TCM, drug targets and diseases, web servers for the prediction of drug targets, and tools for network and functional analysis. Conclusions: This review could help experimental pharmacologists make better use of the existing data and methods in their study of TCM.     

Hidden Information Revealed by Optimal Community Structure from a Protein-Complex Bipartite Network Improves Protein Function Prediction

The task of extracting the maximal amount of information from a biological network has drawn much attention from researchers, for example, predicting the function of a protein from a protein-protein interaction (PPI) network. It is well known that biological networks consist of modules/communities, a set of nodes that are more densely inter-connected among themselves than with the rest of the network. However, practical applications of utilizing the community information have been rather limited. For protein function prediction on a network, it has been shown that none of the existing community-based protein function prediction methods outperform a simple neighbor-based method. Recently, we have shown that proper utilization of a highly optimal modularity community structure for protein function prediction can outperform neighbor-assisted methods. In this study, we propose two function prediction approaches on bipartite networks that consider the community structure information as well as the neighbor information from the network: 1) a simple screening method and 2) a random forest based method. We demonstrate that our community-assisted methods outperform neighbor-assisted methods and the random forest method yields the best performance. In addition, we show that using the optimal community structure information is essential for more accurate function prediction for the protein-complex bipartite network of Saccharomyces cerevisiae. Community detection can be carried out either using a modified modularity for dealing with the original bipartite network or first projecting the network into a single-mode network (i.e., PPI network) and then applying community detection to the reduced network. We find that the projection leads to the loss of information in a significant way. Since our prediction methods rely only on the network topology, they can be applied to various fields where an efficient network-based analysis is required.     

Variation of visual detection over the 24-hour period in humans

A circadian rhythm for visual sensitivity has been intensively assessed in animals. This rhythm may be due to the existence of a circadian clock in the mammalian eye, which could account for fluctuating sensitivity to light over the day in certain species. However, very few studies have been devoted to the human visual system. The present experiment was designed to assess a possible rhythm of visual sensitivity using a psychophysical method over the whole 24h period. Twelve subjects underwent visual detection threshold measures in a protocol that allowed one point every 2h. The results show that the visual detection threshold changes over the 24h period, with high thresholds in the morning, a progressive decrease over the day and the early night, and an increase during the last part of the night. These data suggest that a circadian rhythm influences visual sensitivity to mesopic luminance in humans. (Chronobiology International, 17(6), 795-805, 2000)     

Improving conditional random field model for prediction of protein-RNA residue-base contacts

Background: For understanding biological cellular systems, it is important to analyze interactions between protein residues and RNA bases. A method based on conditional random fields (CRFs) was developed for predicting contacts between residues and bases, which receives multiple sequence alignments for given protein and RNA sequences, respectively, and learns the model with many parameters involved in relationships between neighboring residue-base pairs by maximizing the pseudo likelihood function. Methods: In this paper, we proposed a novel CRF-based model with more complicated dependency relationships between random variables than the previous model, but which takes less parameters for the sake of avoidance of overfitting to training data. Results: We performed cross-validation experiments for evaluating the proposed model, and took the average of AUC (area under receiver operating characteristic curve) scores. The result suggests that the proposed CRF-based model without using L₁-norm regularization (lasso) outperforms the existing model with and without the lasso under several input observations to CRFs. Conclusions: We proposed a novel stochastic model for predicting protein-RNA residue-base contacts, and improved the prediction accuracy in terms of the AUC score. It implies that more dependency relationships in a CRF could be controlled by less parameters.     

Developing a low-cost milliliter-scale chemostat array for precise control of cellular growth

Background: Multiplexed milliliter-scale chemostats are useful for measuring cell physiology under various degrees of nutrient limitation and for carrying out evolution experiments. In each chemostat, fresh medium containing a growth rate-limiting metabolite is pumped into the culturing chamber at a constant rate, while culture effluent exits at an equal rate. Although such devices have been developed by various labs, key parameters — the accuracy, precision, and operational range of flow rate — are not explicitly characterized. Methods: Here we re-purpose a published multiplexed culturing device to develop a multiplexed milliliter-scale chemostat. Flow rates for eight chambers can be independently controlled to a wide range, corresponding to population doubling times of 3~13 h, without the use of expensive feedback systems. Results: Flow rates are precise, with the maximal coefficient of variation among eight chambers being less than 3%. Flow rates are accurate, with average flow rates being only slightly below targets, i.e., 3%–6% for 13-h and 0.6%–1.0% for 3-h doubling times. This deficit is largely due to evaporation and should be correctable. We experimentally demonstrate that our device allows accurate and precise quantification of population phenotypes. Conclusions: We achieve precise control of cellular growth in a low-cost milliliter-scale chemostat array, and show that the achieved precision reduces the error when measuring biological processes.     

