数字细胞模型的研究及应用

组学分析技术的发展推动生物学逐渐成为一门以数据分析为中心的科学。依托生物数据在细胞整体系统水平建立数字细胞模型,对于理解细胞系统组织原理和生命产生进化规律,预测各种环境和基因扰动对细胞功能的影响并指导设计人工生命具有重要意义,因此数字细胞的构建模拟设计已成为合成生物学的核心研究内容与底层支撑技术。本文重点对天津工业生物技术研究所创立十年来在数字细胞研究方面的进展进行回顾介绍,重点包括基因组尺度代谢网络模型的构建、质控以及其在途径设计和指导菌种代谢工程改造方面的应用,进一步结合近年来细胞模型研究的前沿趋势,对整合多种约束的模型的构建和分析研究方面的最新成果进行了介绍,最后对数字细胞研究的未来发展方向进行展望。数字细胞技术将与基因组测序、合成和编辑等合成生物学前沿技术一起提升人们对生命进行读写改创的能力。     

Lower Statistical Support with Larger Data Sets: Insights from the Ochrophyta Radiation

It is commonly assumed that increasing the number of characters has the potential to resolve evolutionary radiations. Here, we studied photosynthetic stramenopiles (Ochrophyta) using alignments of heterogeneous origin mitochondrion, plastid, and nucleus. Surprisingly while statistical support for the relationships between the six major Ochrophyta lineages increases when comparing the mitochondrion (6,762 sites) and plastid (21,692 sites) trees, it decreases in the nuclear (209,105 sites) tree. Statistical support is not simply related to the data set size but also to the quantity of phylogenetic signal available at each position and our ability to extract it. Here, we show that this ability for current phylogenetic methods is limited, because conflicting results were obtained when varying taxon sampling. Even though the use of a better fitting model improved signal extraction and reduced the observed conflicts, the plastid data set provided higher statistical support for the ochrophyte radiation than the larger nucleus data set. We propose that the higher support observed in the plastid tree is due to an acceleration of the evolutionary rate in one short deep internal branch, implying that more phylogenetic signal per position is available to resolve the Ochrophyta radiation in the plastid than in the nuclear data set. Our work therefore suggests that, in order to resolve radiations, beyond the obvious use of data sets with more positions, we need to continue developing models of sequence evolution that better extract the phylogenetic signal and design methods to search for genes/characters that contain more signal specifically for short internal branches.     

SPA: A Quantitation Strategy for MS Data in Patient-derived Xenograft Models

With the development of mass spectrometry (MS)-based proteomics technologies, patient-derived xenograft (PDX), which is generated from the primary tumor of a patient, is widely used for the proteome-wide analysis of cancer mechanism and biomarker identification of a drug. However, the proteomics data interpretation is still challenging due to complex data deconvolution from the PDX sample that is a cross-species mixture of human cancerous tissues and immunodeficient mouse tissues. In this study, by using the lab-assembled mixture of human and mouse cells with different mixing ratios as a benchmark, we developed and evaluated a new method, SPA (shared peptide allocation), for protein quantitation by considering the unique and shared peptides of both species. The results showed that SPA could provide more convenient and accurate protein quantitation in human–mouse mixed samples. Further validation on a pair of gastric PDX samples (one bearing FGFR2 amplification while the other one not) showed that our new method not only significantly improved the overall protein identification, but also detected the differential phosphorylation of FGFR2 and its downstream mediators (such as RAS and ERK) exclusively. The tool pdxSPA is freely available at https://github.com/Li-Lab-Proteomics/pdxSPA.     

基于过程模型CROBAS的全局灵敏度分析方法比较

过程机理模型在开发过程中常受限于生理学参数无法直接或准确测量.全局灵敏度分析可以评估模型预测结果对于生理学参数变化的响应,为模型结构改进、数据收集和参数校准提供参考.本研究基于过程模型CROBAS,以华山松为例,选取模型中描述树木结构关系的10个参数,以树高和各器官生物量的Nash-Sutcliffe效率(NSE)为目...     

Comments on the manna model

WANGERSKY and WANGERSKY'S (1980, 1981, 1983) Manna models on algal patchiness and competition are essentially stochastic models. Analysis of their phase-spatial properties, however, reveals complementary, deterministic features: interspecific competition is relatively ineffective because of the high degree of compartmentalization of resource supply and consumption; the probability of consumption in a given place at a given time is largely independent of the rate of consumption in other places.     

皮质酮诱导的PC12细胞梯度应激损伤模型的构建及评价

目的:建立皮质酮诱导的PC12细胞梯度应激损伤模型,为细胞应激水平的评估和细胞应激损伤调控研究提供实验基础和对象。方法:通过检测不同浓度皮质酮(0～1 000μmol/L)在经过不同干预时间(8～48 h)后PC12细胞活力,观察皮质酮对细胞活力的影响,筛选最佳干预条件的细胞模型。分光光度法和微量法检测细胞模型的关键应激指标(MDA、SOD、NADH、LDH),对模型进行评价。结果:当皮质酮浓度在200μmol/L以下且干预时间为12 h时,细胞活力在半数失活率以下,可减少各组由于细胞活力下降而产生的混杂因素。与空白对照组比较,皮质酮浓度依赖性地升高模型组的MDA、NADH和LDH水平,降低SOD水平(P<0.01),符合梯度应激模型的构建要求。结论:成功建立了PC12细胞梯度应激损伤模型,在干预时间为12 h的情况下,干预浓度为0μmol/L、25μmol/L、50μmol/L、100μmol/L、150μmol/L、200μmol/L,使得细胞模型应激损伤程度梯度增加,可作为开展细胞应激损伤评估及调控实验的基础和对象。     

The modulation of neuroinflammation by inducible nitric oxide synthase

The accumulation and propagation of misfolded proteins in the brain is a pathological hallmark shared by many neurodegenerative diseases, such as the depositions of β-amyloid and hyperphosphorylated tau proteins in Alzheimer''s disease. Initial evidence shows the role of nitric oxide synthases in the development of neurodegenerative diseases. A recent, in an exciting paper (Bourgognon et al. in Proc Natl Acad Sci USA 118, 1–11, 2021. 10.1073/pnas.2009579118) it was shown that the inducible nitric oxide synthase plays an important role in promoting oxidative and nitrergic stress leading to neuroinflammation and consequently neuronal function impairments and decline in synaptic strength in mouse prion disease. In this context, we reviewed the possible mechanisms of nitric oxide synthase in the generation of neurodegenerative diseases.     

2000年以来中国潜在植被净初级生产力的时空分布模拟

潜在植被的净初级生产力(PNPP)是在无人类干扰情况下,立地所能发育形成最稳定成熟植被的净初级生产力,PNPP能够直接反映自然生态系统的质量状况,是分离人类活动对生态环境影响的重要指标。研究改进了CASA(Carnegie-Ames-Stanford Approach)模型,引入潜在光合有效辐射吸收比例(PFPAR)模拟了2000—2020年中国植被PNPP的时空分布格局。结果表明：中国PNPP空间分布差异较大,东南沿海和东北大、小兴安岭地区PNPP较高,新疆、西藏等西部干旱、高寒地区PNPP较低,呈现以400 mm等降水量线为界的空间分异格局。2000—2020年,中国PNPP总体上呈现递增趋势,年际波动小,PNPP减少的区域与增加的区域面积基本相等。PNPP波动较大的地区主要位于青藏高原、四川盆地和贵州高原。研究结果量化了气候变化背景下真实的生态状况和潜在生态状况的差异,可分离出人类活动对自然生态系统的直接影响,为制定针对性的生态修复对策提供了科学依据。