深海白色侧齿霉遗传转化体系建立及渗透压调控相关的EaSHO1基因功能

海洋中具有丰富的动植物及微生物资源,海洋真菌是其重要组成之一。我们前期的研究发现一株深海真菌白色侧齿霉Engyodontium album能产生具有抑菌活性的次级代谢产物engyodontiumin A,该化合物能抑制黑曲霉、金黄色葡萄球菌及创伤弧菌等病原菌的生长,是一种潜在的海洋源抗菌药物。目前,该菌遗传转化体系尚未建立,不利于开展次级代谢产物合成调控机制及其他功能基因研究。本研究成功制备了深海白色侧齿霉菌的原生质体,建立了借助聚乙二醇3350介导的原生质体转化体系,并将pCT74-sGFP载体成功导入白色侧齿霉的原生质体中,结果显示外源GFP能稳定表达。此外,为了明确白色侧齿霉菌是否能够开展基因敲除研究,通过氨基酸序列同源比对,我们选取酵母高渗甘油信号途径中的同源基因EaSHO1进行初步探究。利用同源重组的方法成功将目的基因EaSHO1的开放阅读框(ORF)替换成潮霉素磷酸转移酶基因(HPH),由此获得EaSHO1基因敲除突变体,并对突变体进行Southern杂交验证及初步的表型分析。结果表明,EaSHO1缺失不影响白色侧齿霉菌的营养生长及对高盐胁迫的响应,亚细胞定位结果显示EaS...     

Measuring seasonal dynamics of leaf area index in a mixed conifer-broadleaved forest with direct and indirect methods

利用光学仪器法能够快速、高效地测定森林生态系统的叶面积指数(leaf area index, LAI)。然而, 评估该方法测定针阔混交林LAI季节动态准确性的研究较少。该研究基于凋落物法测定了小兴安岭地区阔叶红松(Pinus koraiensis)林LAI的季节动态, 其结果可代表真实的LAI。参考真实的LAI, 对半球摄影法(digital hemispherical photography, DHP)和LAI-2000植物冠层分析仪测定的有效叶面积指数(effective LAI, L_e)进行了评估。首先对DHP测定LAI过程中采用的不合理曝光模式(自动曝光)进行了系统校正。同时, 测定了光学仪器法估测LAI的主要影响因素(包括木质比例(woody-to-total area ratio, α)、集聚指数(clumping index, Ω_E)和针簇比(needle-to-shoot area ratio, γ_E))的季节变化。结果表明: 3种不同方法测定的LAI均表现为单峰型的季节变化, 8月初达到峰值。从5月至11月, DHP测定的L_e比真实的LAI低估50%-59%, 平均低估55%; 而LAI-2000植物冠层分析仪测定的L_e比真实的LAI低估19%-35%, 平均低估27%。DHP测定的L_e 经过自动曝光, α、Ω_E和γ_E校正后, 精度明显提高, 但仍比真实的LAI低估6%-15%, 平均低估9%; 相对而言, LAI-2000植物冠层分析仪测定的L_e经过α、Ω_E和γ_E校正后, 精度明显提高, 各时期与真实的LAI的差异均小于9%。研究结果表明, 考虑木质部和集聚效应对光学仪器法的影响后, DHP和LAI-2000植物冠层分析仪均能相对准确地测定针阔混交林LAI的季节动态, 其中, DHP的测定精度高于85%, 而LAI-2000植物冠层分析仪的测定精度高于91%。     

motifeR: An Integrated Web Software for Identification and Visualization of Protein Posttranslational Modification Motifs

With an exponential growth in applications identifying protein post‐translational modifications via mass spectrometry, discovery and presentation of motifs surrounding those modification sites have become increasingly desirable. Despite a few tools being designed, there is still a scarcity of effective and polyfunctional software for such analysis and illustrations. In this study, a versatile and user‐friendly web tool is developed, motifeR, for extracting and visualizing statistically significant motifs from large datasets. Particularly, several functions are also integrated for processing multi‐modification sites enrichment. Public datasets are applied to test their usability, indicating that some concurrent modification sites may form motifs and that peptides with low location probability may be not identified randomly and can be included to support motif discovery. In addition, for human phosphoproteomics datasets, the characterization of differential kinase signaling networks can be estimated and modeled by combining kinase‐substrate relations based on the NetworKIN database as an optional feature for users. The motifeR toolkit can be conveniently operated by any scientific community or individuals, even those without any bioinformatics background and is freely available at https://www.omicsolution.org/wukong/motifeR .     

In vitro biological properties of flavonoid conjugates found in vivo

For some flavonoids such as quercetin, isoflavones and catechins, the pathways of absorption and metabolism are now reasonably well characterised and understood. By definition, for biological activity of flavonoids to be manifest, the target tissue, which includes the blood and vascular system, must respond to the form(s) of flavonoid that it encounters. Bioavailability studies have shown that the circulating form of most flavonoids is as conjugates, with a few notable exceptions. There have been several recent papers on the in vitro biological properties of conjugates that have been found in vivo. This paper reviews the properties of these conjugates. Most of the information currently available is on quercetin glucuronides, but also on isoflavone and catechin conjugates. In addition to the biological properties of the conjugates, the partition coefficients and methods of synthesis are also presented.     

PANADA: Protein Association Network Annotation,Determination and Analysis

Increasingly large numbers of proteins require methods for functional annotation. This is typically based on pairwise inference from the homology of either protein sequence or structure. Recently, similarity networks have been presented to leverage both the ability to visualize relationships between proteins and assess the transferability of functional inference. Here we present PANADA, a novel toolkit for the visualization and analysis of protein similarity networks in Cytoscape. Networks can be constructed based on pairwise sequence or structural alignments either on a set of proteins or, alternatively, by database search from a single sequence. The Panada web server, executable for download and examples and extensive help files are available at URL: http://protein.bio.unipd.it/panada/.     

利用直接法和间接法测定针阔混交林叶面积指数的季节动态

利用光学仪器法能够快速、高效地测定森林生态系统的叶面积指数(leaf area index, LAI)。然而, 评估该方法测定针阔混交林LAI季节动态准确性的研究较少。该研究基于凋落物法测定了小兴安岭地区阔叶红松(Pinus koraiensis)林LAI的季节动态, 其结果可代表真实的LAI。参考真实的LAI, 对半球摄影法(digital hemispherical photography, DHP)和LAI-2000植物冠层分析仪测定的有效叶面积指数(effective LAI, L_e)进行了评估。首先对DHP测定LAI过程中采用的不合理曝光模式(自动曝光)进行了系统校正。同时, 测定了光学仪器法估测LAI的主要影响因素(包括木质比例(woody-to-total area ratio, α)、集聚指数(clumping index, Ω_E)和针簇比(needle-to-shoot area ratio, γ_E))的季节变化。结果表明: 3种不同方法测定的LAI均表现为单峰型的季节变化, 8月初达到峰值。从5月至11月, DHP测定的L_e比真实的LAI低估50%-59%, 平均低估55%; 而LAI-2000植物冠层分析仪测定的L_e比真实的LAI低估19%-35%, 平均低估27%。DHP测定的L_e 经过自动曝光, α、Ω_E和γ_E校正后, 精度明显提高, 但仍比真实的LAI低估6%-15%, 平均低估9%; 相对而言, LAI-2000植物冠层分析仪测定的L_e经过α、Ω_E和γ_E校正后, 精度明显提高, 各时期与真实的LAI的差异均小于9%。研究结果表明, 考虑木质部和集聚效应对光学仪器法的影响后, DHP和LAI-2000植物冠层分析仪均能相对准确地测定针阔混交林LAI的季节动态, 其中, DHP的测定精度高于85%, 而LAI-2000植物冠层分析仪的测定精度高于91%。     

虎杖象甲培植真菌营养特性及对菌丝附属物形成的影响

虎杖象甲培植共生真菌形成的共生体系是植菌昆虫菌业中的典型代表。共生真菌Penicillium herquei如何向虎杖象甲Euops chinensis提供营养尚未明确。本研究发现共生真菌P. herquei的菌丝表面存在大量瘤状凸起物及由凸起物衍生的附属丝等特化结构,该结构可能为虎杖象甲提供营养;对共生真菌的营养研究表明,共生真菌能高效利用山梨醇、蔗糖、海藻糖、葡萄糖等单糖或双糖,以及酪氨酸、甘氨酸、谷氨酰胺等昆虫非必须氨基酸,同时在高碳和最适碳源条件下有利于菌丝特化附属物的产生。研究结果不仅提供了植菌卷叶象甲菌业中共生真菌在营养方面的适应性进化证据,而且为进一步揭示共生真菌适应卷叶象甲的营养机制奠定了基础。     

中国东北地区三种蜜环菌的生物学特性及奥氏蜜环菌人工培养

蜜环菌属Armillaria真菌具有较高的食药用价值。由于蜜环菌的生长发育过程较复杂,还未完全实现商业化栽培,野生资源的供应受到季节性和地域性的影响。本研究以采自东北地区蜜环菌属的3个菌株为研究对象,通过培养物的形态特征及分子标记确定菌株JG19016为奥氏蜜环菌A. ostoyae,菌株JG19017为高卢蜜环菌A. gallica,菌株JG19018为中国蜜环菌生物种C。奥氏蜜环菌JG19016最适生长温度为25 ℃,高卢蜜环菌JG19017的最适生长温度为22 ℃,中国蜜环菌生物种C JG19018则在22-25 ℃时菌丝生长速度最快;3个菌株最适pH为5-6。奥氏蜜环菌JG19016对葡萄糖和蔗糖利用率较好,高卢蜜环菌JG19017对葡萄糖利用率较好,中国蜜环菌生物种C JG19018对葡萄糖和淀粉利用率较好;蛋白胨对3个菌株促进作用最强,为最适氮源。培养基中加入VB₁,对3个菌株的菌丝生长均有明显的促进作用。奥氏蜜环菌JG19016菌丝生长的最优培养基配方为：葡萄糖20 g,蛋白胨3 g,磷酸二氢钾2 g,硫酸镁1.5 g,VB₁ 10 mg,琼脂20 g,水1 L。在木屑基质中培养,其配方的最优碳氮比为38:1,最佳木屑粗细比为3:1以上。出菇条件探索结果显示,菌丝及菌索长满菌袋(17 mm×33 mm×5 mm丝聚乙烯袋)需要50-60 d,之后在18 ℃、60%湿度和12 h散射光的环境中,10 d左右可观察到原基产生。增加菇房湿度到90%-95%,2-3 d可观察到1-3 cm的幼子实体,7 d左右菌柄和菌盖完全分化,10 d左右观察到菌盖展开。     

金针菇分子生物学和功能基因研究进展

金针菇是重要的食药用菌,具有很高的经济价值。随着金针菇全基因组序列的公布、多组学分析、转基因技术、基因编辑技术的发展,越来越多的研究者开始关注金针菇重要性状(如生长速度、菌柄长度、生物活性物质含量等)相关的分子调控机制以及关键基因的发掘。本文综述了分子生物学技术在金针菇研究中的应用并分析了不同技术的利弊;同时,系统介绍了金针菇菌丝和子实体生长发育、温度应答、生物活性物质代谢、蓝光响应等重要生物学过程中调控基因的最新研究进展,并对未来金针菇分子生物学研究的方向进行了展望,旨在为我国金针菇产业的发展提供有价值的参考。     

新生隐球菌感染流行病学现状及耐药机制相关研究进展

新生隐球菌是一种广泛存在于环境中的酵母类真菌,主要侵犯中枢神经系统引起隐球菌性脑膜炎。HIV感染是导致隐球菌感染的主要危险因素之一,但近年来关于非HIV患者隐球菌感染的报道不断增加。体外药敏试验证实大部分新生隐球菌对棘白菌素类药物具有内在抗性。两性霉素B和氟康唑是用于隐球菌感染治疗的一线药物,而长期广泛用药引起新生隐球菌对氟康唑的耐药率逐年升高,患者临床治疗失败率居高不下。为进一步加深对新生隐球菌的认识,本文结合国内外流行病学报道及相关研究,从感染现状、生物学特征、诊治方法和耐药性等方面进行综述,以期为新生隐球菌性脑膜炎的临床诊治提供参考。